Endogenous serotonin and serotonin2Creceptors are involved in the ability of M100907 to suppress cortical glutamate release induced by NMDA receptor blockade

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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‐HT2Areceptor antagonist, (R)‐(+)‐(2,3‐dimethoxyphenyl)‐1‐[2‐(4‐fluorophenyl)ethyl]‐4‐piperidine methanol (M100907). We explored the roles of endogenous 5‐HT and 5‐HT1Aand 5‐HT2Creceptors in the mechanisms by which M100907 suppresses CPP‐induced release of cortical GLU and 5‐HT usingin vivomicrodialysis. 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‐HT2Creceptor agonist, (S)‐2‐(6‐chloro‐5‐fluoroindol‐1‐yl)‐1‐methylethylamine fumarate, (Ro60‐0175, 30 μg/kg) while intra‐mPFC (SB242084, 6‐chloro‐5‐methyl‐1‐[[2‐[(2‐methyl‐3‐pyridyl)oxy]‐5‐pyridyl]carbamoyl]‐indoline, 0.1 μM), a 5‐HT2Creceptor antagonist, prevented the effect of M100907 on extracellular GLU. The 5‐HT1Areceptor antagonist,N‐[2‐[4‐(2‐methoxyphenyl)‐1‐piperazinyl]ethyl]‐N‐(2‐pyridinyl)cyclohexane carboxenide trihydrochloride (100 μM) abolished the effect of M100907 on the CPP‐induced 5‐HT release. The data show that blockade of 5‐HT2Areceptors 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‐HT2Creceptors.

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