Cannabinoid CB1 receptor dependent effects of the NMDA antagonist phencyclidine in the social withdrawal model of schizophrenia

Abstract

Clinical and laboratory findings suggest that cannabinoid signalling is implicated in schizophrenia. However, the interaction remains poorly understood, as data are often contradictory. Here we investigated wild-type (WT) and cannabinoid CB1 receptor-knockout (CB1-KO) mice in the phencyclidine-induced social withdrawal model of schizophrenia. N-methyl-D-aspartate (NMDA) antagonists (including phencyclidine) induce psychotic symptoms in humans, and are used to model schizophrenia in a variety of experimental conditions. In WTs, 5 mg/kg phencyclidine increased locomotion and stereotyped behaviours, and decreased social interactions. These changes are consistent with a schizophrenia-like effect. In CB1-KOs, phencyclidine decreased locomotion, enhanced ataxia and stereotypy more markedly than in WTs, but did not affect social interactions. Locomotion showed a significant negative correlation with both ataxia and stereotypy, suggesting that in CB1-KOs, the locomotor suppressive effect of phencyclidine was secondary to changes in these variables. Our findings demonstrate that CB1 gene disruption dramatically alters the behavioural effects of the NMDA antagonist phencyclidine, suggesting that the CB1 receptor is involved in schizophrenia. As social disruption and stereotypy respectively are believed to model negative and positive symptoms of schizophrenia, our findings tentatively suggest that cannabinoids are differentially involved in these two symptom categories. These findings require verification by experiments involving CB1 receptor blockers, as the genetic and pharmacological blockade of receptors may not always provide similar results.

Impaired Fear Memory Specificity Associated with Deficient Endocannabinoid-Dependent Long-Term Plasticity

“…Furthermore, mutations in CNR1 (a gene encoding CB1R) have been associated with a susceptibility to schizophrenia in human genetic studies (Leroy et al, 2001;Ujike et al, 2002). Studies of mutant mice with the CNR1 gene deletion revealed that the schizophrenia-like behavioral responses to an NMDAR inhibitor depended on a functional CB1R (Haller et al, 2005). Thus, our data indicating an abnormality in the eCB system in a schizophrenia model are consistent with the initial findings in humans and rodents.…”

Involvement of the endocannabinoid system in phencyclidine-induced cognitive deficits modelling schizophrenia

“…Generally, CB 1 receptor agonists reduce the hyperlocomotion induced by amphetamine, quinpirole and cocaine (Gorriti et al, 1999 ;Marcellino et al, 2008 ;Moreira and Guimarães, 2005 ;Przegaliń ski et al, 2005), although not always by acting via CB 1 receptors ; CB 1 antagonists can reduce, increase or not affect the hyperlocomotion induced by different dopaminergic agents (Corbillé et al, 2007 ;Ferrer et al, 2007 ;Madsen et al, 2006 ;Masserano et al, 1999 ;Poncelet et al, 1999). Moreover, CB 1 gene deletion reduces the hyperlocomotion induced by both dopaminergic agents and phencyclidine (PCP) (Corbillé et al, 2007 ;Haller et al, 2005). Regarding sensory motor information gating processes, generally CB 1 receptor agonists disrupt pre-pulse inhibition (PPI) (Bortolato et al, 2005 ;Hajó s et al, 2008 ;Martin et al, 2003 ;Schneider and Koch, 2005), whereas cannabidiol and the CB 1 receptor antagonist, SR141716A, reverse MK801-or PCP-induced PPI deficit (Ballmaier et al, 2007 ;Long et al, 2006 ; but see also Martin et al, 2003).…”

Endocannabinoids and Mental Disorders

“…Acute phencyclidine (PCP) administration is a well-accepted preclinical model reproducing some aspects of schizophrenia, since it induces locomotor activation, stereotyped behaviors, and reduced social interactions in wild-type animals. Interestingly, PCP-induced behavioral alterations were different in CB1 ko mice (Haller et al 2005), since reduced locomotion, greater enhancement in ataxia, and stereotypies as well as no alterations in social behavior were observed. As social disruption and stereotypy are believed to model, respectively, negative and positive symptoms of schizophrenia, it can be hypothesized that the CB1r may contribute differently to these two types of symptoms, possibly inhibiting positive but facilitating negative ones.…”

“…However, the chronic administration of AM251, a CB1 receptor antagonist, also counteracted the increase in aggressive behaviors observed in rats reared in isolation (Zamberletti et al 2010). Accordingly, genetic deletion of the CB1 receptor prevented PCP-induced social deficits in mice (Haller et al 2005). So far only a few studies have examined the effect of a pharmacological modulation of the ECS on cognitive deficits in animal models of schizophrenia.…”