5-Hydroxytryptamine2A (5-HT2A) receptor regulation in rat prefrontal cortex: interaction of a phenethylamine hallucinogen and the metabotropic glutamate2/3 receptor agonist LY354740.
5-Hydroxytryptamine2A (5-HT2A) receptor regulation is atypical compared to most other monoaminergic receptors in that chronic administration of both antagonists and agonists results in down-regulation of cortical 5-HT2A receptor number and the functional in vitro and in vivo effects. We have recently found that midline thalamic lesions, which appeared to block glutamate release induced by activation of 5-HT2A receptors, also increased 5-HT2A receptor binding in layers I and Va of the medial prefrontal cortex (mPFC). These layers contain the highest density of both 5-HT2A receptors and thalamocortical terminals from the midline and intralaminar thalamic nuclei. These findings suggest the hypothesis that excitatory amino acid release plays a role in regulation of postsynaptic 5-HT2A receptors, and that down-regulation of 5-HT2A receptors by 5-HT2A agonists may not be attributed only to simple occupancy of the receptor by direct agonists. Therefore, we examined the effect of a single 30 min pretreatment with the metabotropic glutamate2/3 (mGlu2/3) receptor agonist (1S,2S,5R,6S)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylate monohydrate (LY354740; 10 mg/kg, i.p.) on the second of three consecutive days of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) treatment (1.25 mg/kg, i.p.). The subchronic DOI administration significantly decreased binding of [125I]DOI to 5-HT2A receptors in layers I and Va of the mPFC by approximately 25%. In contrast, a single dose of LY354740 on Day 2 of this regimen completely blocked the DOI-induced down-regulation. Thus, a presumed hypoglutamatergic state secondary to thalamic lesions and increased glutamate release induced by a subchronic regimen of a 5-HT2A agonist (and hallucinogenic drug) differentially regulate prefrontal cortical 5-HT2A receptor binding.
Marek
Gerard J
GJ
Yale School of Medicine, Department of Psychiatry, New Haven, CT 06508, USA. Gerard_J_Marek@lilly.com
Wright
Rebecca A
RA
Schoepp
Darryle D
DD
D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D004347:Drug Interactions; D006213:Hallucinogens / Q000494:pharmacology*; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D011985:Receptors, Serotonin / Q000378:metabolism*
D000662:Amphetamines; D001643:Bridged Bicyclo Compounds; D006213:Hallucinogens; D018094:Receptors, Metabotropic Glutamate; D011985:Receptors, Serotonin; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C078730:serotonin 5 receptor; C104753:eglumetad; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine