ADHD and beta-Phenylethylamine -- Neurotransmitter.net

Baker GB, Bornstein RA, Rouget AC, Ashton SE, van Muyden JC, Coutts RT.
Phenylethylaminergic mechanisms in attention-deficit disorder.
Biol Psychiatry 1991 Jan 1;29(1):15-22
"Urinary excretion (24-hr) of beta-phenylethylamine (PEA), phenylacetic acid (PAA), phenylalanine (Phe), and p-tyrosine (Tyr), and plasma levels of PAA, Phe, and Tyr were examined in 18 normal children and 26 children diagnosed as having attention-deficit hyperactivity disorder (ADHD). The results indicated that urinary excretion (expressed per g of creatinine) of free and total PEA was significantly lower in the ADHD patients, and plasma levels of Phe and Tyr were also decreased in the ADHD subjects compared with the normal controls." [Abstract]

Matsuishi T, Yamashita Y.
[Neurochemical and neurotransmitter studies in patients with learning disabilities]
No To Hattatsu 1999 May;31(3):245-8
"To clarify the pathophysiology of learning disability (LD), we measured the urinary levels of 3-methoxy-4-hydroxyphenyl glycol (MHPG), and phenylethylamine (PEA) in urine samples collected in a 24 hour period. Findings were compared with those obtained in age-matched controls and diseased controls including patients with attention deficit-hyperactivity disorder (ADHD), infantile autism, and mental retardation. The mean urinary level of MHPG in LD (n = 6) were not significantly different from those in ADHD (n = 16), mental retardation (n = 4), infantile autism (n = 5), and the controls (n = 6), while the mean urinary levels of PEA were significantly lower in LD (n = 6, 91 +/- 17.3 micrograms/mg) and in ADHD (n = 5, 65 +/- 53.6 micrograms/mg) as compared to age-matched controls (n = 3, 340 +/- 264.5 micrograms/mg) ANOVA, (p < 0.05). PEA is considered to play an important role for the pathogenesis of LD and ADHD." [Abstract]

Kusaga A.
[Decreased beta-phenylethylamine in urine of children with attention deficit hyperactivity disorder and autistic disorder]
No To Hattatsu 2002 May;34(3):243-8
"beta-phenylethylamine (PEA), a biogenic trace amine, acts as a neuromodulator in the nigrostriatal dopaminergic pathway and stimulates the release of dopamine. To clarify the mechanism of neurochemical metabolism in attention deficit hyperactivity disorder (ADHD), we measured the urine levels of PEA using gas chromatography-chemical ionization-mass spectrometry. The urinary levels of 3-methoxy-4-hydroxyphenyl glycol (MHPG), homovanillic acid (HVA), and 5-hydroxy-indoleacetic acid (5-HIAA) were determined by high performance liquid chromatography. Urine samples were collected in a 24 hour period. Findings were compared with those obtained from controls (N = 15), children with ADHD (N = 15), and children with autistic disorder (AD) (N = 5). The mean urinary levels of MHPG, HVA, and 5-HIAA in the children with ADHD were not significantly different from those of the controls or those with AD, whereas PEA levels were significantly lower in children with ADHD (11.23 +/- 13.40 micrograms/g creatinine) compared with controls (56.01 +/- 52.18 micrograms/g creatinine)." [Abstract]

Zametkin AJ, Karoum F, Linnoila M, Rapoport JL, Brown GL, Chuang LW, Wyatt RJ.
Stimulants, urinary catecholamines, and indoleamines in hyperactivity. A comparison of methylphenidate and dextroamphetamine.
Arch Gen Psychiatry 1985 Mar;42(3):251-5
"Children with attention deficit disorder with hyperactivity were given either methylphenidate hydrochloride or dextroamphetamine sulfate to compare the effects on urinary excretion of catecholamines, indoleamines, and phenylethylamine (PEA). Methylphenidate's effects were distinctly different from those of dextroamphetamine. After methylphenidate administration, both norepinephrine (NE) and normetanephrine (NMN) concentrations were significantly elevated, and there was a 22% increase in excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG). In contrast, after dextroamphetamine treatment, MHPG excretion was significantly reduced and NE and NMN values were unchanged. Excretion of dopamine and metabolites was unchanged by either drug. Urinary PEA excretion was not significantly changed after methylphenidate treatment, but increased 1,600% in response to dextroamphetamine. Methylphenidate treatment did not significantly alter serotonin or 5-hydroxyindoleacetic acid excretion. Effects of dextroamphetamine were not tested." [Abstract]

