Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex.
In prefrontal cortex, 5-hydroxytryptamine(2A) (5-HT(2A)) receptors have been linked to the action of hallucinogens and atypical antidepressant/antipsychotic drugs. Previously, we have shown in cortical layer V pyramidal cells that a nonselective metabotropic glutamate (mGlu) receptor agonist suppresses the induction of excitatory postsynaptic potentials/currents (EPSPs/EPSCs) via activation of 5-HT(2A) receptors. In this study, we tested the ability of the selective mGlu2/3 agonist (1S,2S,5R, 6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740) and the selective mGlu2/3 antagonist 2S-2-amino-2-(1S, 2S-2-carboxycycloprop-1-yl)-3(xanthy-9-yl)propanoic acid (LY341495) to modulate serotonin(5-HT)-induced EPSPs and electrically evoked EPSPs by using intracellular recording from layer V pyramidal cells in medial prefrontal cortex. The mGlu2/3 antagonist LY341495 increased the frequency and amplitude of 5-HT-induced EPSCs, suggesting a role for mGlu2/3 receptors in mediating the action of endogenous glutamate on autoreceptors. Conversely, the mGlu2/3 agonist LY354740 was highly effective and potent (EC(50) = 89 nM) in suppressing glutamate release induced by 5-HT(2A) receptor activation in the medial prefrontal cortex, probably via a presynaptic mechanism. The mGlu2/3 antagonist LY341495 potently blocked the suppressant effect of LY354740 on 5-HT-induced EPSCs as well as electrically evoked early EPSPs. Autoradiography with the radioligands [(3)H]LY354740 and [(125)I](+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane showsa striking overlap of the laminar distribution of mGlu2/3 and 5-HT(2A) receptors in the medial prefrontal cortex that is not apparent in other cortical regions. These findings suggest a close coupling between mGlu2/3 and 5-HT(2A) receptors in the prefrontal cortex that may be relevant for novel therapeutic approaches in the treatment of neuropsychiatric syndromes such as depression and schizophrenia.
Marek
G J
GJ
Department of Psychiatry and Pharmacology, Yale University School of Medicine, Ribicoff Research Facilities of the Connecticut Mental Health Center, New Haven, CT 06508, USA. Gerard.Marek@yale.edu
Wright
R A
RA
Schoepp
D D
DD
Monn
J A
JA
Aghajanian
G K
GK
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials; D017397:Prefrontal Cortex / Q000473:pathology / Q000502:physiology*; D011485:Protein Binding; D017966:Pyramidal Cells / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000145:classification / Q000502:physiology*; D017661:Receptors, Presynaptic / Q000187:drug effects; D012701:Serotonin / Q000145:classification / Q000502:physiology*; D014966:Xanthenes / Q000494:pharmacology*
D000596:Amino Acids; D001643:Bridged Bicyclo Compounds; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016166:Free Radical Scavengers; C114624:LY 341495; D018094:Receptors, Metabotropic Glutamate; D017661:Receptors, Presynaptic; D014966:Xanthenes; D012701:Serotonin; D018698:Glutamic Acid; C104753:eglumetad