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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

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Abstract

Rationale

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.

Objectives

The protein and messenger RNA (mRNA) contents of A2A, D2, and CB1 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 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.

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Acknowledgments

This study was supported by the Spanish MICINN (SAF 2006-05481 to RF, SAF 2008-01311 to JAG-S, and SAF 2009-08460 to JJM), Basque Government (INV-200700/0011 to LU, IT-199/07 to JJM), “Fundació La Marató de TV3” (060110 to RF) and ERD Funds. The authors acknowledge the collaboration of the technical staff of Basque Institute of Legal Medicine, Bilbao and Institute of Forensic Medicine, Geneva. LU is supported by Juan de la Cierva Program of MICINN, Spain.

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Author notes

  1. M. Julia García-Fuster

    Present address: The Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, 48109-0720, MI, USA

Authors and Affiliations

  1. Department of Pharmacology, University of the Basque Country, 48940, Leioa, Bizkaia, Spain

    Leyre Urigüen, Luis F. Callado & J. Javier Meana

  2. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) http://www.cibersam.es

    Leyre Urigüen, Luis F. Callado & J. Javier Meana

  3. Laboratory of Neuropharmacology, IUNICS, University of the Balearic Islands, 07122, Palma de Mallorca, Spain

    M. Julia García-Fuster & Jesús A. García-Sevilla

  4. Red Temática de Investigación Cooperativa en Salud (Trastornos Adictivos) http://www.redrta.es/

    M. Julia García-Fuster & Jesús A. García-Sevilla

  5. Basque Institute of Legal Medicine, Bilbao, Spain

    Benito Morentin

  6. Centre Universitaire Romand de Médicine Légale-Site Genève, Faculté de Médecine, University of Geneva, 1211, Geneva, Switzerland

    Romano La Harpe

  7. Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Department of Biochemistry and Molecular Biology, University of Barcelona, 08028, Barcelona, Spain

    Vicent Casadó, Carmen Lluis & Rafael Franco

  8. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) http://www.ciberned.es/

    Vicent Casadó, Carmen Lluis & Rafael Franco

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  1. Leyre Urigüen
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  2. M. Julia García-Fuster
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  10. J. Javier Meana
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Correspondence to J. Javier Meana.

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Urigüen, L., García-Fuster, M.J., Callado, L.F. et al. 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. Psychopharmacology 206, 313–324 (2009). https://doi.org/10.1007/s00213-009-1608-2

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