Thome J, Duman RS, Henn FA.
[Molecular aspects of antidepressive therapy. Transsynaptic effects on signal transduction, gene expression and neuronal plasticity]
Nervenarzt. 2002 Jul;73(7):595-9.
"Simple neurotransmitter theories cannot sufficiently explain the mode of action of antidepressant drugs. Molecular pharmacological studies demonstrate that antidepressive treatment initially modulates the neurotransmitter-receptor interaction, subsequently influences signal transduction cascades beyond the synapse and gene transcription mechanisms, and ultimately triggers the expression of specific target genes. Such genes often code for molecules which play an important role in the maintenance of neural and synaptic plasticity. Chronic (but not acute) treatment with antidepressants modulates, for example, the cAMP-second-messenger system and increases the expression of neurotrophic factors. Furthermore, antidepressants promote hippocampal neurogenesis. Stress, an important risk factor for psychiatric disorders, often induces opposite effects. A better understanding of the molecular and cellular effects of stress and therapy with psychotropic drugs will stimulate the development of innovative treatment strategies for which an optimised antidepressant efficacy with a simultaneously improved tolerance is expected." [Abstract]

Hashimoto K, Shimizu E, Iyo M.
Critical role of brain-derived neurotrophic factor in mood disorders.
Brain Res Brain Res Rev. 2004 May;45(2):104-14.
"The purpose of this review is to integrate what is currently known about the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of mood disorders including major depressive disorder (MDD) and bipolar disorder (BD). We reviewed the pre-clinical and clinical papers demonstrating that BDNF plays a role in the pathophysiology of mood disorders and in the mechanism of action of therapeutic agents. Pre-clinical studies suggest that the expression of BDNF might be a downstream target of antidepressant treatments and mood stabilizers such as lithium and valproate, and that BDNF exerts antidepressant activity in animal models of depression. Furthermore, BDNF protects against stress-induced neuronal damage, and it might affect neurogenesis in the hippocampus, which is thought to be involved in the pathogenesis of mood disorders. Clinical studies have demonstrated that serum levels of BDNF in drug-naive patients with MDD are significantly decreased as compared with normal controls, and that BDNF might be an important agent for therapeutic recovery from MDD. Moreover, recent findings from family-based association studies have suggested that the BDNF gene is a potential risk locus for the development of BD. These findings suggest that BDNF plays a critical role in the pathophysiology of mood disorders and in the activity of therapeutic agents in patients with mood disorders. New agents capable of enhancing BDNF levels may lead aid the development of novel therapeutic drugs for patients with mood disorders." [Abstract]

Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM.
Decreased serum brain-derived neurotrophic factor levels in major depressed patients.
Psychiatry Res. 2002 Mar 15;109(2):143-8.
"Recent findings with animal models have suggested a possible role for brain-derived neurotrophic factor (BDNF) in depression. We have therefore hypothesized that depression could be characterized by low levels of serum BDNF. Major depressed patients (15F + 15M) diagnosed according to DSM-IV criteria and healthy controls (15F + 15M) participated in the study. Serum BDNF was assayed with the ELISA method and the severity of depression was evaluated with Montgomery-Asberg-Depression Rating Scale (MADRS). BDNF levels were significantly lower in patients than in controls: 22.6 +/- 3 and 26.5 +/- 7 ng/ml (t-test = 2.7; d.f. = 58; P < 0.01). They were negatively correlated to the MADRS scores (r = -0.55; P < 0.02). Female patients were more depressed and released less BDNF than men. Analysis of covariance (MADRS and gender as independent variable vs. BDNF as dependent variable) indicated that depression severity mainly accounted for the negative correlation. These results suggest that major depression is characterized by low serum BDNF levels and support the hypothesis of neurotrophic factor involvement in affective disorders." [Abstract]

Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT.
Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication.
Biol Psychiatry. 2001 Aug 15;50(4):260-5.
"BACKGROUND: The cAMP signaling pathway, and its downstream neurotrophic factor BDNF, are major targets of antidepressant medications. Abnormalities in this pathway have previously been reported in postmortem brain of subjects with mood disorders. This study was designed to test whether the diagnosis of a mood disorder, or treatment with an antidepressant or mood stabilizer was associated with changes in hippocampal BDNF in postmortem brain. METHODS: Frozen postmortem anterior hippocampus sections were obtained from the Stanley Foundation Neuropathology Consortium. Tissue from subjects with major depression, bipolar disorder, schizophrenia and nonpsychiatric control subjects were stained for BDNF using immunohistochemistry. RESULTS: Increased BDNF expression was found in dentate gyrus, hilus and supragranular regions in subjects treated with antidepressant medications at the time of death, compared with antidepressant-untreated subjects. Furthermore, there was a trend toward increased BDNF expression in hilar and supragranular regions in depressed subjects treated with antidepressants, compared with the subjects not on these medications at the time of death. CONCLUSIONS: These findings are consistent with recent studies measuring CREB levels in this same subject sample, and support current animal and cellular models of antidepressant function." [Abstract]

Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H, Shinoda N, Okada S, Iyo M.
Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants.
Biol Psychiatry. 2003 Jul 1;54(1):70-5.
"BACKGROUND: Because researchers have reported that antidepressants increase the expression of brain-derived neurotrophic factor (BDNF) in the rat hippocampus, we investigated whether serum BDNF levels may be used as a putative biological marker for major depressive disorders (MDD). METHODS: We measured serum BDNF in the following three groups: antidepressant-naive patients with MDD (n = 16), antidepressant-treated patients with MDD (n = 17), and normal control subjects (n = 50). Patients were evaluated using the Hamilton Rating Scale for Depression (HAM-D). Serum BDNF was assayed with the sandwich ELISA method. RESULTS: We found that serum BDNF was significantly lower in the antidepressant-naive group (mean, 17.6 ng/mL; SD, 9.6) than in the treated (mean, 30.6 ng/mL; SD, 12.3; p =.001) or in the control group (mean, 27.7 ng/mL; SD, 11.4; p =.002). There was a significant negative correlation (r = -.350, z = -2.003, p =.045) between serum BDNF and HAM-D scores in all patients. In a preliminary examination, reduced BDNF values of three drug-naive patients recovered to basal levels after antidepressant treatment. CONCLUSIONS: Our study suggests that low BDNF levels may play a pivotal role in the pathophysiology of MDD and that antidepressants may increase BDNF in depressed patients." [Abstract]

Molnar M, Potkin SG, Bunney WE, Jones EG.
MRNA expression patterns and distribution of white matter neurons in dorsolateral prefrontal cortex of depressed patients differ from those in schizophrenia patients.
Biol Psychiatry. 2003 Jan 1;53(1):39-47.
"Expression of CAMKII-alpha and TBR1 mRNAs was significantly increased in bipolar patients but not in major depressed patients, and there was a trend toward reduced BDNF expression in both groups." [Abstract]

Schaaf MJ, De Kloet ER, Vreugdenhil E.
Corticosterone effects on BDNF expression in the hippocampus. Implications for memory formation.
Stress. 2000 May;3(3):201-8.
"The adrenal steroid corticosterone has profound effect on the structure and function of the hippocampus. Probably as a result of that, it modulates memory formation. In this review, the question is addressed if the corticosterone effects on memory processes are mediated by alterations in the expression of the neurotrophin Brain-Derived Neurotrophic Factor (BDNF) in the hippocampus. First, studies are described investigating the effect of corticosterone on BDNF expression in the rat hippocampus. It appears that corticosterone suppresses the BDNF expression at the mRNA and protein level in a subfield-specific way. Second, a model for the mechanism of action is proposed. In this model, activated mineralocorticoid and glucocorticoid receptors repress transcriptional activity of the BDNF promoter site-specifically via interaction with other transcription factors. Third, the implications for learning and memory are discussed. Studies show that during water maze training, corticosterone levels rise significantly, but the BDNF expression is not suppressed in any hippocampal subfield. Furthermore, high BDNF expression levels in specific subfields correlate with a good memory performance. Therefore, we suggest that the resistance of the hippocampal BDNF expression to suppression by corticosterone, as seen after water maze training, may contribute to an optimal memory performance." [Abstract]

Zhou J, Zhang F, Zhang Y.
Corticosterone inhibits generation of long-term potentiation in rat hippocampal slice: involvement of brain-derived neurotrophic factor.
Brain Res. 2000 Dec 8;885(2):182-91.
"In the present study, the effect of corticosterone (CORT) on the generation of long-term potentiation (LTP) and its underlying mechanism involving neurotrophin gene expression in CA1 synapses of rat hippocampal slice were examined. Our experimental results showed incubation of hippocampal slice with CORT for 3 h had no effect on either the slope or amplitude of excitatory postsynaptic potentials (EPSP) evoked in hippocampal CA1 pyramidal dentrites, indicating no marked change in basal synaptic transmission. However, when tetanic stimulation (100 pulses, 100 Hz) was delivered to the Schaffer collateral pathway, CORT application significantly attenuated the tetanus-induced increases of both EPSP slope and amplitude, demonstrating an inhibitory effect of CORT on LTP generation. In addition, CORT treatment significantly reduced both slope and amplitude ratios of the second evoked EPSP to the first one when paired-pulse facilitation (PPF) was established at different interpulse intervals from 20 to 40 ms, suggesting that a presynaptic mechanism may be involved in CORT-induced hippocampal synaptic plasticity. Reverse-transcription polymerase chain reaction (RT-PCR) analysis showed that CORT-treated hippocampal CA1 cells underwent a significant decrease in the expression of mRNA for nerve growth factor-beta (NGF-beta) and brain-derived neurotrophic factor (BDNF), but not for neurotrophin-3 (NT-3) compared with those in control. Moreover, BDNF co-applied with CORT significantly antagonized CORT-induced deficit in PPF. Taken together, the present results suggest that CORT-induced inhibition of LTP may be, at least to some extent, mediated by a presynaptic mechanism and decrease in the BDNF expression in rat hippocampal CA1 cells induced by CORT may partially account for this presynaptic mechanism." [Abstract]

Blom JM, Tascedda F, Carra S, Ferraguti C, Barden N, Brunello N.
Altered regulation of CREB by chronic antidepressant administration in the brain of transgenic mice with impaired glucocorticoid receptor function.
Neuropsychopharmacology. 2002 May;26(5):605-14.
"Various effects of antidepressant drugs on gene transcription have been described and altered gene expression has been proposed as being a common biological basis underlying depressive illness. One target for the common action of antidepressants is a modifying effect on the regulation of postreceptor pathways and genes related to the cAMP cascade. Recent studies have demonstrated that long-term antidepressant treatment resulted in sustained activation of the cyclic adenosine 3',5'-monophosphate system and in increased expression of the transcription factor cAMP response element binding protein (CREB). A transgenic animal model of depression with impaired glucocorticoid receptor function was used to investigate the effect of chronic antidepressant treatments on CREB expression in different brain areas. Wild-type and transgenic mice received one administration of saline, desipramine, or fluoxetine, daily for 21 days. The effects of antidepressants on CREB mRNA were analyzed using a sensitive RNase protection assay. Antidepressant treatment resulted in a neuroanatomically and animal specific expression pattern of CREB. Our findings suggest that life-long central glucocorticoid receptor dysfunction results in an altered sensitivity with respect to the effects of antidepressants on the expression of CREB." [Abstract]