Kusaga A, Yamashita Y, Koeda T, Hiratani M, Kaneko M, Yamada S, Matsuishi T.
Increased urine phenylethylamine after methylphenidate treatment in children with ADHD.
Ann Neurol 2002 Sep;52(3):372-4
"The urine levels of beta-phenylethylamine, 3-methoxy-4-hydroxyphenyl glycol, homovanillic acid, and 5-hydroxyindoleacetic acid were measured to clarify the neurochemical mechanism in attention deficit hyperactivity disorder. beta-Phenylethylamine levels were significantly lower in attention deficit hyperactivity disorder individuals (n = 37) than in controls (n = 21). The 22 children with attention deficit hyperactivity disorder were treated with methylphenidate, and they were further divided into methylphenidate responders (n = 18) and nonresponders (n = 4). beta-Phenylethylamine levels significantly increased after methylphenidate therapy in responders, whereas they did not increase in nonresponders." [Abstract]

Niddam R, Arbilla S, Baud P, Langer SZ.
[3H] beta-phenylethylamine but not [3H](+)-amphetamine is released by electrical stimulation from perfused rat striatal slices.
Eur J Pharmacol 1985 Mar 26;110(1):121-4
"Perfused rat striatal slices were prelabelled with either [3H](+)-amphetamine or [3H] beta-phenylethylamine. Electrical stimulation released a significant amount of radioactivity only from the slices prelabelled with [3H] beta-phenylethylamine. The electrically evoked release of radioactivity from slices labelled with [3H] beta-phenylethylamine was entirely calcium-dependent and was abolished after pretreatment with reserpine (5 mg/kg s.c., 24 h). In addition, S-sulpiride (1 microM), which facilitates the electrically evoked release of radioactivity from slices labelled with [3H]DA by blocking dopamine autoreceptors, also induced an increase of the radioactivity released by electrical stimulation from slices labelled with [3H] beta-phenylethylamine. Our results indicate that, in spite of the structural similarities between AMPH and PEA, only the latter which is the naturally occurring analog of AMPH can be released by electrical stimulation in a calcium-dependent manner." [Abstract]
Zhu MY, Juorio AV, Paterson IA, Boulton AA.
Regulation of aromatic L-amino acid decarboxylase by dopamine receptors in the rat brain.
J Neurochem 1992 Feb;58(2):636-41
"Decarboxylation of phenylalanine by aromatic L-amino acid decarboxylase (AADC) is the rate-limiting step in the synthesis of 2-phenylethylamine (PE), a putative modulator of dopamine transmission. Because neuroleptics increase the rate of accumulation of striatal PE, these studies were performed to determine whether this effect may be mediated by a change in AADC activity. Administration of the D1 antagonist SCH 23390 at doses of 0.01-1 mg/kg significantly increased rat striatal AADC activity in an in vitro assay (by 16-33%). Pimozide, a D2-receptor antagonist, when given at doses of 0.01-3 mg/kg, also increased AADC activity in the rat striatum (by 25-41%). In addition, pimozide at doses of 0.3 and 1 mg/kg increased AADC activity in the nucleus accumbens (by 33% and 45%) and at doses of 0.1, 0.3, and 1 mg/kg increased AADC activity in the olfactory tubercles (by 23%, 30%, and 28%, respectively). Analysis of the enzyme kinetics indicated that the Vmax increased with little change in the Km with L-3,4-dihydroxyphenylalanine as substrate. The AADC activity in the striatum showed a time-dependent response after the administration of SCH 23390 and pimozide: the activity was increased within 30 min and the increases lasted 2-4 h. Inhibition of protein synthesis by cycloheximide (10 mg/kg, 0.5 h) had no effect on the striatal AADC activity or on the increases in striatal AADC activity produced by pimozide or SCH 23390. The results indicate that the increases in AADC activity induced by dopamine-receptor blockers are not due to de novo synthesis of the enzyme." [Abstract]
Cho S, Neff NH, Hadjiconstantinou M.
Regulation of tyrosine hydroxylase and aromatic L-amino acid decarboxylase by dopaminergic drugs.
Eur J Pharmacol 1997 Apr 4;323(2-3):149-57
"We provide evidence that dopamine receptors differentially modulate tyrosine hydroxylase and aromatic L-amino acid decarboxylase in the mouse striatum. The dopamine D1 receptor family (D1-like) antagonist, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benazepine (SCH 23390), elevated aromatic L-amino acid decarboxylase activity and protein content in striatum, as well as the mRNA for the enzyme in midbrain. The dopamine D1-like receptor agonist, (+/-)-1-phenyl-2,3,4,5-tetrahydro-(1 H)-3-benzazepine-7,8-diol (SKF 38393), had no effect on aromatic L-amino acid decarboxylase. The dopamine D1-like drugs had no effect on tyrosine hydroxylase. In contrast, the dopamine D2 receptor family (D2-like) antagonists haloperidol and spiperone elevated both tyrosine hydroxylase and aromatic L-amino acid decarboxylase activities. The increase in aromatic L-amino acid decarboxylase activity was accompanied by elevated enzyme protein content but not mRNA. The dopamine D2-like receptor agonists, bromocriptine, quinpirole and (+/-)-7-hydroxydipropylaminotetralin (7-OH-DPAT), all decreased striatal tyrosine hydroxylase. Under the conditions used, bromocriptine and 7-OH-DPAT, but not quinpirole, decreased aromatic L-amino acid decarboxylase activity of striatum. Both the dopamine D1- and D2-like receptor antagonists enhanced the turnover of striatal dopamine to differing degrees, as judged by the ratio of acid metabolites of dopamine to dopamine. Taken together our results indicate that aromatic L-amino acid decarboxylase can be modulated independently of tyrosine hydroxylase." [Abstract]

