Journal
INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY
Volume 13, Issue 10, Pages 1299-1314Publisher
OXFORD UNIV PRESS
DOI: 10.1017/S146114571000009X
Keywords
Antipsychotic drugs; dopamine; prefrontal cortex; 5-HT1A receptor; 5-HT2A receptor
Funding
- SENY Fundacio
- MICINN-IDIBAPS
- CSIC
- [SAF 2007-62378]
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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-HT1A receptor (5-HT1AR). 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-HT2A receptors (5-HT(2A)Rs) in the PFC, this effect might result from the imbalance of 5-HT1AR and 5-HT2AR 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-HT1AR and 5-HT2AR 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-HT2AR KO mice whereas the DA increase was absent in 5-HT1AR 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/2C)Rs in the mPFC were selectively protected with the respective antagonists WAY-100635 or ritanserin. The inactivation of GPCRs while preserving similar to 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 (similar to 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-HT2AR blockade by APDs.
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