Document Detail

Dopamine release induced by atypical antipsychotics in prefrontal cortex requires 5-HT(1A) receptors but not 5-HT(2A) receptors.
MedLine Citation:
PMID:  20158933     Owner:  NLM     Status:  MEDLINE    
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.
Analía Bortolozzi; Mercè Masana; Llorenç Díaz-Mataix; Roser Cortés; María Cecilia Scorza; Jay A Gingrich; Miklos Toth; Francesc Artigas
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-02-17
Journal Detail:
Title:  The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)     Volume:  13     ISSN:  1469-5111     ISO Abbreviation:  Int. J. Neuropsychopharmacol.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-10-04     Completed Date:  2011-03-18     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  9815893     Medline TA:  Int J Neuropsychopharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1299-314     Citation Subset:  IM    
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MeSH Terms
Antipsychotic Agents / pharmacology*
Benzodiazepines / pharmacology
Clozapine / pharmacology
Dopamine / metabolism*
Dopamine Antagonists / pharmacology
Mice, Inbred C57BL
Mice, Knockout
Models, Animal
Prefrontal Cortex / drug effects*
Quinolines / metabolism
Rats, Wistar
Receptor, Serotonin, 5-HT1A / metabolism*
Receptor, Serotonin, 5-HT2A / metabolism*
Receptors, G-Protein-Coupled / antagonists & inhibitors
Risperidone / pharmacology
Schizophrenia / drug therapy
Grant Support
Reg. No./Substance:
0/Antipsychotic Agents; 0/Dopamine Antagonists; 0/Quinolines; 0/Receptor, Serotonin, 5-HT2A; 0/Receptors, G-Protein-Coupled; 112692-38-3/Receptor, Serotonin, 5-HT1A; 12794-10-4/Benzodiazepines; 132539-06-1/olanzapine; 16357-59-8/EEDQ; J60AR2IKIC/Clozapine; L6UH7ZF8HC/Risperidone; VTD58H1Z2X/Dopamine

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