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Recent ADHD and beta-Phenylethylamine Research
1) Revel FG, Meyer CA, Bradaia A, Jeanneau K, Calcagno E, Andr� CB, Haenggi M, Miss MT, Galley G, Norcross RD, Invernizzi RW, Wettstein JG, Moreau JL, Hoener MC
Brain-Specific Overexpression of Trace Amine-Associated Receptor 1 Alters Monoaminergic Neurotransmission and Decreases Sensitivity to Amphetamine.
Neuropsychopharmacology. 2012 Jul 4;
Trace amines (TAs) such as ?-phenylethylamine, p-tyramine, or tryptamine are biogenic amines found in the brain at low concentrations that have been implicated in various neuropsychiatric disorders like schizophrenia, depression, or attention deficit hyperactivity disorder. TAs are ligands for the recently identified trace amine-associated receptor 1 (TAAR1), an important modulator of monoamine neurotransmission. Here, we sought to investigate the consequences of TAAR1 hypersignaling by generating a transgenic mouse line overexpressing Taar1 specifically in neurons. Taar1 transgenic mice did not show overt behavioral abnormalities under baseline conditions, despite augmented extracellular levels of dopamine and noradrenaline in the accumbens nucleus (Acb) and of serotonin in the medial prefrontal cortex. In vitro, this was correlated with an elevated spontaneous firing rate of monoaminergic neurons in the ventral tegmental area, dorsal raphe nucleus, and locus coeruleus as the result of ectopic TAAR1 expression. Furthermore, Taar1 transgenic mice were hyposensitive to the psychostimulant effects of amphetamine, as it produced only a weak locomotor activation and failed to alter catecholamine release in the Acb. Attenuating TAAR1 activity with the selective partial agonist RO5073012 restored the stimulating effects of amphetamine on locomotion. Overall, these data show that Taar1 brain overexpression causes hyposensitivity to amphetamine and alterations of monoaminergic neurotransmission. These observations confirm the modulatory role of TAAR1 on monoamine activity and suggest that in vivo the receptor is either constitutively active and/or tonically activated by ambient levels of endogenous agonist(s).Neuropsychopharmacology advance online publication, 4 July 2012; doi:10.1038/npp.2012.109. [PubMed Citation] [Order full text from Infotrieve]

