Immunodensity and mRNA expression of A2A adenosine, D2 dopamine, and CB1 cannabinoid receptors in postmortem frontal cortex of subjects with schizophrenia: effect of antipsychotic treatment.
BACKGROUND
Dopamine D2 receptors are the main target of antipsychotic drugs. In the brain, D2 receptors coexpress with adenosine A2A and CB1 cannabinoid receptors, leading to functional interactions.


OBJECTIVE
The protein and messenger RNA (mRNA) contents of A2A, D2, and CB1 receptors were quantified in postmortem prefrontal cortex of subjects with schizophrenia.


METHODS
The study was performed in subjects suffering schizophrenia (n=31) who mainly died by suicide, matched with non-schizophrenia suicide victims (n=13) and non-suicide controls (n=33). The density of receptor proteins was evaluated by immunodetection techniques, and their relative mRNA expression was quantified by quantitative real-time polymerase chain reaction.


RESULTS
In schizophrenia, the densities of A2A (90+/-6%, n=24) and D2-like receptors (95+/-5%, n=22) did not differ from those in controls (100%). Antipsychotic treatment did not induce changes in the protein expression. In contrast, the immunodensity of CB1 receptors was significantly decreased (71+/-7%, n=11; p<0.05) in antipsychotic-treated subjects with schizophrenia but not in drug-free subjects (104+/-13%, n=11). The relative mRNA amounts encoding for A2A, D2, and CB1 receptors were similar in brains of drug-free, antipsychotic-treated subjects with schizophrenia and controls.


CONCLUSIONS
The findings suggest that antipsychotics induce down-regulation of CB1 receptors in brain. Since A2A, D2, and CB1 receptors coexpress on brain GABAergic neurons and reductions in markers of GABA neurotransmission have been identified in schizophrenia, a lower density of CB1 receptor induced by antipsychotics could represent an adaptative mechanism that reduces the endocannabinoid-mediated suppression of GABA release, contributing to the normalization of cognitive functions in the disorder.
Urigüen
Leyre
L
Department of Pharmacology, University of the Basque Country, 48940, Leioa, Bizkaia, Spain.
García-Fuster
M Julia
MJ
Callado
Luis F
LF
Morentin
Benito
B
La Harpe
Romano
R
Casadó
Vicent
V
Lluis
Carmen
C
Franco
Rafael
R
García-Sevilla
Jesús A
JA
Meana
J Javier
JJ
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D011180:Postmortem Changes; D012333:RNA, Messenger / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000235:genetics* / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D013405:Suicide / Q000523:psychology; D055815:Young Adult
D014150:Antipsychotic Agents; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D043884:Receptor, Cannabinoid, CB1; D017448:Receptors, Dopamine D2