Dwivedi Y, Rao JS, Rizavi HS, Kotowski J, Conley RR, Roberts RC, Tamminga CA, Pandey GN.
Abnormal expression and functional characteristics of cyclic adenosine monophosphate response element binding protein in postmortem brain of suicide subjects.
Arch Gen Psychiatry. 2003 Mar;60(3):273-82.
"BACKGROUND: Cyclic adenosine monophosphate response element binding protein (CREB) is a transcription factor that, on phosphorylation by protein kinases, is activated, and in response, regulates the transcription of many neuronally expressed genes. In view of the recent observations that catalytic properties and/or expression of many kinases that mediate their physiological responses through the activation of CREB are altered in the postmortem brain of subjects who commit suicide (hereafter referred to as suicide subjects), we examined the status of CREB in suicidal behavior. METHODS: These studies were performed in Brodmann area (BA) 9 and hippocampus obtained from 26 suicide subjects and 20 nonpsychiatric healthy control subjects. Messenger RNA levels of CREB and neuron-specific enolase were determined in total RNA by means of quantitative reverse transcriptase-polymerase chain reaction. Protein levels and the functional characteristics of CREB were determined in nuclear fractions by means of Western blot and cyclic adenosine monophosphate response element (CRE)-DNA binding activity, respectively. In the same nuclear fraction, we determined the catalytic activity of cyclic adenosine monophosphate-stimulated protein kinase A by means of enzymatic assay. RESULTS: We observed a significant reduction in messenger RNA and protein levels of CREB, CRE-DNA binding activity, and basal and cyclic adenosine monophosphate-stimulated protein kinase A activity in BA 9 and hippocampus of suicide subjects, without any change in messenger RNA levels of neuron-specific enolase in BA 9. Except for protein kinase A activity, changes in CREB expression and CRE-DNA binding activity were present in all suicide subjects, irrespective of diagnosis. These changes were unrelated to postmortem intervals, age, sex, or antidepressant treatment. CONCLUSIONS: Given the significance of CREB in mediating various physiological functions through gene transcription, our results of decreased expression and functional characteristics of CREB in postmortem brain of suicide subjects suggest that CREB may play an important role in suicidal behavior." [Abstract]

Young LT, Bezchlibnyk YB, Chen B, Wang JF, MacQueen GM.
Amygdala cyclic adenosine monophosphate response element binding protein phosphorylation in patients with mood disorders: effects of diagnosis, suicide, and drug treatment.
Biol Psychiatry. 2004 Mar 15;55(6):570-7.
"BACKGROUND: Signal transduction abnormalities have been identified in patients with bipolar (BD) and major depressive (MDD) disorders and are targets for lithium and antidepressant drugs. A key downstream target for signal transduction pathways is the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). Therefore, we measured the levels of phosphorylated CREB (pCREB) in the amygdala, a region critical to emotional processing and important in the pathophysiology of both BD and MDD. METHODS: Human postmortem amygdala sections were generously provided by the Stanley Foundation Neuropathology Consortium. Samples consisted of subjects with MDD, BD, schizophrenia (SCZ), and nonpsychiatric-nonneurologic comparison subjects (n = 15 per group). Levels of pCREB were measured by immunohistochemistry, relative to total cell number. RESULTS: There were no differences between diagnostic groups--control subjects and subjects with BD, MDD, or SCZ--but increased numbers of pCREB stained cells were found in several amygdalar nuclei in subjects who had died by suicide. In contrast, patients treated with lithium at the time of death had significantly lower pCREB levels in the same region. CONCLUSIONS: These results suggest that CREB activity may be an important factor in the neurobiology of suicide and the well-documented antisuicidal effect of lithium." [Abstract]

Koch JM, Kell S, Hinze-Selch D, Aldenhoff JB.
Changes in CREB-phosphorylation during recovery from major depression.
J Psychiatr Res. 2002 Nov-Dec;36(6):369-75.
"For decades psychiatrists have been looking for biological state markers measurable by easy blood test in order to follow up and predict early on treatment response in patients with major depression. In the present study we investigated whether or not measuring CREB (cAMP-response-element-binding-protein) phosphorylation in peripheral blood T lymphocytes is a state marker of treatment response. CREB is an ubiquitous key-element of intracellular signal transduction cascades and its transcriptional activity depends on phosphorylation at Ser-133. Several studies in animals demonstrated that the transcriptional activity of CREB is up-regulated by antidepressant treatment. Therefore, it has been hypothesized that antidepressant treatment exerts its therapeutic effect by this mechanism. In the present study, we investigated CREB-phosphorylation in T-lymphocytes of 20 patients before and in the end of week one and two of either psychopharmacological or psychotherapeutic treatment. After two weeks, 15 patients fulfilled the criteria of treatment response (i.e. 30% reduction in HAMD score compared to baseline), whereas five patients did not. In the end of week two, the responders showed a significant increase in CREB-phosphorylation (P = 0.018) compared to the non-responders. This was true for all patients with either treatment regimen. In conclusion, these results indicate for the first time that the increase in CREB-phosphorylation might be a molecular state marker for the response to antidepressant treatment." [Abstract]

Lai IC, Hong CJ, Tsai SJ.
Expression of cAMP response element-binding protein in major depression before and after antidepressant treatment.
Neuropsychobiology. 2003;48(4):182-5
"Antidepressants usually take weeks to exert significant therapeutic effects. This lag phase is suggested to be due to neural plasticity, which may be mediated by the coupling of receptors to their respective intracellular signal transduction pathways. Phosphorylated cAMP response element-binding protein (CREB), a downstream target of the cAMP signaling pathway, has been reported to be a molecular state marker for the response to antidepressant treatment in patients with major depressive disorder (MDD). In order to explore the role of CREB expression in MDD, we used quantitative reverse transcriptase-polymerase chain reaction to quantify CREB messenger RNA of the peripheral lymphocytes obtained from 21 MDD patients, before and after antidepressant treatment, and 21 normal controls. The results revealed no significant difference of CREB expression between untreated MDD patients and normal controls. However, after 8 weeks of antidepressant treatment, CREB expression was significantly decreased in MDD patients (p = 0.025). The CREB change is not associated with the types of antidepressants and therapeutic response." [Abstract]

Dowlatshahi D, MacQueen GM, Wang JF, Reiach JS, Young LT.
G Protein-coupled cyclic AMP signaling in postmortem brain of subjects with mood disorders: effects of diagnosis, suicide, and treatment at the time of death.
J Neurochem. 1999 Sep;73(3):1121-6.
"Components of cyclic AMP (cAMP) signaling were examined in postmortem cerebral cortex of a well characterized group of patients with mood disorders and nonpsychiatric control subjects. We measured G protein levels, adenylyl cyclase (AC) activity, and CREB levels in cerebral cortex of the subjects with respect to diagnosis, treatment, and suicide. There was no effect of diagnosis on any measure, except for a trend toward decreased stimulated AC activity in subjects with mood disorders relative to control subjects. We also detected a significant effect of suicide on temporal cortex CREB levels in subjects that died as a result of suicide relative to those that did not, which was more evident in patients with major depressive disorder. Bipolar disorder (BD) subjects treated with anticonvulsants at the time of death had decreased temporal cortex CREB levels relative to those not receiving anticonvulsants. Furthermore, we found a trend toward decreased occipital cortex G alpha(s) (short) levels in BD subjects treated with lithium. These results support the hypothesis of altered cAMP signaling in mood disorders and raise the possibility that factors other than diagnosis, such as treatment and suicide, may be relevant to cell-signaling abnormalities reported in the literature." [Abstract]

Odagaki Y, Garcia-Sevilla JA, Huguelet P, La Harpe R, Koyama T, Guimon J.
Cyclic AMP-mediated signaling components are upregulated in the prefrontal cortex of depressed suicide victims.
Brain Res. 2001 Apr 20;898(2):224-31.
"The components of cyclic AMP signaling cascade (catalytic (Calpha) subunit of cyclic AMP-dependent protein kinase (PKA) and cyclic AMP response element binding protein (CREB)) were quantitated by Western blotting in the prefrontal cortex of depressed suicide victims (n=23) and their matched controls (n=14). There was a significant increase in the levels of CREB, both in total (tCREB; 121+/-8% (mean+/-S.E.M.), P<0.02) and phosphorylated (pCREB; 128+/-9%, P<0.01) forms, but not in PKA Calpha levels (109+/-9%, ns), in brains of depressed suicides compared to those in control subjects. The increases in CREB were specifically observed in antidepressant drug-free subjects (tCREB: 137+/-11%, P<0.01; pCREB: 136+/-12%, P<0.02; n=9), but not in the antidepressant-treated subjects (tCREB: 108+/-18%, ns; pCREB: 111+/-17%, ns; n=8). There were significant correlations between the levels of PKA and those of tCREB and pCREB in the prefrontal cortex of depressed suicides. These results indicate that the components of cyclic AMP signaling are upregulated in a coordinated manner in brains of depressed suicides and that this alteration is not related to antidepressant treatment." [Abstract]

Yamada S, Yamamoto M, Ozawa H, Riederer P, Saito T.
Reduced phosphorylation of cyclic AMP-responsive element binding protein in the postmortem orbitofrontal cortex of patients with major depressive disorder.
J Neural Transm. 2003 Jun;110(6):671-80.
"In this study, we examined the amounts of cAMP-responsive element binding protein (CREB) and its phosphorylated form in homogenate preparations from postmortem orbitofrontal cortices of antidepressant drug-free patients with major depressive disorder and age-matched controls by immunoblotting. Immunoreactivies of both CREB and phosphorylated CREB were significantly decreased in depressive subjects compared to controls. The immunoreactivity of phosphorylated CREB was diminished to a greater extent than that of CREB in depressive patients. It has been indicated from animal studies that a transcription factor likely mediates neural plasticity in the mammalian brain and neural tissues. Our results suggest that alterations in the cAMP signaling system, especially in CREB, may be involved in the pathophysiology of depression and be potential targets for antidepressant treatment." [Abstract]

Thome, J., Sakai, N., Shin, K.-H., Steffen, C., Zhang, Y.-J., Impey, S., Storm, D., Duman, R. S.
cAMP Response Element-Mediated Gene Transcription Is Upregulated by Chronic Antidepressant Treatment
J. Neurosci. 2000 20: 4030-4036
"Regulation of gene transcription via the cAMP-mediated second messenger pathway has been implicated in the actions of antidepressant drugs, but studies to date have not demonstrated such an effect in vivo. To directly study the regulation of cAMP response element (CRE)-mediated gene transcription by antidepressants, transgenic mice with a CRE-LacZ reporter gene construct were administered one of three different classes of antidepressants: a norepinephrine selective reuptake inhibitor (desipramine), a serotonin selective reuptake inhibitor (fluoxetine), or a monoamine oxidase inhibitor (tranylcypromine). Chronic, but not acute, administration of these antidepressants significantly increased CRE-mediated gene transcription, as well as the phosphorylation of CRE binding protein (CREB), in several limbic brain regions thought to mediate the action of antidepressants, including the cerebral cortex, hippocampus, amygdala, and hypothalamus. These results demonstrate that chronic antidepressant treatment induces CRE-mediated gene expression in a neuroanatomically differentiated pattern and further elucidate the molecular mechanisms underlying the actions of these widely used therapeutic agents." [Full Text]

