Role of different monoamine receptors controlling MK-801-induced release of serotonin and glutamate in the medial prefrontal cortex: relevance for antipsychotic action

Abstract

Several studies have demonstrated that systemically administered N-methyl-d-aspartate (NMDA) receptor antagonists increase serotonin (5-HT) and glutamate release in the medial prefrontal cortex (mPFC). Previously we showed that the perfusion of clozapine in the mPFC prevented the MK-801-induced increase in extracellular glutamate and 5-HT whereas haloperidol blocked only the effect of MK-801 on glutamate. To study the contribution of different monoaminergic receptors (for which clozapine and haloperidol exhibit distinct affinities) to these effects, here we used in-vivo microdialysis to examine the role of local blockade of dopamine D2, 5-HT2A and alpha1-adrenergic receptors as well as agonism at dopamine D1 and 5-HT1A receptors in the mPFC on the increased efflux of glutamate and 5-HT elicited by MK-801. The results show that M100907 (5-HT2A antagonist), BAY x 3702 (5-HT1A agonist) and prazosin (alpha1-adrenergic antagonist) blocked the MK-801-induced increase of 5-HT and glutamate in the mPFC. However, raclopride, eticlopride (dopamine D2 antagonists) and SKF-38393 (dopamine D1 agonist) were able to prevent the increased efflux of glutamate (but not that of 5-HT) elicited by MK-801. We propose that D2 receptor antagonists and D1 agonists would act predominantly on a subpopulation of GABAergic interneurons of the mPFC, thus leading to an enhanced cortical inhibition that would prevent an excessive glutamatergic transmission. On the other hand, atypical antipsychotic drugs might further act upon 5-HT2A, 5-HT1A and alpha1-adrenoceptors present in pyramidal cells (including those projecting to the dorsal raphe nucleus), which would directly inhibit an excessive excitability of these cells.

Sertindole restores attentional performance and suppresses glutamate release induced by the NMDA receptor antagonist CPP

“…Thus, suppression of GLU release may play a major role in the effects of these drugs on accuracy deficit (a measure of attentional functioning) in the 5-CSRTT and further extend our previous observations that 5-HT receptor agents preventing accuracy deficits, abolish cortical GLU release induced by CPP or MK-801 (Calcagno et al 2009;Calcagno et al 2006;Ceglia et al 2004;Lopez-Gil et al 2009). In addition, the mGlu 2/3 receptor agonist LY379268 reversed CPP-induced impairment in attentional functioning and the effect on cortical GLU release (Pozzi et al, submitted).…”

Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain

“…Several antipsychotics influence the glutamatergic functions most likely via balanced effects on dopamine and serotonin 5HT1A and 5HT2A receptors (Lopez-Gil et al 2009, 2010. In several animal models (Table 1), an enhancement of NMDA-R expression or binding had been observed after an application of haloperidol and clozapine (Fitzgerald et al 1995;Schmitt et al 2003a;Ulas et al 1993).…”

Effects of aripiprazole, olanzapine, and haloperidol in a model of cognitive deficit of schizophrenia in rats: relationship with glutamate release in the medial prefrontal cortex

“…Aripiprazole and/or olanzapine have moderate to high affinity for other receptors, including dopamine D 1 , D 3 , and D 4 , 5-HT 2C , α 1 -adrenergic, histamine H 1 , and cholinergic M 1 receptors (Bymaster et al 1996;DeLeon et al 2004), some of which modulate attention and GLU release under basal conditions or in response to NMDA receptor blockade (Lopez-Gil et al 2009;. Thus, it cannot be excluded that an action on one of these receptors or a concomitant effect on several of them contributes to the ability of these drugs to prevent attention deficits and cortical GLU release.…”