Erdal ME, Herken H, Yilmaz M, Bayazit YA.
Association of the T102C polymorphism of 5-HT2A receptor gene with aura in migraine.
J Neurol Sci. 2001 Jul 15;188(1-2):99-101.
OBJECTIVE: To find out the significance of the 5-HT2A receptor gene polymorphism in migraine. Study design: A PCR study in which 61 migraineurs and 44 healthy controls were included. METHODS: The T102C polymorphism of the 5-HT2A receptor gene was studied. The results of the migraineurs and controls were compared. The relationship between the gene polymorphism and aura was also assessed. RESULTS: The representations of the 5-HT2A genotypes were similar in migraineurs and controls (p>0.05) as well as in the male and female migraineurs (p>0.05). The family history of migraine did not associate with 5-HT2A receptor gene polymorphism (p>0.05). There was a significant relationship between the presence of C/C genotype and migraine with aura (p=0.02) while C/T and T/T genotypes were over represented in the patients with migraine without aura (p<0.01). CONCLUSION: The T102C polymorphism of the 5-HT2A receptor gene is not directly related to the increased risk of migraine. The associations between the genotypes of this gene and aura may suggest that 5-HT2A receptor gene polymorphism may be involved in determining the subtypes of or accompanying symptoms in the migraine disease. [Abstract]

Regina MJ, Bucelli RC, Winter JC, Rabin RA.
Cellular mechanisms of serotonin 5-HT2A receptor-mediated cGMP formation: the essential role of glutamate.
Brain Res. 2004 Apr 2;1003(1-2):168-75.
The current study explores the mechanisms by which activation of serotonin(2A) (5-HT(2A)) receptors increase production of cyclic guanosine monophosphate (cGMP) in slices of rat frontal cortex. Contrary to results in cortical slices, stimulation of 5-HT(2A) receptors in cells stably expressing this serotonin receptor did not alter cGMP levels. In cortical slices, stimulation of cGMP formation by 2,5-dimethoxy-4-methylamphetamine (DOM), a 5-HT(2A/2C) receptor agonist, was blocked by tetanus toxin, a substance that prevents vesicular neurotransmitter release. However, this stimulation was not altered by tetrodotoxin, an agent that inhibits depolarization-induced neurotransmitter release. Addition of an N-methyl-d-aspartate (NMDA) receptor antagonist, d-AP-7, but not of an AMPA/kainate receptor antagonist CNQX, completely inhibited DOM-mediated cGMP production in the slices. Combined application of maximally effective concentrations of NMDA and DOM elicited a greater increase in cGMP content than either drug alone. The present study shows that 5-HT(2A) receptors do not directly stimulate cGMP formation, but rather that 5-HT(2A) receptor-mediated cGMP production is dependent on extracellular glutamate activating NMDA receptors. The results indicate that 5-HT(2A) receptor-mediated cGMP production could be at least partially attributed to potentiation of NMDA receptor-mediated cGMP formation. [Abstract]

Srikiatkhachorn A, Suwattanasophon C, Ruangpattanatawee U, Phansuwan-Pujito P.
2002 Wolff Award. 5 -HT2A receptor activation and nitric oxide synthesis: a possible mechanism determining migraine attacks.
Headache. 2002 Jul-Aug;42(7):566-74.
OBJECTIVE: To determine the effect of the 5-HT2A receptor in control of spinal nociception, cerebral circulation, and nitric oxide synthase (nNOS) expression in trigeminovascular neurons. BACKGROUND: The plasticity of the 5-HT2A receptor is a possible factor determining the course of migraine. Up-regulation of this receptor has been demonstrated to correlate with the increasing frequency of migraine attacks and may underlie the development of chronic daily headache. METHODS: Adult male Wistar rats were divided into groups receiving the 5-HT2A agonist, 1,2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), nitroglycerin, or normal saline. The tail flick test and chemical nociception-evoked Fos-expression in dorsal horn neurons were used as indicators of nociception. Regional cerebral blood flow was monitored using laser Doppler flowmetry. Expression of Fos and nNOS was studied using immunohistochemical method. RESULTS: Administration of DOI led to the shortening of tail flick latency (1.3 +/- 0.2 and 7.2 +/- 0.6 seconds for DOI-treated and control groups, respectively). The number of Fos-immunoreactive neurons was also greater in the DOI-treated group compared with the control group. DOI also produced long-lasting cerebral hyperemia (123% of baseline value) associated with the enlargement of perivascular nNOS-immunoreactive nerve fibers and increased nNOS-immunoreactive neurons in trigeminal ganglia and trigeminal nucleus caudalis. These findings resembled those observed in the rats exposed to nitroglycerin. CONCLUSION: Our results suggest that activation of the 5-HT2A receptor leads to an enhancement of NO production in trigeminovascular pathway. NO may trigger migraine attacks by inducing cerebral vasodilation and sensitizing the perivascular nociceptors and central nociceptive neurons in trigeminovascular system. Up-regulation of this pronociceptive receptor can increase headache attacks and contributes to the development of chronic daily headache. [Abstract]