Dias BG, Banerjee SB, Duman RS, Vaidya VA.
Differential regulation of Brain Derived Neurotrophic Factor transcripts by antidepressant treatments in the adult rat brain.
Neuropharmacology. 2003 Sep;45(4):553-63.
"Antidepressants are known to increase brain derived neurotrophic factor (BDNF) mRNA in the adult rat brain. The BDNF gene has four differentially regulated promoters that generate four transcript forms, each containing a unique non-coding 5' exon (exon I-IV) and a common 3' coding exon. Using in situ hybridization with exon-specific riboprobes, we have examined whether diverse classes of antidepressants recruit a single or multiple BDNF promoters to regulate BDNF mRNAs. The antidepressants tested were electroconvulsive seizure (ECS) and the pharmacological antidepressants tranylcypromine, desipramine and fluoxetine. The effects of both acute and chronic ECS were the most prominent on exon I and II containing BDNF mRNAs in hippocampal and cortical subfields. Chronic ECS enhanced the acute induction of exon I, II and IV mRNAs but did not influence the acute upregulation of exon III mRNAs. Acute pharmacological antidepressants resulted in region-specific decreases in distinct exon-specific BDNF transcripts. In contrast, chronic administration with tranylcypromine and desipramine enhanced exon II and exon III mRNAs, respectively, in discrete hippocampal and cortical subfields. Chronic fluoxetine treatment did not have a significant effect on the exon-specific BDNF transcripts. The results indicate that distinct antidepressants differentially regulate BDNF mRNAs through a region-specific recruitment of the four BDNF promoters and suggest that diverse signaling mechanisms may be recruited to regulate BDNF transcripts." [Abstract]

Altar CA, Whitehead RE, Chen R, Wortwein G, Madsen TM.
Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain.
Biol Psychiatry. 2003 Oct 1;54(7):703-9.
"BACKGROUND: The antidepressant-like effects of brain-derived neurotrophic factor (BDNF) infusions in brain, and the upregulation of BDNF mRNA and its receptor in rats exposed to electroconvulsive seizure (ECS) and antidepressants, suggested a role for increased BDNF protein. METHODS: We measured BDNF protein levels with a two-site enzyme-linked immunosorbent assay (ELISA) in six brain regions of adult male rats that received daily ECS or daily injections of antidepressant drugs. RESULTS: The BDNF ELISA method was validated by the 50% loss of BDNF protein in the brains of +/- BDNF knockout mice, the 60%-100% recovery of spiked recombinant BDNF, and by the amounts and regional variations of BDNF measured in the six brain regions. Ten consecutive daily exposures to ECS increased BDNF protein in the parietal cortex (219%), entorhinal cortex (153%), hippocampus (132%), frontal cortex (94%), neostriatum (67%), and septum (29%). BDNF increased gradually in the hippocampus and frontal cortex, with a peak response by the fourth day of ECS. Increases peaked at 15 hours after the last ECS and lasted at least 3 days thereafter. Two weeks of daily injections with the monoamine (MAO)-A and -B inhibitor tranylcypromine (8-10 mg/kg, IP) increased BDNF by 15% in the frontal cortex, and 3 weeks treatment increased it by 18% in the frontal cortex and by 29% in the neostriatum. Tranylcypromine, fluoxetine, and desmethylimipramine did not elevate BDNF in the hippocampus. CONCLUSIONS: Elevations in BDNF protein in brain are consistent with the greater treatment efficacy of ECS and MAO inhibitors in drug-resistant major depressive disorder and may be predictive for the antidepressant action of the more highly efficacious interventions." [Abstract]

Nibuya M, Morinobu S, Duman RS.
Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments.
J Neurosci. 1995 Nov;15(11):7539-47.
"The influence of chronic electroconvulsive seizure (ECS) or antidepressant drug treatments on expression of brain-derived neurotrophic factor (BDNF) and its receptor, trkB, was examined by in situ hybridization and Northern blot. In frontal cortex, acute ECS increased BDNF mRNA approximately twofold, an effect significantly augmented by a prior course of chronic ECS treatment (10 d). In the hippocampus, the influence of chronic ECS varied between the major subfields. In the dentate gyrus granule cell layer, chronic ECS decreased the acute induction of BDNF and trkB mRNA by approximately 50%, but prolonged their expression: levels remained elevated two- to threefold 18 hr later after the last chronic ECS treatment, but returned to control 18 hr after acute ECS. In CA3 and CA1 pyramidal cell layers, chronic ECS significantly elevated the acute induction of BDNF, and tended to prolong the expression of BDNF and trkB mRNA. A similar effect was observed in layer 2 of the piriform cortex, where chronic ECS significantly increased the acute induction and prolonged the expression of BDNF and trkB mRNA. Chronic (21 d), but not acute (1 d), administration of several different antidepressant drugs, including tranylcypromine, sertraline, desipramine, or mianserin, significantly increased BDNF mRNA and all but mianserin increased trkB mRNA in hippocampus. In contrast, chronic administration of nonantidepressant psychotropic drugs, including morphine, cocaine, or haloperidol, did not increase levels of BDNF mRNA. Furthermore, chronic administration of ECS or antidepressant drugs completely blocked the down-regulation of BDNF mRNA in the hippocampus in response to restraint stress. The enhanced induction and prolonged expression of BDNF in response to chronic ECS and antidepressant drug treatments could promote neuronal survival, and protect neurons from the damaging effects of stress." [Abstract]

Van Hoomissen JD, Chambliss HO, Holmes PV, Dishman RK.
Effects of chronic exercise and imipramine on mRNA for BDNF after olfactory bulbectomy in rat.
Brain Res. 2003 Jun 6;974(1-2):228-35.
"We examined the effects of chronic activity wheel running and antidepressant treatment on brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) in multiple brain regions-hippocampal formation (HF), ventral tegmental area/substantia nigra (VTA/SN), nucleus accumbens (NAc), and piriform cortex (PFx)-after bilateral olfactory bulbectomy (OBX). Male, Long-Evans rats (n=72) underwent either sham or OBX surgery and were randomly divided into eight experimental groups in a 2 (sham vs. OBX) x 2 (sedentary vs. activity wheel)x2 (saline vs. imipramine) factorial design. Animals were killed after 21 days of treatment. Drug x exercise interaction effects were observed for HF (P=0.006-0.023) and VTA/SN (P=0.021); exercise increased BDNF mRNA in the saline treated animals but not in the imipramine treated animals. OBX did not affect BDNF mRNA in the HF or VTA/SN (P>0.05). BDNF mRNA levels in the PFx were not altered by exercise, drug, or OBX (P>0.05). These results suggest that the effect of exercise on BDNF mRNA extends beyond the HF to the mesolimbic ventral tegmental area and that the potentiation of BDNF mRNA by exercise and antidepressant pharmacotherapy, reported by other investigators, is time limited." [Abstract]

Russo-Neustadt A, Ha T, Ramirez R, Kesslak JP.
Physical activity-antidepressant treatment combination: impact on brain-derived neurotrophic factor and behavior in an animal model.
Behav Brain Res. 2001 Apr 8;120(1):87-95.
"The mechanism of antidepressant action, at the cellular level, is not clearly understood. It has been reported that chronic antidepressant treatment leads to an up-regulation of brain-derived neurotrophic factor (BDNF) mRNA levels in the hippocampus, and that physical activity (voluntary running) enhances this effect. We wished to investigate whether BDNF expression brought about by these interventions may overcome deficits caused by acute stress, and might impact behavior in an animal model. In this report, we have tested the hypothesis that the combination of the antidepressant, tranylcypromine, and physical exercise could lead to decreased neurotrophin deficits and enhanced swimming time in animals that have been forced to swim in an inescapable water tank. Rats were either treated with tranylcypromine, engaged in voluntary running, or both for one week. After these treatments, the animals underwent a two-day forced swimming procedure. BDNF mRNA levels were significantly depressed in untreated animals subjected to forced swimming. Animals that either underwent prior activity or received antidepressant showed BDNF mRNA levels restored to baseline. Animals receiving the combined intervention showed an increase in hippocampal BDNF mRNA well above baseline. Swimming time during a five-minute test was significantly enhanced in animals receiving the combined intervention over untreated animals. Swimming time was not significantly enhanced over that of animals receiving antidepressant alone, however. Enhanced swimming time correlated with increased levels of BDNF mRNA in one hippocampal sub-region (CA4-hilus). These results suggest that the combination of exercise and antidepressant treatment may have significant neurochemical, and possibly behavioral, effects. In addition, these results support the possibility that the enhancement of BDNF expression may be an important element in the clinical response to antidepressant treatment. The induction of BDNF expression by activity/pharmacological treatment combinations could represent an important intervention for further study, to potentially improve depression treatment and management." [Abstract]

Okamoto H, Shino Y, Hashimoto K, Kumakiri C, Shimizu E, Shirasawa H, Iyo M.
Dynamic changes in AP-1 transcription factor DNA binding activity in rat brain following administration of antidepressant amitriptyline and brain-derived neurotrophic factor.
Neuropharmacology. 2003 Aug;45(2):251-259.
"The present study was undertaken to examine the effects of the antidepressant, amitriptyline, and brain-derived neurotrophic factor (BDNF) on activator protein-1 (AP-1) DNA binding activity in the rat brain. Acute administration of amitriptyline (5 or 10 mg/kg) initially increased but then decreased AP-1 DNA binding activity in the rat frontal cortex and hippocampus. Chronic administration of amitriptyline (5 or 10 mg/kg, once daily for 3 weeks) initially decreased AP-1 DNA binding activity but ultimately resulted in its persistent elevation in the rat frontal cortex. In contrast, the chronic administration of amitriptyline did not affect the low activity of AP-1 DNA binding in the hippocampus. However, chronic administration of amitriptyline (10 mg/kg, once daily for 3 weeks) significantly increased BDNF protein levels in the hippocampus (by 26.9%) and frontal cortex (by 24.6%). Direct infusion of BDNF (1 microg) into the hippocampal dentate gyrus significantly increased hippocampal AP-1 DNA binding activity. These results suggest that AP-1 transcription factor may be modulated by BDNF and that it may be an important target for the action of antidepressants." [Abstract]