2) Bortolato M, Shih JC
Behavioral outcomes of monoamine oxidase deficiency: preclinical and clinical evidence.
Int Rev Neurobiol. 2011;100:13-42.
Monoamine oxidase (MAO) isoenzymes A and B are mitochondrial-bound proteins, catalyzing the oxidative deamination of monoamine neurotransmitters as well as xenobiotic amines. Although they derive from a common ancestral progenitor gene, are located at X-chromosome and display 70% structural identity, their substrate preference, regional distribution, and physiological role are divergent. In fact, while MAO-A has high affinity for serotonin and norepinephrine, MAO-B primarily serves the catabolism of 2-phenylethylamine (PEA) and contributes to the degradation of other trace amines and dopamine. Convergent lines of preclinical and clinical evidence indicate that variations in MAO enzymatic activity--due to either genetic or environmental factors--can exert a profound influence on behavioral regulation and play a role in the pathophysiology of a large spectrum of mental and neurodegenerative disorders, ranging from antisocial personality disorder to Parkinson's disease. Over the past few years, numerous advances have been made in our understanding of the phenotypical variations associated with genetic polymorphisms and mutations of the genes encoding for both isoenzymes. In particular, novel findings on the phenotypes of MAO-deficient mice are highlighting novel potential implications of both isoenzymes in a broad spectrum of mental disorders, ranging from autism and anxiety to impulse-control disorders and ADHD. These studies will lay the foundation for future research on the neurobiological and neurochemical bases of these pathological conditions, as well as the role of gene � environment interactions in the vulnerability to several mental disorders. [PubMed Citation] [Order full text from Infotrieve]

3) Kitamura T, Munakata M, Haginoya K, Tsuchiya S, Iinuma K
Beta-phenylethylamine inhibits K+ currents in neocortical neurons of the rat: a possible mechanism of beta-phenylethylamine-induced seizures.
Tohoku J Exp Med. 2008 Aug;215(4):333-40.
beta-Phenylethylamine (beta-PEA), an endogenous amine synthesized in the brain, serves as a neuromodulator and is involved in the pathophysiology of various neurological disorders such as depression, schizophrenia, and attention-deficit hyperactivity disorder. beta-PEA fully exerts the physiological effects within the nanomolar concentration range via the trace amine receptors, but beta-PEA also causes convulsions at much higher concentrations via an as yet unknown mechanism. To investigate the electrophysiological mechanism by which beta-PEA induces convulsions, we examined the effect of beta-PEA on ionic currents passing through the cell membrane of dissociated rat cerebral cortical neurons, using a patch-clamp technique. The external application of beta-PEA suppressed ionic currents which continuously flowed when the membrane potential was held at -25 mV. The suppression was in a concentration-dependent manner and a half-maximal effective concentration was 540 muM. These currents suppressed by beta-PEA consisted of two K(+) currents: a time- and voltage-dependent K(+) current (M-current) and a leakage K(+) current. The suppression of the M-current reduces the efficacy of the current in limiting excessive neuronal firing, and the suppression of the leakage K(+) current can cause membrane depolarization and thus promote neuronal excitation. Reducing both of these currents in concert may produce neuronal seizing activity, which could conceivably underlie the convulsions induced by high-dose beta-PEA. [PubMed Citation] [Order full text from Infotrieve]

4) Bortolato M, Chen K, Shih JC
Monoamine oxidase inactivation: from pathophysiology to therapeutics.
Adv Drug Deliv Rev. 2008 Oct-Nov;60(13-14):1527-33.
Monoamine oxidases (MAOs) A and B are mitochondrial bound isoenzymes which catalyze the oxidative deamination of dietary amines and monoamine neurotransmitters, such as serotonin, norepinephrine, dopamine, beta-phenylethylamine and other trace amines. The rapid degradation of these molecules ensures the proper functioning of synaptic neurotransmission and is critically important for the regulation of emotional behaviors and other brain functions. The byproducts of MAO-mediated reactions include several chemical species with neurotoxic potential, such as hydrogen peroxide, ammonia and aldehydes. As a consequence, it is widely speculated that prolonged excessive activity of these enzymes may be conducive to mitochondrial damages and neurodegenerative disturbances. In keeping with these premises, the development of MAO inhibitors has led to important breakthroughs in the therapy of several neuropsychiatric disorders, ranging from mood disorders to Parkinson's disease. Furthermore, the characterization of MAO knockout (KO) mice has revealed that the inactivation of this enzyme produces a number of functional and behavioral alterations, some of which may be harnessed for therapeutic aims. In this article, we discuss the intriguing hypothesis that the attenuation of the oxidative stress induced by the inactivation of either MAO isoform may contribute to both antidepressant and antiparkinsonian actions of MAO inhibitors. This possibility further highlights MAO inactivation as a rich source of novel avenues in the treatment of mental disorders. [PubMed Citation] [Order full text from Infotrieve]

