Dopamine release induced by atypical antipsychotics in prefrontal cortex requires 5-HT(1A) receptors but not 5-HT(2A) receptors.
Atypical antipsychotic drugs (APDs) increase dopamine (DA) release in prefrontal cortex (PFC), an effect probably mediated by the direct or indirect activation of the 5-HT(1A) receptor (5-HT(1A)R). Given the very low in-vitro affinity of most APDs for 5-HT(1A)Rs and the large co-expression of 5-HT(1A)Rs and 5-HT(2A) receptors (5-HT(2A)Rs) in the PFC, this effect might result from the imbalance of 5-HT(1A)R and 5-HT(2A)R activation after blockade of these receptors by APDs, for which they show high affinity. Here we tested this hypothesis by examining the dependence of the APD-induced DA release in medial PFC (mPFC) on each receptor by using in-vivo microdialysis in wild-type (WT) and 5-HT(1A)R and 5-HT(2A)R knockout (KO) mice. Local APDs (clozapine, olanzapine, risperidone) administered by reverse dialysis induced a dose-dependent increase in mPFC DA output equally in WT and 5-HT(2A)R KO mice whereas the DA increase was absent in 5-HT(1A)R KO mice. To examine the relative contribution of both receptors to the clozapine-induced DA release in rat mPFC, we silenced G-protein-coupled receptors (GPCRs) in vivo with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) while 5-HT(1A)Rs or 5-HT(2A)/2CRs in the mPFC were selectively protected with the respective antagonists WAY-100635 or ritanserin. The inactivation of GPCRs while preserving ∼70% of 5-HT(2A)/(2C)Rs prevented the clozapine-induced DA rise in mPFC. In contrast, clozapine increased DA in mPFC of EEDQ-treated rats whose 5-HT(1A)Rs were protected (∼50% of control rats). These results indicate that (1) 5-HT(1A)Rs are necessary for the APDs-induced elevation in cortical DA transmission, and (2) this effect does not require 5-HT(2A)R blockade by APDs.
Bortolozzi
Analía
A
Department of Neurochemistry and Neuropharmacology, IIBB-CSIC (IDIBAPS), Barcelona, Spain.
Masana
Mercè
M
Díaz-Mataix
Llorenç
L
Cortés
Roser
R
Scorza
María Cecilia
MC
Gingrich
Jay A
JA
Toth
Miklos
M
Artigas
Francesc
F
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D023421:Models, Animal; D000077152:Olanzapine; D017397:Prefrontal Cortex / Q000187:drug effects*; D011804:Quinolines / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D018967:Risperidone / Q000494:pharmacology; D012559:Schizophrenia / Q000188:drug therapy
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D011804:Quinolines; D044402:Receptor, Serotonin, 5-HT2A; D043562:Receptors, G-Protein-Coupled; D044282:Receptor, Serotonin, 5-HT1A; D001569:Benzodiazepines; C000470:EEDQ; D003024:Clozapine; D018967:Risperidone; D000077152:Olanzapine; D004298:Dopamine