Xu H, Steven Richardson J, Li XM.
Dose-related effects of chronic antidepressants on neuroprotective proteins BDNF, Bcl-2 and Cu/Zn-SOD in rat hippocampus.
Neuropsychopharmacology. 2003 Jan;28(1):53-62.
"It has been proposed that antidepressants have neuroprotective effects on hippocampal neurons. To further test this hypothesis, brain-derived neurotrophic factor (BDNF), B cell lymphoma protein-2 (Bcl-2), and copper-zinc superoxide dismutase (Cu/Zn-SOD) were examined immunohistochemically in hippocampal neurons of Sprague-Dawley rats following daily treatment with 5 or 10 mg/kg of amitriptyline or venlafaxine for 21 days. At 5 mg/kg, both amitriptyline and venlafaxine increased the intensity of BDNF immunostaining in hippocampal pyramidal neurons, and the intensity of Bcl-2 immunostaining in hippocampal mossy fibers, but did not alter the Cu/Zn-SOD immunoreactivity. The high dose of venlafaxine, however, decreased the intensity of BDNF immunostaining in all subareas of the hippocampus and increased the intensity of Cu/Zn-SOD immunostaining in the dentate granular cell layer. The high dose of amitriptyline increased the intensity of Cu/Zn-SOD immunostaining, but did not affect the immunoreactivity of Bcl-2 or BDNF. These findings suggest that the chronic administration of amitriptyline or venlafaxine at 5 mg/kg, but not 10 mg/kg, may be neuroprotective to hippocampal neurons. These dose-related effects of antidepressant drugs on hippocampal neurons may have relevance to disparate findings in the field." [Abstract]

Butterweck V, Winterhoff H, Herkenham M.
St John's wort, hypericin, and imipramine: a comparative analysis of mRNA levels in brain areas involved in HPA axis control following short-term and long-term administration in normal and stressed rats.
Mol Psychiatry. 2001 Sep;6(5):547-64.
"Clinical studies demonstrate that the antidepressant efficacy of St John's wort (Hypericum) is comparable to that of tricyclic antidepressants such as imipramine. Onset of efficacy of these drugs occurs after several weeks of treatment. Therefore, we used in situhybridization histochemistry to examine in rats the effects of short-term (2 weeks) and long-term (8 weeks) administration of imipramine, Hypericum extract, and hypericin (an active constituent of St John's wort) on the expression of genes that may be involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Imipramine (15 mg kg(-1)), Hypericum (500 mg kg(-1)), and hypericin (0.2 mg kg(-1)) given daily by gavage for 8 weeks but not for 2 weeks significantly decreased levels of corticotropin-releasing hormone (CRH) mRNA by 16-22% in the hypothalamic paraventricular nucleus (PVN) and serotonin 5-HT(1A) receptor mRNA by 11-17% in the hippocampus. Only imipramine decreased tyrosine hydroxylase (TH) mRNA levels in the locus coeruleus (by 23%), and only at 8 weeks. The similar delayed effects of the three compounds on gene transcription suggests a shared action on the centers that control HPA axis activity. A second study was performed to assess the effects of long-term imipramine and Hypericum administration on stress-induced changes in gene transcription in stress-responsive circuits. Repeated immobilization stress (2 h daily for 7 days) increased mRNA levels of CRH in the PVN, proopiomelanocortin (POMC) in the anterior pituitary, glutamic acid decarboxylase (GAD 65/67) in the bed nucleus of the stria terminalis (BST), cyclic AMP response element binding protein (CREB) in the hippocampus, and TH in the locus coeruleus. It decreased mRNA levels of 5-HT(1A) and brain-derived neurotrophic factor (BDNF) in the hippocampus. Long-term pre-treatment with either imipramine or Hypericum reduced to control levels the stress-induced increases in gene transcription of GAD in the BST, CREB in the hippocampus, and POMC in the pituitary. The stress-induced increases in mRNA levels of CRH in the PVN and TH in the locus coeruleus were reduced by imipramine but not by Hypericum. The stress-induced decreases in BDNF and 5-HT(1A)mRNA levels were not prevented by either drug. Taken together, these data show: (1) that Hypericum and hypericin have delayed effects on HPA axis control centers similar to those of imipramine; and (2) that select stress-induced changes in gene transcription in particular brain areas can be prevented by long-term treatment with either the prototypic tricyclic antidepressant imipramine or the herbiceutical St John's wort. However, imipramine appears to be more effective in blocking stress effects on the HPA axis than the plant extract." [Abstract]

Li YF, Yang M, Zhao YM, Luo ZP.
[Protective effect of bajitian oligosaccharide on PC12 cells lesioned by corticosterone]
Zhongguo Zhong Yao Za Zhi. 2000 Sep;25(9):551-4.
"OBJECTIVE: To study the possible mechanism of antidepressant effect of Bajitian oligosaccharide (MW-97). METHODS AND RESULTS: After incubating with the PC12 cells in the presence of corticosterone(2 x 10(-4) mol.L-1) for 48 h, it was found that MW-97 could protect PC12 cells from the lesion done by corticosterone in a concentration-dependent manner. Furthermore, using RT-PCR mediated cross-species partial cDNA cloning, it was found that MW-97 and desipramine(DIM) increased NGF, BDNF mRNA in the frontal cortex after chronic administration for 21 days, meanwhile, BDNF mRNA in hippocampus was also increased. CONCLUSION: The cytoprotective effect of MW-97 consists in the possible mechanism of its antidepressant action, while the increasing expression of neurotrophic factors (NGF, BDNF mRNA) may be contributes to the cytoprotective effect." [Abstract]

Coppell AL, Pei Q, Zetterstrom TS.
Bi-phasic change in BDNF gene expression following antidepressant drug treatment.
Neuropharmacology. 2003 Jun;44(7):903-10.
"The gene for brain derived neurotrophic factor (BDNF) has recently received attention in relation to the therapeutic action of antidepressant treatment. This study aimed to clarify the influence of post drug interval on the effect of acute and repeated treatment with antidepressant drugs on BDNF gene expression in the rat brain. It was found that repeated administration of either the monoamine oxidase inhibitor tranylcypromine (TCP) or 5-hydroxytryptamine (5-HT) re-uptake inhibitors (fluoxetine, paroxetine and sertraline), evoke a bi-phasic and time-dependent effect on BDNF gene expression in the rat hippocampus (especially dentate gyrus). A down-regulation of the BDNF gene was detected at 4 h (TCP and fluoxetine) and an up-regulation at 24 h (TCP, paroxetine, fluoxetine, sertraline) after the last of twice daily injections for 14 days. After a single injection the down-regulation was detected at 4 h (TCP, fluoxetine, paroxetine and sertraline) but BDNF mRNA levels were not altered at 24 h post drug (TCP, fluoxetine and paroxetine). Administration of inhibitors of noradrenaline re-uptake (desipramine and maprotiline) or the atypical antidepressant mianserin had no effect on BDNF mRNA levels at either single (4 h post drug, desipramine) or repeated (24 h post drug, desipramine, maprotiline, mianserin) treatment. The gene expression for NT-3, which is distributed in a high density in the dentate gyrus, was not affected by single or repeated injections of antidepressant drugs (TCP, fluoxetine, paroxetine, sertraline, desipramine, maprotiline or mianserin) at 4 or 24 h post drug. In conclusion, these data show that the effect of antidepressant drugs on BDNF gene expression may be more complex and less widespread across treatments than previously thought. Thus, in this study drugs interacting with the central 5-HT system altered BDNF expression but the effect was bi-phasic over the 24 h post drug period." [Abstract]

Manji HK, Quiroz JA, Sporn J, Payne JL, Denicoff K, A Gray N, Zarate CA Jr, Charney DS.
Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression.
Biol Psychiatry. 2003 Apr 15;53(8):707-42.
"There is growing evidence from neuroimaging and ostmortem studies that severe mood disorders, which have traditionally been conceptualized as neurochemical disorders, are associated with impairments of structural plasticity and cellular resilience. It is thus noteworthy that recent preclinical studies have shown that critical molecules in neurotrophic signaling cascades (most notably cyclic adenosine monophosphate [cAMP] response element binding protein, brain-derived neurotrophic factor, bcl-2, and mitogen activated protein [MAP] kinases) are long-term targets for antidepressant agents and antidepressant potentiating modalities. This suggests that effective treatments provide both trophic and neurochemical support, which serves to enhance and maintainnormal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. For many refractory patients, drugs mimicking "traditional" strategies, which directly or indirectly alter monoaminergic levels, may be of limited benefit. Newer "plasticity enhancing" strategies that may have utility in the treatment of refractory depression include N-methyl-D-aspartate antagonists, alpha-amino-3-hydroxy-5-methylisoxazole propionate (AMPA) potentiators, cAMP phosphodiesterase inhibitors, and glucocorticoid receptor antagonists. Small-molecule agents that regulate the activity f growth factors, MAP kinases cascades, and the bcl-2 family of proteins are also promising future avenues. The development of novel, nonaminergic-based therapeutics holds much promise for improved treatment of severe, refractory mood disorders." [Abstract]

Nibuya M, Nestler EJ, Duman RS.
Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus.
J Neurosci. 1996 Apr 1;16(7):2365-72.
"The present study demonstrates that chronic, but not acute, adminstration of several different classes of antidepressants, including serotonin- and norepinephrine-selective reuptake inhibitors, increases the expression of cAMP response element binding protein (CREB) mRNA in rat hippocampus. In contrast, chronic administration of several nonantidepressant psychotropic drugs did not influence expression of CREB mRNA, demonstrating the pharmacological specificity of this effect. In situ hybridization analysis demonstrates that antidepressant administration increases expression of CREB mRNA in CA1 and CA3 pyramidal and dentate gyrus granule cell layers of the hippocampus. In addition, levels of CRE immunoreactivity and of CRE binding activity were increased by chronic antidepressant administration, which indicates that expression and function of CREB protein are increased along with its mRNA. Chronic administration of the phosphodiesterase (PDE) inhibitors rolipram or papaverine also increased expression of CREB mRNA in hippocampus, demonstrating a role for the cAMP cascade. Moreover, coadministration of rolipram with imipramine resulted in a more rapid induction of CREB than with either treatment alone. Increased expression and function of CREB suggest that specific target genes may be regulated by these treatments. We have found that levels of brain-derived neurotrophic factor (BDNF) and trkB mRNA are also increased by administration of antidepressants or PDE inhibitors. These findings indicate that upregulation of CREB is a common action of chronic antidepressant treatments that may lead to regulation of specific target genes, such as BDNF and trkB, and to the long-term effects of these treatments on brain function." [Abstract]

Miro X, Perez-Torres S, Artigas F, Puigdomenech P, Palacios JM, Mengod G.
Regulation of cAMP phosphodiesterase mRNAs expression in rat brain by acute and chronic fluoxetine treatment. An in situ hybridization study.
Neuropharmacology. 2002 Dec;43(7):1148-57.
"Changes in brain cyclic AMP (cAMP) have been suggested to underlie the clinical action of antidepressant treatments. Also, a regionally-selective regulation of cAMP-specific phosphodiesterases (PDEs) has been demonstrated for some antidepressants. To further investigate the effects of antidepressant treatments on PDEs, we examined the expression of different cAMP-specific PDEs in the brain of rats treated (1 and 14 days) with fluoxetine 3 mg/kg day. The mRNAs coding for PDE4A, PDE4B, PDE4D, and the five known PDE4D splice variants were analyzed by in situ hybridization on 45 brain structures of acute and chronic fluoxetine-treated rats. We also examined the binding sites for the putative antidepressant drug [(3)H]rolipram, a PDE4-selective inhibitor. In some brain areas single fluoxetine administration increased the density of the mRNA of all PDE4 isozymes, except PDE4D and PDE4D5. Chronic fluoxetine treatment increased PDE4A mRNA levels and decreased those for PDE4B, PDE4D and PDE4D1 mRNAs in some brain regions. The study was complemented with the analysis of the expression of the transcripts of BDNF. Chronic fluoxetine treatment down-regulated the expression of BDNF. These results show that the expression of PDE4 isozymes is modulated by a clinically relevant fluoxetine dose. The significance of these changes in PDE4 expression to the antidepressant effect of fluoxetine is discussed." [Abstract]

