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

• Published in: Psychopharmacologia Vol. 206; no. 2; pp. 313 - 324
• Main Authors: Urigüen, Leyre, García-Fuster, M. Julia, Callado, Luis F., Morentin, Benito, La Harpe, Romano, Casadó, Vicent, Lluis, Carmen, Franco, Rafael, García-Sevilla, Jesús A., Meana, J. Javier
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.10.2009; Springer; Springer Nature B.V
• Subjects: Adenosine; Adult; Adult and adolescent clinical studies; Aged; Analysis of Variance; Antipsychotic Agents - pharmacology; Antipsychotic Agents - therapeutic use; Antipsychotics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Brain; Dopamine; Female; Frontal Lobe - drug effects; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Humans; Hypotheses; Legal medicine; Male; Medical sciences; Medicine; Middle Aged; Neuropharmacology; Neurosciences; Original Investigation; Pharmacology. Drug treatments; Pharmacology/Toxicology; Postmortem Changes; Proteins; Psychiatry; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Psychoses; Psychotropic drugs; Receptor, Adenosine A2A - genetics; Receptor, Adenosine A2A - metabolism; Receptor, Cannabinoid, CB1 - genetics; Receptor, Cannabinoid, CB1 - metabolism; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D2 - metabolism; RNA, Messenger - metabolism; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - metabolism; Schizophrenia - pathology; Suicide - psychology; Suicides & suicide attempts; Young Adult; Switzerland; Spain; Antipsychotic drugs; receptor; Postmortem human brain; Schizophrenia; Dopamine D; Cannabinoid receptor CB; Adenosine A; CB1 cannabinoid receptor; Purine nucleoside; Neuroleptic; Psychotropic; Central nervous system; Pharmacotherapy; Frontal cortex; Encephalon; Psychosis; A2A adenosine receptor; Adult; Antipsychotic; Human; Drug; Adenosine; Dopamine; receptors; Postmortem; Postmortem human brains; Catecholamine; Gene expression; Treatment; D2 Dopamine receptor; Neurotransmitter
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-009-1608-2

Rationale Dopamine D 2 receptors are the main target of antipsychotic drugs. In the brain, D 2 receptors coexpress with adenosine A 2A and CB 1 cannabinoid receptors, leading to functional interactions. Objectives The protein and messenger RNA (mRNA) contents of A 2A , D 2 , and CB 1 receptors were quantified in postmortem prefrontal cortex of subjects with schizophrenia. Materials and 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 A 2A (90 ± 6%, n  = 24) and D 2 -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 CB 1 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 A 2A , D 2 , and CB 1 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 CB 1 receptors in brain. Since A 2A , D 2 , and CB 1 receptors coexpress on brain GABAergic neurons and reductions in markers of GABA neurotransmission have been identified in schizophrenia, a lower density of CB 1 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.