Endogenous serotonin and serotonin2C receptors are involved in the ability of M100907 to suppress cortical glutamate release induced by NMDA receptor blockade.

ABSTRACT

Blockade of NMDA receptors by intracortical infusion of 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) increases glutamate (GLU) and serotonin (5-HT) release in the medial prefrontal cortex and impairs attentional performance in the 5-choice serial reaction time task. These effects are prevented by the 5-HT(2A) receptor antagonist, (R)-(+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol (M100907). We explored the roles of endogenous 5-HT and 5-HT(1A) and 5-HT(2C) receptors in the mechanisms by which M100907 suppresses CPP-induced release of cortical GLU and 5-HT using in vivo microdialysis. CPP raised extracellular GLU and 5-HT by about 250% and 170% respectively. The 5-HT synthesis inhibitor, p-chlorophenylalanine (300 mg/kg), prevented M100907 suppressing CPP-induced GLU release. The effect of M100907 on these rises of GLU and 5-HT and attentional performance deficit was mimicked by the 5-HT(2C) receptor agonist, (S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine fumarate, (Ro60-0175, 30 microg/kg) while intra-mPFC (SB242084, 6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline, 0.1 microM), a 5-HT(2C) receptor antagonist, prevented the effect of M100907 on extracellular GLU. The 5-HT(1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexane carboxenide trihydrochloride (100 microM) abolished the effect of M100907 on the CPP-induced 5-HT release. The data show that blockade of 5-HT(2A) receptors is not sufficient to suppress the CPP-induced rise of extracellular GLU and 5-HT and suggest that M100907 suppresses GLU release induced by CPP by enhancing the action of endogenous 5-HT on 5-HT(2C) receptors.