Cannabinoid Receptor Antagonists Counteract Sensorimotor Gating Deficits in the Phencyclidine Model of Psychosis

Abstract

Clinical and laboratory findings suggest that cannabinoids and their receptors are implicated in schizophrenia. The role of cannabinoids in schizophrenia remains however poorly understood, as data are often contradictory. The primary aim of this study was to investigate whether the cannabinoid CB1 receptor antagonists rimonabant and AM251 are able to reverse deficits of sensorimotor gating induced by phencyclidine and to mimic the 'atypical' antipsychotic profile of clozapine. The prepulse inhibition (PPI) of the startle reflex was used to measure deficits of sensorimotor gating. PPI-disruptive effects of phencyclidine and their antagonism by rimonabant, AM251, and clozapine were studied in rats. The effects of rimonabant were carefully examined taking into account dose ranges, vehicle, and route of administration. We also examined the ability of rimonabant to reduce the PPI-disruptive effects of dizocilpine and apomorphine. Rimonabant as well as AM251 significantly counteracted the phencyclidine-disruptive model of PPI, comparable to the restoring effect of clozapine; no augmentation effect was observed with rimonabant and clozapine as cotreatment. Rimonabant also significantly attenuated the PPI disruptive effects of dizocilpine and apomorphine. Taken together, our results indicate that CB1 receptor antagonists do produce 'atypical' antipsychotic profile mimicking that of clozapine in the phencyclidine disruption of sensorimotor gating. Our findings further suggest that CB1 receptor antagonism may be involved in restoring disturbed interactions between the activity of the endocannabinoid system and glutamate neurotransmitter system implied in schizophrenia.

Effect of social isolation on CB1 and D2 receptor and fatty acid amide hydrolase expression in rats

“…However, whether endocannabinoid levels are altered in rats as a result of social isolation remains an open question. Interestingly, we (Malone et al, 2004) and others (Ballmaier et al, 2007) have shown that PPI gating deficits induced by drugs such as apomorphine can be reversed by pretreatment with the CB 1 receptor antagonist SR 141716 (rimonabant), implying that the endocannabinoid system has a role in modulating sensorimotor gating processes.…”

Psychosis Following Anti-Obesity Treatment with Rimonabant

“…A full-blown psychosic episode developed with a latency of a few months following the discontinuation of rimonabant and despite being on antipsychotic treatment. These clinical observations contradict theoretical considerations that cannabinoid receptor antagonists unfold antipsychotic effects [10,11]. These theoretical considerations are widely supported by findings in rodents, which suggest a negative impact of rimonabant on dopamine D2 receptor-mediated neurotransmission [15] as well as functional and metabolic similarities between antipsychotics and rimonabant [16,17].…”

“…The psychotogenic effects are epidemiologically well established and may be due to the fact that agonists such as THC increase dopamine release [9]. Since rimonabant has an antagonistic impact on CB1 receptors, it decreases appetite [2] and may have antipsychotic propensities due to a decrease of the mesolimbic dopamine release [10]. However, a first trial of this hypothesis was not conclusive [11].…”

Interactions of Cannabis and Amphetamine-Type Stimulants

“…Notably, this gene has been associated with schizophrenia vulnerability in several studies [159,160]. While preclinical results have suggested that antagonism of CB 1 may attenuate schizophrenia symptoms [161,162], preliminary clinical trials have failed to support this possibility [163].…”