D'Sa C, Tolbert LM, Conti M, Duman RS.
Regulation of cAMP-specific phosphodiesterases type 4B and 4D (PDE4) splice variants by cAMP signaling in primary cortical neurons.
J Neurochem. 2002 May;81(4):745-57.
"This study examined the regulation of all known phosphodiesterase (PDE) type PDE4A, PDE4B and PDE4D splice variants in cortical neurons by cAMP signaling. Treatment with dibutyryl-cAMP (db-cAMP) caused the induction of two of the known splice variants, PDE4B2 and PDE4D1/PDE4D2. Although the splice variants PDE4A1, PDE4A5/PDE4A10, PDE4B3, PDE4B1, PDE4D3 and PDE4D4 were present in cortical neurons, their mRNA was not regulated at the transcriptional level by db-cAMP. To assess the increase in PDE4B2 and PDE4D1/D2 mRNA expression, the promoters containing these genes were characterized. Transcription from both promoters was stimulated by db-cAMP. Because chronic antidepressant treatment increases PDE4B, and not PDE4D, mRNA expression, we focused on the regulation of the PDE4B2 promoter by cAMP and CREB. Dominant negative mutants of CREB suppressed PDE4B2 promoter activity and a constitutively active form of CREB robustly stimulated it. These data demonstrate that in cortical neurons, a short PDE4B2 intronic promoter is regulated by CREB, confers cAMP responsitivity and directs PDE4B2 mRNA and protein expression." [Abstract]

Fujimaki K, Morinobu S, Duman RS.
Administration of a cAMP phosphodiesterase 4 inhibitor enhances antidepressant-induction of BDNF mRNA in rat hippocampus.
Neuropsychopharmacology. 2000 Jan;22(1):42-51.
"The influence of two selective phosphodiesterase 4 (PDE4) inhibitors, rolipram and Ro 20-1724, on the induction of BDNF mRNA by antidepressant treatment was examined. Coadministration of rolipram or Ro 20-1724 with an antidepressant (either desipramine or Org 4428) for 21 d resulted in a significant induction of BDNF mRNA in hippocampus relative to administration of vehicle. Coadministration of a PDE4 inhibitor with an antidepressant for 7 or 14 d also increased levels of BDNF mRNA. In contrast, acute coadministration did not influence levels of BDNF mRNA. In situ hybridization analysis demonstrated that the induction of BDNF mRNA in response to the repeated coadministration paradigm occurs in the dentate gyrus granule and CA1 and CA3 pyramidal cell layers of hippocampus. These findings demonstrate that coadministration shortens the time required for the upregulation of BDNF mRNA, supporting the possibility that this treatment may provide an effective therapy for major depression." [Abstract]

Muller MB, Toschi N, Kresse AE, Post A, Keck ME.
Long-term repetitive transcranial magnetic stimulation increases the expression of brain-derived neurotrophic factor and cholecystokinin mRNA, but not neuropeptide tyrosine mRNA in specific areas of rat brain.
Neuropsychopharmacology. 2000 Aug;23(2):205-15.
"Repetitive transcranial magnetic stimulation (rTMS) is increasingly used as a therapeutic tool in various neurological and psychiatric disorders, and we recently found that it has a neuroprotective effect both in vitro and in vivo. However, the neurochemical mechanisms underlying the therapeutic effects are still unknown. We investigated the effects of long-term rTMS on the expression of brain-derived neurotrophic factor (BDNF), cholecystokinin (CCK), and neuropeptide tyrosine (NPY) mRNA in rat brain. In situ hybridization revealed a significant increase in BDNF mRNA in the hippocampal areas CA3 and CA3c, the granule cell layer, as well as in the parietal and the piriform cortex after rTMS. BDNF-like immunoreactivity was markedly increased in the same areas. A significant increase in CCK mRNA was observed in all brain regions examined. NPY mRNA expression, in contrast, was not altered. The present results suggest that BDNF may contribute to the neuroprotective effects of rTMS. Furthermore, the rTMS-induced changes in BDNF and CCK expression are similar to those reported after antidepressant drug treatment and electroconvulsive seizures, suggesting that a common molecular mechanism may underlie different antidepressant treatment strategies." [Abstract]

REID, IAN C., STEWART, CAROLINE A.
How antidepressants work: New perspectives on the pathophysiology of depressive disorder
Br J Psychiatry 2001 178: 299-303
"BACKGROUND: New research in animals is beginning to change radically our understanding of the biology of stress and the effects of antidepressant agents. AIMS: To relate recent findings from the basic neurosciences to the pathophysiology of depressive disorder. METHOD: Drawing together findings from molecular and physiological studies in rats, social studies in primates and neuropsychological studies in humans, we review the neurotrophic and neuroplastic effects of antidepressants and stress. RESULTS: Stress and antidepressants have reciprocal actions on neuronal growth and vulnerability (mediated by the expression of neurotrophins) and synaptic plasticity (mediated by excitatory amino acid neurotransmission) in the hippocampus and other brain structures. Stressors have the capacity to progressively disrupt both the activities of individual cells and the operating characteristics of networks of neurons throughout the life cycle, while antidepressant treatments act to reverse such injurious effects. CONCLUSIONS: We propose a central role for the regulation of synaptic connectivity in the pathophysiology of depressive disorder.""" [Full Text]

Robert M. Sapolsky
Depression, antidepressants, and the shrinking hippocampus
PNAS 98: 12320-12322. 2001. [Full Text]

Glenda M. MacQueen, Stephanie Campbell, Bruce S. McEwen, Kathryn Macdonald, Shigeko Amano, Russell T. Joffe, Claude Nahmias, and L. Trevor Young
Course of illness, hippocampal function, and hippocampal volume in major depression
PNAS 100: 1387-1392; published online before print as 10.1073/pnas.0337481100
"Studies have examined hippocampal function and volume in depressed subjects, but none have systematically compared never-treated first-episode patients with those who have had multiple episodes. We sought to compare hippocampal function, as assessed by performance on hippocampal-dependent recollection memory tests, and hippocampal volumes, as measured in a 1.5-T magnetic resonance imager, in depressed subjects experiencing a postpubertal onset of depression. Twenty never-treated depressed subjects in a first episode of depression were compared with matched healthy control subjects. Seventeen depressed subjects with multiple past episodes of depression were also compared with matched healthy controls and to the first-episode patients. Both first- and multiple-episode depressed groups had hippocampal dysfunction apparent on several tests of recollection memory; only depressed subjects with multiple depressive episodes had hippocampal volume reductions. Curve-fitting analysis revealed a significant logarithmic association between illness duration and hippocampal volume. Reductions in hippocampal volume may not antedate illness onset, but volume may decrease at the greatest rate in the early years after illness onset." [Full Text]

Sheline, Yvette I., Sanghavi, Milan, Mintun, Mark A., Gado, Mokhtar H.
Depression Duration But Not Age Predicts Hippocampal Volume Loss in Medically Healthy Women with Recurrent Major Depression
J. Neurosci. 1999 19: 5034-5043
"This study takes advantage of continuing advances in the precision of magnetic resonance imaging (MRI) to quantify hippocampal volumes in a series of human subjects with a history of depression compared with controls. We sought to test the hypothesis that both age and duration of past depression would be inversely and independently correlated with hippocampal volume. A sample of 24 women ranging in age from 23 to 86 years with a history of recurrent major depression, but no medical comorbidity, and 24 case-matched controls underwent MRI scanning. Subjects with a history of depression (post-depressed) had smaller hippocampal volumes bilaterally than controls. Post-depressives also had smaller amygdala core nuclei volumes, and these volumes correlated with hippocampal volumes. In addition, post-depressives scored lower in verbal memory, a neuropsychological measure of hippocampal function, suggesting that the volume loss was related to an aspect of cognitive functioning. In contrast, there was no difference in overall brain size or general intellectual performance. Contrary to our initial hypothesis, there was no significant correlation between hippocampal volume and age in either post-depressive or control subjects, whereas there was a significant correlation with total lifetime duration of depression. This suggests that repeated stress during recurrent depressive episodes may result in cumulative hippocampal injury as reflected in volume loss." [Full Text]

Sheline, Yvette I., Gado, Mokhtar H., Kraemer, Helena C.
Untreated Depression and Hippocampal Volume Loss
Am J Psychiatry 2003 160: 1516-1518
"OBJECTIVE: The purpose of this study was to investigate the effect of antidepressant treatment on hippocampal volumes in patients with major depression. METHOD: For 38 female outpatients, the total time each had been in a depressive episode was divided into days during which the patient was receiving antidepressant medication and days during which no antidepressant treatment was received. Hippocampal gray matter volumes were determined by high resolution magnetic resonance imaging and unbiased stereological measurement. RESULTS: Longer durations during which depressive episodes went untreated with antidepressant medication were associated with reductions in hippocampal volume. There was no significant relationship between hippocampal volume loss and time depressed while taking antidepressant medication or with lifetime exposure to antidepressants. CONCLUSIONS: Antidepressants may have a neuroprotective effect during depression." [Abstract]

D'Sa C, Duman RS.
Antidepressants and neuroplasticity.
Bipolar Disord. 2002 Jun;4(3):183-94.
"OBJECTIVE: We review the literature on the cellular changes that underlie the structural impairments observed in brains of animals exposed to stress and in subjects with depressive disorders. We discuss the molecular, cellular and structural adaptations that underlie the therapeutic responses of different classes of antidepressants and contribute to the adaptive plasticity induced in the brain by these drugs. METHODS: We review results from various clinical and basic research studies. RESULTS: Studies demonstrate that chronic antidepressant treatment increases the rate of neurogenesis in the adult hippocampus. Studies also show that antidepressants up-regulate the cyclic adenosine monophosphate (cAMP) and the neurotrophin signaling pathways involved in plasticity and survival. In vitro and in vivo data provide direct evidence that the transcription factor, cAMP response element-binding protein (CREB) and the neurotrophin, brain derived-neurotrophic factor (BDNF) are key mediators of the therapeutic response to antidepressants. CONCLUSIONS: These results suggest that depression maybe associated with a disruption of mechanisms that govern cell survival and neural plasticity in the brain. Antidepressants could mediate their effects by increasing neurogenesis and modulating the signaling pathways involved in plasticity and survival." [Abstract]

