The 5‐HT_2A receptor antagonist M100,907 prevents extracellular glutamate rising in response to NMDA receptor blockade in the mPFC

Abstract

We recently found that intracortical injection of the selective and competitive N-methyl-D-aspartate (NMDA) receptor antagonist 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) impaired attentional performance in rats and blockade of 5-hydroxytryptamine (5-HT) 2A receptors antagonized this effect. Here, we used the microdialysis technique in conscious rats to study the effect of CPP on extracellular glutamate (GLU) in the medial prefrontal cortex (mPFC) and the regulation of this effect by 5-HT 2A receptors. Intraperitoneal injection of 20 mg/kg CPP increased extracellular GLU in the mPFC (201% of basal levels) but had no effect on 5-HT. Intracortical infusion of 100 lM CPP increased extracellular GLU (230% of basal values) and 5-HT (150% of basal values) in the mPFC, whereas 30 lM had no significant effect. The effect of 100 lM CPP on extracellular GLU was abolished by tetrodotoxin, suggesting that neuronal activity is required. Subcutaneous injection of 40 lg/kg M100,907 completely antagonized the effect of 100 lM CPP on extracellular GLU, whereas 10 lg/kg caused only partial attenuation. Likewise, intracortical infusion of 0.1 lM M100,907 completely reversed the increase of extracellular GLU induced by CPP. These findings show that blockade of NMDA receptors in the mPFC is sufficient to increase extracellular GLU locally. The increase of cortical extracellular GLU may contribute to CPP-induced cognitive deficits and blockade of 5-HT 2A receptors may provide a molecular mechanism for reversing these deficits caused by dysfunctional glutamatergic transmission in the mPFC.

Dissociable Contribution of 5-HT1A and 5-HT2A Receptors in the Medial Prefrontal Cortex to Different Aspects of Executive Control such as Impulsivity and Compulsive Perseveration in Rats

“…That enhanced glutamate and 5-HT release may not be involved in CPP's effects on perseverative responses is indicated by studies showing that lowering CPP-induced glutamate release by M100907 does not abolish perseverative responding Ceglia et al, 2004; the present results). In addition, reducing but not increasing 5-HT function in the PFC leads to response perseveration in tasks such as reversal learning (Clarke et al, 2004(Clarke et al, , 2005 and in some instances in a 5-CSRT (Winstanley et al, 2004).…”

“…Various behavioral deficits induced by NMDA antagonists have been associated with enhanced glutamate release in the mPFC (Moghaddam et al, 1997;Moghaddam and Adams, 1998) and findings in our laboratory indicate that CPP in the mPFC increases glutamate efflux locally and that this was prevented by systemic or intra-mPFC M100907 (Ceglia et al, 2004). Thus, 5-HT 2A receptors in the mPFC play a major role in controlling CPP-induced glutamate release and some aspects of attentional performance in a 5-CSRT task.…”

“…The NMDA receptor antagonists either infused into the mPFC or injected systemically increase the release of 5-HT in the mPFC (Ceglia et al, 2004;Martin et al, 1998). Therefore, overactivation of 5-HT 2A but not 5-HT 1A receptors in the mPFC as a consequence of elevated 5-HT release may be an important mechanism that increases active responding in anticipation of reward.…”

“…In normal humans, NMDA receptor antagonists cause cognitive deficits analogous to those in schizophrenic patients (Javitt and Zukin, 1991;Krystal et al, 1994). In experimental animals, administration of NMDA receptor antagonists systemically or locally into the medial prefrontal cortex (mPFC) dysregulates the firing and bursting activity of pyramidal neurons (Jackson et al, 2004) and cortical glutamate release (Ceglia et al, 2004;Moghaddam and Adams, 1998;Verma and Moghaddam, 1996), and produce a range of behavioral impairments reminiscent of frontal lobe dysfunction Egerton et al, 2005;Higgins et al, 2003a;Jentsch and Roth, 1999;Le Pen et al, 2003;Murphy et al, 2005;Rodefer et al, 2005).…”

Opposing Roles for 5-HT2A and 5-HT2C Receptors in the Nucleus Accumbens on Inhibitory Response Control in the 5-Choice Serial Reaction Time Task

“…Several studies have shown that 5-HT 2A and 5-HT 2C receptors mediate opposing effects on behavioral inhibition, which may relate to their differential effects on dopamine (DA) function (Carli and Samanin, 1992;Koskinen et al, 2000a, b;Ruotsalainen et al, 1997;Passetti et al, 2003;Winstanley et al, 2003Winstanley et al, , 2004Winstanley et al, , 2005. Recent findings also imply a role for 5-HT 2A receptors in regulating glutamate function in PFC , Ceglia et al, 2004.…”