title: Unraveling monoamine receptors involved in the action of typical and atypical antipsychotics on glutamatergic and serotonergic transmission in prefrontal cortex.
abstract: 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.
authors.affiliation: Department of Neurochemistry and Neuropharmacology, Instituto de Investigaciones Biomédicas de Barcelona, CSIC (IDIBAPS), Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: López-Gil
authors.forename: Francesc
authors.initials: F
authors.lastname: Artigas
authors.forename: Albert
authors.initials: A
authors.lastname: Adell
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008845:Microinjections; D008959:Models, Neurological; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011954:Receptors, Dopamine / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D014150:Antipsychotic Agents; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D012701:Serotonin; D018698:Glutamic Acid; D016291:Dizocilpine Maleate