Srikiatkhachorn A, Anthony M.
Serotonin receptor adaptation in patients with analgesic-induced headache.
Cephalalgia. 1996 Oct;16(6):419-22.
Analgesic abuse has recently been recognized as a cause of deterioration in primary headache patients. Although the pathogenesis of this headache transformation is still obscure, alteration of serotonin receptor function is one possible mechanism. To assess the plasticity of 5HT2 serotonin receptors in this condition, we investigated receptor binding by the platelet membrane in patients with analgesic-induced headache (AIH), migraine and non-headache controls. The technique involved radioligand binding with (phenyl-4-3H)spiperone and ketanserin. A greater density of receptor numbers (Bmax) was found in patients with AIH and in non-headache controls (96.47 +/- 10.21 and 92.01 +/- 13.15 fmol/mg protein), as compared to migraine patients (49.52 +/- 5.14 fmol/mg protein). The value of dissociation equilibrium constant (KD) remained unchanged (3.07 +/- 0.49, 2.24 +/- 0.24 and 2.91 +/- 0.42 nM for patients with AIH, migraine and non-headache controls, respectively). Based on these findings, we suggest that up-regulation of 5HT2 serotonin receptors may be a possible mechanism of headache transformation in patients with AIH. [Abstract]

Gold L, Back T, Arnold G, Dreier J, Einhaupl KM, Reuter U, Dirnagl U.
Cortical spreading depression-associated hyperemia in rats: involvement of serotonin.
Brain Res. 1998 Feb 9;783(2):188-93.
We investigated whether the vasoactive neurotransmitter serotonin (5-HT) is involved in cortical spreading depression (CSD)-associated hyperemia in the rat. We focused on the 5-HT2 receptor, which is engaged in 5-HT induced small arteriolar relaxation in cats, as well as on the 5-HT1D/1B receptor, the binding site of the potent antimigraine drug sumatriptan. In male barbiturate anaesthetized Wistar rats (n=25) CSDs were elicited by brain topical application of 1 M KCl, and the DC-potential and regional cerebral blood flow (rCBF, by Laser Doppler flowmetry) were measured over the same hemisphere through dura and thinned bone, respectively. Intravenous application of 8 mg/kg of the 5-HT2A/2C receptor antagonist ritanserin (group I; n=8) significantly reduced the hyperperfusion amplitude during CSD by approximately 44% (p<0.05, from 342+/-124 to 194+/-97%, baseline before CSD=100%), and prolonged its duration by approx. 30%. Vehicle alone (group II; n=4) did not affect CSD hyperperfusion. The highly selective 5-HT1D/1B receptor agonist 311C90 was given in two doses: 100 micrograms/kg i.v. (n=5) had no effect on CSD hyperperfusion, while 800 micrograms/kg (n=5) increased hyperperfusion significantly (p<0.05, from 224+/-86 to 310+/-148%). We conclude that serotonin is, probably via 5-HT2 receptors, involved in the modulation of the regional cerebral blood flow increase during CSD. Novel highly selective receptor antagonists may help to discriminate the differential contribution of various 5-HT receptor subspecies. [Abstract]