Garcia R.
Stress, metaplasticity, and antidepressants.
Curr Mol Med. 2002 Nov;2(7):629-38.
"A large body of evidence has established a link between stressful life events and development or exacerbation of depression. At the cellular level, evidence has emerged indicating neuronal atrophy and cell loss in response to stress and in depression. At the molecular level, it has been suggested that these cellular deficiencies, mostly detected in the hippocampus, result from a decrease in the expression of brain-derived neurotrophic factor (BDNF) associated with elevation of glucocorticoids. Thus, an increase in expression of BDNF, facilitating both neuronal survival and neurogenesis, is thought to represent a converging mechanism of action of various types of antidepressant treatments (e.g., antidepressant drugs and transcranial magnetic stimulation). However, as also revealed by converging lines of evidence, high levels of glucocorticoids down-regulate hippocampal synaptic connectivity ('negative' metaplasticity), whereas an increase in expression of BDNF up-regulates connectivity in the hippocampus ('positive' metaplasticity). Therefore, antidepressant treatments might not only restore cell density but also regulate higher-order synaptic plasticity in the hippocampus by abolishing 'negative' metaplasticity, and thus restore hippocampal cognitive processes that are altered by stress and in depressed patients. This antidepressant regulatory effect on hippocampal synaptic plasticity function, which may, in turn, suppress 'negative' metaplasticity in other limbic structures, is discussed." [Abstract]

Duman, Ronald S., Malberg, Jessica, Nakagawa, Shin
Regulation of Adult Neurogenesis by Psychotropic Drugs and Stress
J Pharmacol Exp Ther 2001 299: 401-407
"Proliferation and maturation of neurons has been demonstrated to occur at a significant rate in discrete regions of adult brain, including the hippocampus and subventricular zone. Moreover, adult neurogenesis is an extremely dynamic process that is regulated in both a positive and negative manner by neuronal activity and environmental factors. It has been suggested to play a role in several important neuronal functions, including learning, memory, and response to novelty. In addition, exposure to psychotropic drugs or stress regulates the rate of neurogenesis in adult brain, suggesting a possible role for neurogenesis in the pathophysiology and treatment of neurobiological illnesses such as depression, post-traumatic stress disorder, and drug abuse. As the mechanisms that control adult neurogenesis continue to be identified, the exciting prospect of developing pharmacological agents that specifically regulate the proliferation and maturation of neurons in the adult brain could be fulfilled." [Full Text]

Malberg, Jessica E., Eisch, Amelia J., Nestler, Eric J., Duman, Ronald S.
Chronic Antidepressant Treatment Increases Neurogenesis in Adult Rat Hippocampus
J. Neurosci. 2000 20: 9104-9110
"Recent studies suggest that stress-induced atrophy and loss of hippocampal neurons may contribute to the pathophysiology of depression. The aim of this study was to investigate the effect of antidepressants on hippocampal neurogenesis in the adult rat, using the thymidine analog bromodeoxyuridine (BrdU) as a marker for dividing cells. Our studies demonstrate that chronic antidepressant treatment significantly increases the number of BrdU-labeled cells in the dentate gyrus and hilus of the hippocampus. Administration of several different classes of antidepressant, but not non-antidepressant, agents was found to increase BrdU-labeled cell number, indicating that this is a common and selective action of antidepressants. In addition, upregulation of the number of BrdU-labeled cells is observed after chronic, but not acute, treatment, consistent with the time course for the therapeutic action of antidepressants. Additional studies demonstrated that antidepressant treatment increases the proliferation of hippocampal cells and that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal- or glial-specific markers. These findings raise the possibility that increased cell proliferation and increased neuronal number may be a mechanism by which antidepressant treatment overcomes the stress-induced atrophy and loss of hippocampal neurons and may contribute to the therapeutic actions of antidepressant treatment." [Full Text]

Santarelli, Luca, Saxe, Michael, Gross, Cornelius, Surget, Alexandre, Battaglia, Fortunato, Dulawa, Stephanie, Weisstaub, Noelia, Lee, James, Duman, Ronald, Arancio, Ottavio, Belzung, Catherine, Hen, Rene
Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants
Science 2003 301: 805-809
"Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus." [Abstract]

Conti AC, Cryan JF, Dalvi A, Lucki I, Blendy JA.
cAMP response element-binding protein is essential for the upregulation of brain-derived neurotrophic factor transcription, but not the behavioral or endocrine responses to antidepressant drugs.
J Neurosci. 2002 Apr 15;22(8):3262-8.
"Antidepressant drugs activate the cAMP signal transduction pathway through a variety of monoamine neurotransmitter receptors. Recently, molecular studies have identified a role for cAMP response element-binding protein (CREB) in the mechanism of action of chronically administered antidepressant drugs. However, the function of CREB in the behavioral and endocrine responses to these drugs has not been thoroughly investigated. We have used CREB-deficient mice to study the effects of two antidepressants, desipramine (DMI) and fluoxetine (FLX), in behavioral, endocrine, and molecular analyses. Behaviorally, CREB-deficient mice and wild-type mice respond similarly to DMI and FLX administration in the forced swim test and tail suspension test. Furthermore, the ability of DMI to suppress an acute corticosterone response after swim stress is maintained in CREB-deficient mice. However, upregulation of a molecular target of CREB, BDNF, is abolished in the CREB-deficient mice after chronic administration of DMI. These data are the first to demonstrate that CREB activation is upstream of BDNF mechanistically in response to antidepressant drug treatment. Therefore, although behavioral and endocrine responses to antidepressants may occur by CREB-independent mechanisms, CREB is critical to target gene regulation after chronic drug administration, which may contribute to long-term adaptations of the system to antidepressant drug treatment." [Full Text]

Chen AC, Shirayama Y, Shin KH, Neve RL, Duman RS.
Expression of the cAMP response element binding protein (CREB) in hippocampus produces an antidepressant effect.
Biol Psychiatry. 2001 May 1;49(9):753-62.
"BACKGROUND: Recent studies have demonstrated that chronic antidepressant treatment increases the expression of the cyclic amp (cAMP) response element binding protein (CREB) in rat hippocampus. The study presented here was conducted to determine if CREB is a relevant target that produces an antidepressant-like effect. METHODS: We employed the herpes simplex virus (HSV)-mediated gene transfer technique to overexpress CREB and determined its effect on the learned helplessness and forced swim tests, two established models used for pharmacological screening of antidepressant drugs. RESULTS: In the learned helplessness model, rats that received bilateral microinjection of HSV-CREB into the dentate gyrus showed significantly fewer escape failures in the subsequent conditioned avoidance test than those injected with control vector (HSV-LacZ). In contrast, microinjection of HSV-CREB in either the CA1 pyramidal cell layer of hippocampus or the prefrontal cortex did not produce an antidepressant response. In the forced swim test, CREB expression in the dentate gyrus resulted in a significantly shorter immobility time than those injected with HSV-LacZ. CONCLUSIONS: These results demonstrate that over-expression of CREB in hippocampus results in an antidepressant effect and suggest that CREB may serve as a potential molecular target for novel therapeutic agents." [Abstract]

Nakagawa, Shin, Kim, Ji-Eun, Lee, Rena, Malberg, Jessica E., Chen, Jingshan, Steffen, Cathy, Zhang, Ya-Jun, Nestler, Eric J., Duman, Ronald S.
Regulation of Neurogenesis in Adult Mouse Hippocampus by cAMP and the cAMP Response Element-Binding Protein
J. Neurosci. 2002 22: 3673-3682
"The cAMP cascade, including the cAMP response element-binding protein (CREB), is known to play an important role in neuronal survival and plasticity. Here the influence of this cascade on neurogenesis in adult hippocampus was determined. Activation of the cAMP cascade by administration of rolipram, an inhibitor of cAMP breakdown, increased the proliferation of newborn cells in adult mouse hippocampus. In addition, rolipram induction of cell proliferation resulted in mature granule cells that express neuronal-specific markers. Increased cell proliferation is accompanied by activation of CREB phosphorylation in dentate gyrus granule cells, suggesting a role for this transcription factor. This possibility is supported by studies demonstrating that cell proliferation is decreased in conditional transgenic mice that express a dominant negative mutant of CREB in hippocampus. The results suggest that the cAMP-CREB cascade could contribute to the actions of neurotransmitters and neurotrophic factors on adult neurogenesis." [Full Text]

Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME.
Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism.
Neuron. 1998 Apr;20(4):709-26.
"CREB is a transcription factor implicated in the control of adaptive neuronal responses. Although one function of CREB in neurons is believed to be the regulation of genes whose products control synaptic function, the targets of CREB that mediate synaptic function have not yet been identified. This report describes experiments demonstrating that CREB or a closely related protein mediates Ca2+-dependent regulation of BDNF, a neurotrophin that modulates synaptic activity. In cortical neurons, Ca2+ influx triggers phosphorylation of CREB, which by binding to a critical Ca2+ response element (CRE) within the BDNF gene activates BDNF transcription. Mutation of the BDNF CRE or an adjacent novel regulatory element as well as a blockade of CREB function resulted in a dramatic loss of BDNF transcription. These findings suggest that a CREB family member acts cooperatively with an additional transcription factor(s) to regulate BDNF transcription. We conclude that the BDNF gene is a CREB family target whose protein product functions at synapses to control adaptive neuronal responses." [Abstract]

Shieh PB, Hu SC, Bobb K, Timmusk T, Ghosh A.
Identification of a signaling pathway involved in calcium regulation of BDNF expression.
Neuron. 1998 Apr;20(4):727-40.
"A signaling pathway by which calcium influx regulates the expression of the major activity-dependent transcript of BDNF in cortical neurons has been elucidated. Deletion and mutational analysis of the promoter upstream of exon III reveals that transactivation of the BDNF gene involves two elements 5' to the mRNA start site. The first element, located between 72 and 47 bp upstream of the mRNA start site, is a novel calcium response element and is required for calcium-dependent BDNF expression in both embryonic and postnatal cortical neurons. The second element, located between 40 and 30 bp upstream of the mRNA start site, matches the consensus sequence of a cAMP response element (CRE) and is required for transactivation of the promoter in postnatal but not embryonic neurons. The CRE-dependent component of the response appears to be mediated by CREB since it is part of the complex that binds to this CRE, and since dominant negative mutants of CREB attenuate transactivation of the promoter. A constitutively active mutant of CaM kinase IV, but not of CaM kinase II, leads to activation of the promoter in the absence of extracellular stimuli, and partially occludes calcium-dependent transactivation. The effects of CaM kinase IV on the promoter require an intact CRE. These mechanisms, which implicate CaM kinase IV and CREB in the control of BDNF expression, are likely to be centrally involved in activity-dependent plasticity during development." [Abstract]

Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, MacDonald E, Agerman K, Haapasalo A, Nawa H, Aloyz R, Ernfors P, Castren E.
Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects.
J Neurosci. 2003 Jan 1;23(1):349-57.
"Recent studies have indicated that exogenously administered neurotrophins produce antidepressant-like behavioral effects. We have here investigated the role of endogenous brain-derived neurotrophic factor (BDNF) and its receptor trkB in the mechanism of action of antidepressant drugs. We found that trkB.T1-overexpressing transgenic mice, which show reduced trkB activation in brain, as well as heterozygous BDNF null (BDNF(+/)-) mice, were resistant to the effects of antidepressants in the forced swim test, indicating that normal trkB signaling is required for the behavioral effects typically produced by antidepressants. In contrast, neurotrophin-3(+/)- mice showed a normal behavioral response to antidepressants. Furthermore, acute as well as chronic antidepressant treatment induced autophosphorylation and activation of trkB in cerebral cortex, particularly in the prefrontal and anterior cingulate cortex and hippocampus. Tyrosines in the trkB autophosphorylation site were phosphorylated in response to antidepressants, but phosphorylation of the shc binding site was not observed. Nevertheless, phosphorylation of cAMP response element-binding protein was increased by antidepressants in the prefrontal cortex concomitantly with trkB phosphorylation and this response was reduced in trkB.T1-overexpressing mice. Our data suggest that antidepressants acutely increase trkB signaling in a BDNF-dependent manner in cerebral cortex and that this signaling is required for the behavioral effects typical of antidepressant drugs. Neurotrophin signaling increased by antidepressants may induce formation and stabilization of synaptic connectivity, which gradually leads to the clinical antidepressive effects and mood recovery." [Abstract]

Bayer TA, Schramm M, Feldmann N, Knable MB, Falkai P.
Antidepressant drug exposure is associated with mRNA levels of tyrosine receptor kinase B in major depressive disorder.
Prog Neuropsychopharmacol Biol Psychiatry. 2000 Aug;24(6):881-8.
"1. Recent studies have provided support for the notion that the high affinity neurotrophin receptor tyrosine receptor kinase B (trk B) may be involved in the treatment of depression. 2. Using a quantitative RT-PCR approach trk B mRNA levels were determined in brain material from cerebellum, temporal cortex, and frontal cortex of control specimen and patients with major depressive disorder, schizophrenia and bipolar disorder (15 subjects each). 3. Interestingly, elevated trk B mRNA levels were found in cerebellum (3.6-fold) in patients with major depressive disorder, reaching statistical significance (p=0.03). 4. The major depressive disorder-on drugs group differed from controls (p=0.006) in the cerebellum. 5. Since only patients with major depressive disorder received antidepressants, elevated trk B mRNA levels are possibly related to drug treatment." [Abstract]

Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS.
Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression.
J Neurosci. 2002 Apr 15;22(8):3251-61.
"Previous studies demonstrated that antidepressant treatment increases the expression of brain-derived neurotrophic factor (BDNF) in rat hippocampus. The present study was conducted to test the hypothesis that BDNF in the hippocampus produces an antidepressant effect in behavioral models of depression, the learned helplessness (LH) and forced swim test (FST) paradigms. A single bilateral infusion of BDNF into the dentate gyrus of hippocampus produced an antidepressant effect in both the LH and FST that was comparable in magnitude with repeated systemic administration of a chemical antidepressant. These effects were observed as early as 3 d after a single infusion of BDNF and lasted for at least 10 d. Similar effects were observed with neurotrophin-3 (NT-3) but not nerve growth factor. Infusions of BDNF and NT-3 did not influence locomotor activity or passive avoidance. The results provide further support for the hypothesis that BDNF contributes to the therapeutic action of antidepressant treatment." [Full Text]

Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM.
Antidepressant-like effect of brain-derived neurotrophic factor (BDNF).
Pharmacol Biochem Behav. 1997 Jan;56(1):131-7. [Abstract]

Mague SD, Pliakas AM, Todtenkopf MS, Tomasiewicz HC, Zhang Y, Stevens WC Jr, Jones RM, Portoghese PS, Carlezon WA Jr.
Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats.
J Pharmacol Exp Ther. 2003 Apr;305(1):323-30.
"We showed previously that cAMP response element-binding protein (CREB) within the nucleus accumbens (NAc) of rats regulates immobility in the forced swim test (FST), an assay used to study depression. Because CREB regulates expression of dynorphin (which acts at kappa-opioid receptors) in NAc neurons, these findings raised the possibility that kappa-receptors mediate immobility behaviors in the FST. Here, we report that i.c.v. administration of the kappa-antagonist nor-binaltorphimine dose dependently decreased immobility in the FST, suggesting that it has antidepressant-like effects. Implicating a specific effect at kappa-receptors, similar antidepressant-like effects were seen after treatment with either of two novel, structurally dissimilar kappa-antagonists: 5'-guanidinonaltrindole, which was effective after i.c.v. but not systemic treatment, and 5'-acetamidinoethylnaltrindole (ANTI), which was potent and effective after systemic treatment. The behavioral effects of the kappa-antagonists resembled those of tricyclic antidepressants (desipramine) and selective serotonin reuptake inhibitors (fluoxetine and citalopram). Conversely, systemic administration of the kappa-agonist [5alpha,7alpha,8beta]-N-methyl-N-[7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec8-yl]-benzenacetamide (U-69593) dose dependently increased immobility in the FST, consistent with prodepressant-like effects. The effects of the kappa-ligands in the FST were not correlated with nonspecific effects on locomotor activity. Furthermore, the most potent and effective kappa-antagonist (ANTI) did not affect the rewarding impact of lateral hypothalamic brain stimulation at a dose with strong antidepressant-like effects. These findings are consistent with the hypothesis that CREB-mediated induction of dynorphin in the NAc "triggers" immobility behavior in the FST. Furthermore, they raise the possibility that kappa-antagonists may have efficacy as antidepressants, but lack stimulant or reward-related effects." [Abstract]

Newton SS, Thome J, Wallace TL, Shirayama Y, Schlesinger L, Sakai N, Chen J, Neve R, Nestler EJ, Duman RS.
Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect.
J Neurosci. 2002 Dec 15;22(24):10883-90.
"The cAMP response element-binding protein (CREB) is a critical integrator of neural plasticity that is responsive in a brain region-specific manner to a variety of environmental and pharmacological stimuli, including widely prescribed antidepressant medications. We developed inducible transgenic lines of mice that express either CREB or a dominant-negative mutant of CREB (mCREB) in forebrain regions and used these mice to determine the functional significance of this transcription factor in the learned helplessness paradigm, a behavioral model of depression. We also use a complementary viral-mediated gene transfer approach to directly test the effect of mCREB in the nucleus accumbens, a brain region important for motivation and reward. The results demonstrate that blockade of CREB by overexpression of mCREB in transgenic mice or by viral expression of mCREB in the nucleus accumbens produces an antidepressant-like effect, whereas overexpression of CREB in transgenic mice results in the opposite phenotype. In addition, mCREB expression was colocalized with and decreased the expression of prodynorphin in nucleus accumbens medium spiny neurons, and antagonism of dynorphin in the nucleus accumbens was sufficient to produce an antidepressant-like effect similar to that observed after blockade of CREB. Together, the results demonstrate that nucleus accumbens CREB-dynorphin influence behavior in the learned helplessness model and suggest that this signaling cascade may contribute to symptoms of depression." [Abstract]

Michel Barrot, Jocelien D. A. Olivier, Linda I. Perrotti, Ralph J. DiLeone, Olivier Berton, Amelia J. Eisch, Soren Impey, Daniel R. Storm, Rachael L. Neve, Jerry C. Yin, Venetia Zachariou, and Eric J. Nestler
CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli
PNAS 99: 11435-11440; published online before print as 10.1073/pnas.172091899
"The transcription factor cAMP response element (CRE)-binding protein (CREB) has been shown to regulate neural plasticity. Drugs of abuse activate CREB in the nucleus accumbens, an important part of the brain's reward pathways, and local manipulations of CREB activity have been shown to affect cocaine reward, suggesting an active role of CREB in adaptive processes that follow exposure to drugs of abuse. Using CRE-LacZ reporter mice, we show that not only rewarding stimuli such as morphine, but also aversive stimuli such as stress, activate CRE-mediated transcription in the nucleus accumbens shell. Using viral-mediated gene transfer to locally alter the activity of CREB, we show that this manipulation affects morphine reward, as well as the preference for sucrose, a more natural reward. We then show that local changes in CREB activity induce a more general syndrome, by altering reactions to anxiogenic, aversive, and nociceptive stimuli as well. Increased CREB activity in the nucleus accumbens shell decreases an animal's responses to each of these stimuli, whereas decreased CREB activity induces an opposite phenotype. These results show that environmental stimuli regulate CRE-mediated transcription within the nucleus accumbens shell, and that changes in CREB activity within this brain area subsequently alter gating between emotional stimuli and their behavioral responses. This control appears to be independent of the intrinsic appetitive or aversive value of the stimulus. The potential relevance of these data to addiction and mood disorders is discussed." [Full Text]

Koch JM, Kell S, Aldenhoff JB.
Differential effects of fluoxetine and imipramine on the phosphorylation of the transcription factor CREB and cell-viability.
J Psychiatr Res. 2003 Jan-Feb;37(1):53-9.
"It has been shown that antidepressants increase the expression of CREB (cAMP-response-element-binding-protein) and BDNF (brain derived neurotrophic factor) in vivo. Apparently inconsistent to these survival-promoting properties for many years antidepressants are known to induce apoptosis in various cell types in vitro. In the present study we evaluated if the antidepressants imipramine and fluoxetine are capable to influence the translational expression and phosphorylation of CREB (pCREB) in cells known to be apoptosis-inducible by antidepressants. We therefore used jurkat cells and quantified apoptosis via propidiumiodid-staining and FACS-analysis. CREB-expression and -phosphorylation was quantified via western blot. Both antidepressants induced apoptosis within 24 h. Fluoxetin starts to induce significant apoptosis at a concentration of 20 microM, whereas imipramine at 100 microM. At these concentrations both antidepressants also increased the phosphorylation of CREB within 6 h. But even in concentrations to low to induce apoptosis both antidepressants still increased CREB-phosphorylation. Treating cells with lowest concentrations only imipramine revealed an increase of CREB-phosphorylation after long-time treatment over 3 weeks. In all experiments overall CREB-expression remained unchanged. In conclusion our experiments indicate that antidepressants are capable to increase CREB-phosphorylation without induction of apoptosis depending on concentration and duration of treatment. We further assume that antidepressants induce CREB-phosphorylation via signal transduction pathways that are different from those inducing apoptosis." [Abstract]

Manier DH, Shelton RC, Sulser F.
Noradrenergic antidepressants: does chronic treatment increase or decrease nuclear CREB-P?
J Neural Transm. 2002;109(1):91-9.
"Chronic administration of noradrenergic antidepressants causes a desensitization of the beta adrenoceptor coupled adenylate cyclase system. In the present studies, we attempted to answer the question of whether or not this deamplification is reflected beyond the second messenger system. Nuclear CREB-P was determined in frontal cortex of rats following acute and chronic administration of desipramine (DMI) or reboxetine and in human fibroblasts following incubation for 48 hours with DMI, reboxetine or venlafaxine. Nuclear CREB-P in the frontal cortex was significantly decreased following chronic administration of DMI or reboxetine. Moreover, incubation of human fibroblasts with DMI or reboxetine, but not with venlafaxine, caused a highly significant reduction in nuclear CREB-P suggesting that the noradrenergic antidepressants exert direct effects beyond beta adrenoceptors. The results are consistent with the view that chronic treatment with antidepressants causes a net deamplification of the norepinephrine mediated signal transduction cascade which might "normalize" the increased noradrenergic activity evident in major depression." [Abstract]