5) Berry MD
The potential of trace amines and their receptors for treating neurological and psychiatric diseases.
Rev Recent Clin Trials. 2007 Jan;2(1):3-19.
Mining of the human genome has revealed approximately 7000 novel proteins, which could serve as potential targets for the development of novel therapeutics. Of these, approximately 2000 are predicted to be G-protein coupled receptors. Within this group of proteins, a family of 18 mammalian receptors has recently been identified that appear to exhibit selectivity toward the so-called trace amines. The trace amines are a family of endogenous compounds with strong structural similarity to classical monoamine neurotransmitters, consisting primarily of 2-phenylethylamine, m- and p-tyramine, tryptamine, m- and p-octopamine and the synephrines. The endogenous levels of these compounds are at least two orders of magnitude below those of neurotransmitters such as dopamine, noradrenaline and 5-HT. The effects of these low physiological concentrations have been difficult to demonstrate but it has been suggested that they may serve to maintain the neuronal activity of monoamine neurotransmitters within defined physiological limits. Such an effect of trace amines would make them ideal candidates for the development of novel therapeutics for a wide range of human disorders. Although the demonstration of a trace amine family of receptors has seen a resurgence of interest in these endogenous compounds, with recent articles reviewing trace amine pharmacological and physiological responses, the potential clinical utility of the trace amine receptors has not been specifically addressed. Historically, trace amines have been implicated in a diverse array of human pathologies ranging from schizophrenia to affective disorders to migraine. Recent studies have strengthened some of this historical data by linking trace amine receptor polymorphisms and mutations to distinct clinical conditions. The aim of the current article is to review the previous studies linking trace amines to human pathology in the context of the recently discovered trace amine receptors and evidence of the existence of trace amine receptor polymorphisms and mutations associated with such disorders. In addition, recent evidence linking trace amines to the development of drug dependence will be discussed. [PubMed Citation] [Order full text from Infotrieve]

6) Marchei E, Mu�oz JA, Garc�a-Algar O, Pellegrini M, Vall O, Zuccaro P, Pichini S
Development and validation of a liquid chromatography-mass spectrometry assay for hair analysis of methylphenidate.
Forensic Sci Int. 2008 Mar 21;176(1):42-6.
Methylphenidate (MPH) is a phenethylamine derivative used in the treatment of childhood attention-deficit hyperactivity disorder. MPH is biotransformed in the body by the hydrolysis of the methyl ester linkage to its metabolite, ritalinic acid. Whereas both compounds are usually measured in plasma and urine, preliminary observations show that only the parent compound is present in hair from treated individuals. Since in children hair samples can be easily collected without the need for special skills and exposing a patient to discomfort, hair testing of MPH should be an alternative to check compliance in a wider time-window than if using blood. A procedure based on liquid chromatography-mass spectrometry (LC-MS) has been developed for the determination of MPH in hair of treated children. After addition of 3,4-methylenedioxypropylamphetamine as internal standard, hair samples were overnight digested with 0.1M HCl at 37 degrees C. Then, after pH adjustment to 6 using 1N NaOH, and 0.1M phosphate buffer, the analyte was extracted with Bond-Elut Certify columns. Chromatographic separation was achieved at ambient temperature using a reverse phase column and a mobile phase of 80% 10mM ammonium acetate-20% acetonitrile with a 20 min gradient program. The mass spectrometer was operated in positive electrospray ionization and selected ion monitoring acquisition mode. The method was validated in the range 0.15-50 ng MPH/mg hair, using 20mg hair per assay. At three concentrations spanning the linear dynamic range of the assay, mean recoveries ranged between 73.2 and 77.1%. First results show MPH hair concentration varying from 0.15 to 4.17 ng/mg hair, with decreasing drug concentration in distal hair segments, even in children treated with the same MPH dose during the period corresponding to different segments. This fact could be either attributed to sebum or sweat shunt with the most proximal hair segment or drug degradation by cosmetic treatments in more distal segments. [PubMed Citation] [Order full text from Infotrieve]