Nouchine Hadjikhani, Margarita Sanchez del Rio, Ona Wu, Denis Schwartz, Dick Bakker, Bruce Fischl, Kenneth K. Kwong, F. Michael Cutrer, Bruce R. Rosen, Roger B. H. Tootell, A. Gregory Sorensen, and Michael A. Moskowitz
Mechanisms of migraine aura revealed by functional MRI in human visual cortex
PNAS 98: 4687-4692; published online before print as 10.1073/pnas.071582498
"Cortical spreading depression (CSD) has been suggested to underlie migraine visual aura. However, it has been challenging to test this hypothesis in human cerebral cortex. Using high-field functional MRI with near-continuous recording during visual aura in three subjects, we observed blood oxygenation level-dependent (BOLD) signal changes that demonstrated at least eight characteristics of CSD, time-locked to percept/onset of the aura. Initially, a focal increase in BOLD signal (possibly reflecting vasodilation), developed within extrastriate cortex (area V3A). This BOLD change progressed contiguously and slowly (3.5 +/- 1.1 mm/min) over occipital cortex, congruent with the retinotopy of the visual percept. Following the same retinotopic progression, the BOLD signal then diminished (possibly reflecting vasoconstriction after the initial vasodilation), as did the BOLD response to visual activation. During periods with no visual stimulation, but while the subject was experiencing scintillations, BOLD signal followed the retinotopic progression of the visual percept. These data strongly suggest that an electrophysiological event such as CSD generates the aura in human visual cortex." [Full Text]

Lauritzen M.
Pathophysiology of the migraine aura. The spreading depression theory.
Brain. 1994 Feb;117 ( Pt 1):199-210.
"The characteristic form and development of sensory disturbances during migraine auras suggests that the underlying mechanism is a disturbance of the cerebral cortex, probably the cortical spreading depression (CSD) of Leao. The demonstration of unique changes of brain blood flow during attacks of migraine with aura, which have been replicated in animal experiments during CSD, constitutes another important line of support for the 'spreading depression' theory, which may be a key to an understanding of the migraine attack. Cortical spreading depression is a short-lasting depolarization wave that moves across the cortex at a rate of 3-5 mm/min. A brief phase of excitation heralds the reaction which is immediately followed by prolonged nerve cell depression synchronously with a dramatic failure of brain ion homeostasis, efflux of excitatory amino acids from nerve cells and enhanced energy metabolism. Recent experimental work has shown that CSD in the neocortex of a variety of species including man is dependent on activation of a single receptor, the N-methyl-D-aspartate receptor, one of the three subtypes of glutamate receptors. The combined experimental and clinical studies point to fruitful areas in which to look for migraine treatments of the future and provide a framework within which important aspects of the migraine attack can be modelled." [Abstract]

Gorji A, Scheller D, Straub H, Tegtmeier F, Kohling R, Hohling JM, Tuxhorn I, Ebner A, Wolf P, Werner Panneck H, Oppel F, Speckmann EJ.
Spreading depression in human neocortical slices.
Brain Res. 2001 Jul 6;906(1-2):74-83.
"Cortical spreading depression (CSD) occurrence has been suggested to be associated with seizures, migraine aura, head injury and brain ischemia-infarction. Only few studies identified CSD in human neocortical slices and no comprehensive study so far evaluated this phenomenon in human. Using the neocortical tissue excised for treatment of intractable epilepsy, we aimed to investigate CSD in human. CSD was induced by KCl injection and by modulating T-type Ca(2+) currents in incubated human neocortical tissues in an interphase mode. The DC-fluctuations were recorded by inserting microelectrodes into different cortical layers. Local injection of KCl triggered single CSD that propagated at 3.1+/-0.1 mm/min. Repetitive CSD also occurred spontaneously during long lasting application (5 h) of the T-type Ca(2+) channel blockers amiloride (50 microM) or NiCl(2) (10 microM) which was concomitant with a reversible extracellular potassium increase up to 50 mM. CSD could be blocked by the N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonovaleric acid in all cases. The results demonstrate that modulation of the Ca(2+) dynamics conditioned human neocortical slices and increased their susceptibility to generate CSD. Furthermore, these data indicate that glutamatergic pathway plays a role in CSD phenomenon in human." [Abstract]