Unraveling monoamine receptors involved in the action of typical and atypical antipsychotics on glutamatergic and serotonergic transmission in prefrontal cortex

Curr Pharm Des. 2010;16(5):502-15. doi: 10.2174/138161210790361416.


The systemic administration of noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists has been considered as a pharmacological model of schizophrenia. In the present work, we used in vivo microdialysis to examine: first, the effects of MK-801, on the efflux of glutamate and serotonin (5-HT) in the medial prefrontal cortex (mPFC) of the rat; second, whether the MK-801-induced changes in the cortical efflux of both transmitters could be blocked by atypical (clozapine and olanzapine) and classical (haloperidol and chlorpromazine) antipsychotic drugs given intra-mPFC; and third, the role of local blockade of dopamine D(2)/D(3)/D(4), serotonin 5-HT(2A) and alpha(1)-adrenergic receptors as well as agonism at dopamine D(1)/D(5) and 5-HT(1A) receptors in the mPFC on the increased efflux of glutamate and 5-HT elicited by MK-801. The four antipsychotic drugs blocked the MK-801-induced increase in glutamate, whereas only clozapine and olanzapine were able to block the increased efflux of 5-HT. Furthermore, M100907 (5-HT(2A) antagonist), BAY x 3702 (5-HT(1A) agonist) and prazosin (alpha(1)-adrenergic antagonist) blocked the MK-801-induced increase of 5-HT and glutamate in the mPFC. In contrast, raclopride (D(2)/D(3) antagonist) and L-745,870 (D(4) antagonist) were able to prevent the increased efflux of glutamate (but not that of 5-HT) elicited by MK-801. SKF-38393 (dopamine D(1)/D(5) agonist) also prevented the MK-801-induced increase of glutamate in the mPFC, but the same effect on cortical 5-HT was reached only at the highest concentration tested. We suggest that the blockade of an exacerbated 5-HT release in the mPFC induced by NMDA antagonists can be a characteristic of atypical antipsychotic drugs. Moreover, we propose that D(2)/D(3)/D(4) receptor antagonists would act predominantly on a subpopulation of GABAergic interneurons of the mPFC, thus enhancing cortical inhibition, which would prevent an excessive glutamatergic transmission. Dopamine D(1)/D(5) agonists would further stimulate GABA release from other subpopulation of interneurons controlling cortical output to the dorsal raphe nucleus. Atypical antipsychotic drugs might further act upon 5-HT(2A), 5-HT(1A) and alpha(1)-adrenoceptors present in pyramidal cells (including those projecting to the dorsal raphe nucleus), which would directly inhibit an excessive excitability of these cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists*
  • Animals
  • Antipsychotic Agents / administration & dosage
  • Antipsychotic Agents / pharmacology*
  • Dizocilpine Maleate / antagonists & inhibitors
  • Dizocilpine Maleate / pharmacology
  • Glutamic Acid / metabolism*
  • Humans
  • Microinjections
  • Models, Neurological
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / metabolism
  • Receptors, Dopamine / drug effects*
  • Receptors, Serotonin / drug effects*
  • Serotonin / metabolism*
  • Synaptic Transmission / drug effects


  • Adrenergic alpha-1 Receptor Antagonists
  • Antipsychotic Agents
  • Receptors, Dopamine
  • Receptors, Serotonin
  • Serotonin
  • Glutamic Acid
  • Dizocilpine Maleate