Garcia C, Chen MJ, Garza AA, Cotman CW, Russo-Neustadt A.
The influence of specific noradrenergic and serotonergic lesions on the expression of hippocampal brain-derived neurotrophic factor transcripts following voluntary physical activity.
Neuroscience. 2003;119(3):721-32.
"Previous studies have shown that hippocampal brain-derived neurotrophic factor (BDNF) mRNA levels are significantly increased in rats allowed free access to exercise wheels and/or administered antidepressant medications. Enhancement of BDNF may be crucial for the clinical effect of antidepressant interventions. Since increased function of the noradrenergic and/or serotonergic systems is thought to be an important initial mechanism of antidepressant medications, we sought to test the hypothesis that noradrenergic or serotonergic function is essential for the increased BDNF transcription occurring with exercise. In addition, individual transcript variants of BDNF were examined, as evidence exists they are differentially regulated by discrete interventions, and are expressed in distinct sub-regions of the hippocampus. The neurotransmitter system-specific neurotoxins p-chloroamphetamine (serotonergic) and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (noradrenergic) were administered to rats prior to commencing voluntary wheel-running activity. In situ hybridization experiments revealed an absence of exercise-induced full-length BDNF mRNA elevations in the hippocampi of noradrenergic-lesioned rats. In addition, the striking elevation of the exon I transcript in the dentate gyrus was removed with this noradrenergic lesion. In contrast, other transcript variants (exons II and III) were elevated in several hippocampal regions as a result of this lesion. In serotonin-lesioned rats, the significant increases in full-length BDNF, exon I and exon II mRNA levels were sustained without alteration (with the exception of exon IV in the cornus ammonis subregion 4, CA4). Overall, these results indicate that an intact noradrenergic system may be crucial for the observed ability of exercise to enhance full-length and exon I hippocampal BDNF mRNA expression. In addition, these results suggest that the promoter linked to exon I may provide a major regulatory point for BDNF mRNA expression in the dentate gyrus. Elevations of other exons, such as II and III, may require the activation of separate neurotransmitter systems and intracellular pathways." [Abstract]

Mattson MP, Maudsley S, Martin B.
BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders.
Trends Neurosci. 2004 Oct;27(10):589-94.
Brain-derived neurotrophic factor (BDNF) and serotonin (5-hydroxytryptamine, 5-HT) are known to regulate synaptic plasticity, neurogenesis and neuronal survival in the adult brain. These two signals co-regulate one another such that 5-HT stimulates the expression of BDNF, and BDNF enhances the growth and survival of 5-HT neurons. Impaired 5-HT and BDNF signaling is central to depression and anxiety disorders, but could also play important roles in the pathogenesis of several age-related disorders, including insulin resistance syndrome, Alzheimer's disease and Huntington's disease. Enhancement of BDNF signaling may be a key mechanism whereby cognitive stimulation, exercise, dietary restriction and antidepressant drugs preserve brain function during aging. Behavioral and pharmacological manipulations that enhance 5-HT and BDNF signaling could help promote healthy brain aging. [Abstract]

Ivy AS, Rodriguez FG, Garcia C, Chen MJ, Russo-Neustadt AA.
Noradrenergic and serotonergic blockade inhibits BDNF mRNA activation following exercise and antidepressant.
Pharmacol Biochem Behav. 2003 Apr;75(1):81-8.
"Antidepressants and physical exercise have been shown to increase the transcription of hippocampal brain-derived neurotrophic factor (BDNF). Much evidence regarding the initial actions of antidepressant medications as well as exercise leads to the hypothesis that noradrenergic (NE) and/or serotonergic (5-HT) activation is a key element in the BDNF transcriptional elevation common to both interventions. Currently, we used short-term beta-adrenergic, 5-HT(1A), or 5-HT(2A/C) receptor blockade to characterize the influence of NE and 5-HT systems on BDNF transcription during physical exercise and antidepressant treatment. In situ hybridization revealed that beta-adrenergic blockade significantly blunted the BDNF mRNA elevations due to exercise, and also inhibited the modest elevations in the CA3 and dentate gyrus following short-term treatment with tranylcypromine. In contrast, 5-HT(2A/C) blockade only minimally altered exercise-induced BDNF mRNA levels, but inhibited up-regulation of BDNF transcription via tranylcypromine. Finally, 5-HT(1A) blockade did not inhibit exercise-induced BDNF mRNA elevations, but significantly enhanced levels above those achieved with exercise alone in the CA4. These results suggest that NE activation via beta-adrenergic receptors may be essential for both exercise and antidepressant-induced BDNF regulation. 5-HT(1A) and 5-HT(2A/C) activation, on the other hand, appear to be most important for antidepressant-induced BDNF regulation, but may also participate significantly in exercise-induced regulation in the CA4." [Abstract]

Angelucci F, Aloe L, Vasquez PJ, Mathe AA.
Mapping the differences in the brain concentration of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in an animal model of depression.
Neuroreport. 2000 Apr 27;11(6):1369-73.
"Antidepressant drugs as well as electroconvulsive stimuli can significantly influence brain concentrations of neurotrophic factors. However, it is not known whether the baseline brain concentrations of neurotrophic factors are altered in human subjects suffering from affective disorders or whether there are sex differences in concentrations of neurotrophins in human brain. In order to elucidate some of these questions, we measured by ELISA brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in an animal model of depression, the Flinders Sensitive Line (FSL) rats and their controls, the Flinders Resistant Line (FRL). Altered BDNF and NGF concentrations were found in frontal cortex, occipital cortex, and hypothalamus of depressed FSL compared to FRL control rats. Furthermore, different levels of these neurotrophins were also found in the male and female brain. Cumulatively these observations suggest that BDNF and NGF may play a role in depression and, hypothetically, different brain regional concentrations of BDNF and NGF in male and female animals may be relevant to gender differences in vulnerability to depression." [Abstract]

Takebayashi M, Hayashi T, Su TP.
Nerve growth factor-induced neurite sprouting in PC12 cells involves sigma-1 receptors: implications for antidepressants.
J Pharmacol Exp Ther. 2002 Dec;303(3):1227-37.
"One theory concerning the action of antidepressants relates to the drugs' ability to induce an adaptive plasticity in neurons such as neurite sprouting. Certain antidepressants are known to bind to sigma-1 receptors (Sig-1R) with high affinity. Sig-1R are dynamic endoplasmic reticulum proteins that are highly concentrated at the tip of growth cones in cultured cells. We therefore tested the hypotheses that Sig-1R might participate in the neurite sprouting and that antidepressants with Sig-1R affinity may promote the neuronal sprouting via Sig-1R. The prototypic Sig-1R agonist (+)-pentazocine [(+)PTZ], as well as the Sig-1R-active antidepressants imipramine and fluvoxamine, although ineffective by themselves, were found to enhance the nerve growth factor (NGF)-induced neurite sprouting in PC12 cells in a dose-dependent manner. A Sig-1R antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE100) blocked the enhancements caused by these Sig-1R agonists. In separate experiments, we found that NGF dose and time dependently increased Sig-1R in PC12 cells. Chronic treatment of cells with (+)PTZ, imipramine, or fluvoxamine also increased Sig-1R. These latter results suggested that NGF induces the neurite sprouting by increasing Sig-1R. Indeed, the overexpression of Sig-1R per se in PC12 cells enhanced the NGF-induced neurite sprouting. Furthermore, antisense deoxyoligonucleotides directed against Sig-1R attenuated the NGF-induced neurite sprouting. Thus, when taken together, our results indicate that Sig-1R play an important role in the NGF-induced neurite sprouting and that certain antidepressants may facilitate neuronal sprouting in the brain via Sig-1R." [Abstract]

Manier DH, Shelton RC, Sulser F.
Cross-talk between PKA and PKC in human fibroblasts: what are the pharmacotherapeutic implications?
J Affect Disord. 2001 Aug;65(3):275-9.
"BACKGROUND: The present study was designed to confirm or refute in human fibroblasts the hypothesized cross-talk elicited via neurotransmitter transduction cascades at the level of protein kinase mediated phosphorylation of the nuclear transcription factor CREB. METHODS: Human fibroblasts from normal control subjects were subcultured and incubated at confluency after five growth passages with isoproterenol (stimulation of PKA mediated phosphorylation) and/or phorbol 12-myristate 13-acetate (PMA) (stimulation of PKC mediated phosphorylation) followed by the determination of nuclear CREB-P by immunoblotting, enhanced chemiluminescence and quantitation of the autoradiograms by laser densitometry. RESULTS: Using the nuclear transcription factor CREB as a target, both the activation of the cyclic AMP-PKA pathway by isoproterenol and the activation of the PKC pathway by PMA caused phosphorylation of nuclear CREB. This phosphorylation is additive in nature and appears to occur at the same molecular site, serine133 of CREB. CONCLUSIONS: The present results in human fibroblasts demonstrate that the hypothesized cross-talk at the level of protein kinase mediated phosphorylation of transcription factors is no longer hypothetical. Since it is the phosphorylation of nuclear CREB that determines its dimerization and transcriptional activation of programs of CRE containing genes, the results suggest that this convergence of the neurotransmitter signals may be the critical mechanism in gene expression following the administration of antidepressant drugs that affect noradrenergic, serotonergic or both transduction cascades. The results may also provide a rationale for the apparent superior clinical efficacy of dual uptake inhibitors." [Abstract]

Nakagawa S, Kim JE, Lee R, Chen J, Fujioka T, Malberg J, Tsuji S, Duman RS.
Localization of phosphorylated cAMP response element-binding protein in immature neurons of adult hippocampus.
J Neurosci. 2002 Nov 15;22(22):9868-76.
"Neurogenesis continues to occur in the adult hippocampus, although many of the newborn cells degenerate 1-2 weeks after birth. The number and survival of newborn cells are regulated by a variety of environmental stimuli, but very little is known about the intracellular signal transduction pathways that control adult neurogenesis. In the present study, we examine the expression of the phosphorylated cAMP response element-binding protein (pCREB) in immature neurons in adult hippocampus and the role of the cAMP cascade in the survival of new neurons. The results demonstrate that virtually all immature neurons, identified by triple immunohistochemistry for bromodeoxyuridine (BrdU) and polysialic acid-neural cell adhesion molecule (PSA-NCAM), are also positive for pCREB. In addition, upregulation of cAMP (via pharmacological inhibition of cAMP breakdown or by antidepressant treatment) increases the survival of BrdU-positive cells. A possible role for pCREB in the regulation of PSA-NCAM, a marker of immature neurons involved in neuronal remodeling and neurite outgrowth, is supported by cell culture studies demonstrating that the cAMP-CREB pathway regulates the expression of a rate-limiting enzyme responsible for the synthesis of PSA-NCAM. These findings indicate that the cAMP-CREB pathway regulates the survival, and possibly the differentiation and function, of newborn neurons." [Abstract]