CB1 cannabinoid receptor expression in postmortem prefrontal cortex of schizophrenic suicides

Leyre Uriguen1, Rebeca Diez-Alarcia1, David Arteta1, Jesus A Garcia-Sevilla2, Luis F Callado1, J Javier Meana1. 1Departament of Pharmacology, Faculty of Medicine, University of the Basque Country, Leioa, Bizkaia, Spain, 2Neuropharmacology Laboratory, IUNICS, University of the Balearic Islands, Palma de Mallorca, Spain.

Large body of evidence suggests a role of the endogenous cannabinoid system in the development and physiopathology of schizophrenia.

The hypothesis that a dysfunction in endocannabinoid signalling may be involved in schizophrenia is supported by studies showing elevated endocannabinoid levels in plasma and cerebrospinal fluid (Giuffrida et al., 2004) of schizophrenic subjects. Moreover, it has been reported that CB1 receptor expression may change in different brain regions closely related to schizophrenia (Zavitsanou et al., 2004). Moreover, some studies indicate that clozapine, an atypical antipsychotic drug, may decrease the CB1 receptor expression in rat brain (Sundram et al., 2005). However, little is known about the role that endogenous cannabinoid system plays in the therapeutic efficacy of antipsychotic drugs.

The aim of this study was to evaluate the CB1 cannabinoid receptor expression in post-mortem prefrontal cortex of schizophrenic suicidal drug-free and treated subjects.

For that purpose, gene expression studies and protein analyses were carried out in schizophrenic suicidal drug-free subjects (n=11), schizophrenic suicidal subjects treated with antipsychotics (n=11), non-schizophrenic suicidal subjects (n=11) and in sex, age and postmortem delay-matched controls (11). Gene expression analyses were carried out using the Affymetrix® GeneChip® technology and synthesized cRNAs from total RNA isolated from tissue samples were used for the chips hybridization. Immunodetection of CB1 protein was made in total homogenates of prefrontal cortex by western blot experiments using the rabbit polyclonal anti-human CB1 (hCB1) isoform antibody, purchased from Sigma Chemical Co. (St. Louis, Mo, USA) as previously described by López de Jesús et al. (2006). Gene expression results indicate that CB1 gene is up-regulated (fold change=1,28; P-value=0,03) in drug-free schizophrenic subjects as well as in those treated with antipsychotic drugs (fold change=1,32; P-value=0,008) when comparing to their controls. The immunoreactivity of the CB1 protein (60 kDa band) in drug-free schizophrenic subjects was increased when comparing to their controls, although it was no statistically significantly. On the contrary, CB1 protein expression was significantly decreased in schizophrenic suicidal subjects treated with antipsychotics (Δ= -32.64%; SEM=14.40; p<0.05) while no changes were observed in non-schizophrenic suicidal subjects.

Taken together, data suggest not only that CB1 receptor is involved in schizophrenia but also that antipsychotic treatment is able to modulate the endocannabinoid system in schizophrenic subjects.

Giuffrida, A., et al., (2004). Neuropsychopharmacology. 29, 2108-2114

Zavitsanou, K et al., (2004). Prog Neuropsychopharmacol Biol Psychiatry. 28, 355-360

Sundram, S., et al., (2005). Naunyn Schmiedebergs Arch Pharmacol. 371, 428-433.

Supported by FIS 03/0498 to L.F. Callado and FIS 04/0190 to J.J. Meana