7) Federici M, Geracitano R, Tozzi A, Longone P, Di Angelantonio S, Bengtson CP, Bernardi G, Mercuri NB
Trace amines depress GABA B response in dopaminergic neurons by inhibiting G-betagamma-gated inwardly rectifying potassium channels.
Mol Pharmacol. 2005 Apr;67(4):1283-90.
Trace amines (TAs) are present in the central nervous system in which they up-regulate catecholamine release and are implicated in the pathogenesis of addiction, attention-deficit/hyper-activity disorder, Parkinson's disease, and schizophrenia. By using intracellular and patch-clamp recordings from dopaminergic cells in the rat midbrain slices, we report a depressant postsynaptic action of two TAs, beta-phenylethylamine (beta-PEA) and tyramine (TYR) on the GABA(B)-mediated slow inhibitory postsynaptic potential and baclofen-activated outward currents. beta-PEA and TYR activated G-proteins, interfering with the coupling between GABA(B) receptors and G-betagamma-gated inwardly rectifying potassium channels. This is the first demonstration that beta-PEA and TYR depress inhibitory synaptic potentials in neurons of the central nervous system, supporting their emerging role as neuromodulators. [PubMed Citation] [Order full text from Infotrieve]

8) Mangani G, Canestrari F, Berloni A, Maione M, Pagliarani S, Mangani F
Gas chromatographic--mass spectrometric determination of phenylacetic acid in human blood.
Ann Chim. 2004 Sep-Oct;94(9-10):715-9.
Phenyl acetic acid, a metabolite of 2-phenyl ethylamine, acts as a neuromodulator in the nigrostriatal dopaminergic pathway stimulating the release of dopamine. The evaluation of phenyl acetic acid concentration in the biological fluid reflects phenyl ethylamine levels thus allowing the assessment of the modulatory role of this endogenous substance. Changes in biological fluids levels of 2-phenylethylamine and/or in its metabolite have been reported in affective disorders, such as depression and schizophrenia. Recently, the occurrence of the "attention deficit hyperactivity syndrome" has been frequently reported in childhood population and involvement of dopaminergic dysfunction in this disease has been suspected. A fast, reliable and reproducible method for the determination of phenyl acetic acid in human blood, is therefore needed in order to have a screening tool for monitoring both healthy childhood population and suspected "attention deficit hyperactivity syndrome" patients. The gas chromatographic-mass spectrometric method here described makes use of a deuterated internal standard in order to overcome problems related to the lack of reproducibility often encountered when a derivatization step is performed. [PubMed Citation] [Order full text from Infotrieve]

9) Geracitano R, Federici M, Prisco S, Bernardi G, Mercuri NB
Inhibitory effects of trace amines on rat midbrain dopaminergic neurons.
Neuropharmacology. 2004 May;46(6):807-14.
Trace amines are biological compounds that are still awaiting identification of their role in neuronal function. Using intracellular electrophysiological recordings, we investigated the depressant action of two trace amines (beta-phenylethylamine and tyramine) on the firing activity of dopaminergic neurons of the substantia nigra pars compacta and ventral tegmental area. This inhibition was due to a membrane hyperpolarisation that was blocked by the D2 dopamine receptor antagonist sulpiride and was not potentiated by the dopamine-uptake blocker, cocaine. Inhibition of the dopamine transporter did not mediate the effects of trace amines, because unlike cocaine, trace amines did not potentiate the inhibitory responses to exogenously applied dopamine. The inhibitory actions of beta-phenylethylamine and tyramine were present in reserpine-treated animals but were abolished when the dopamine-synthesis inhibitor carbidopa was applied. Our data suggest that trace amines cause an indirect activation of dopamine autoreceptors, by an increased efflux of newly synthesised dopamine. The inhibition of dopaminergic activity by trace amines may relate to their involvement in neuronal processes linked to drug addiction, schizophrenia, attention deficit hyperactive disorders and Parkinson's disease. [PubMed Citation] [Order full text from Infotrieve]