ABSTRACT
Title
Inhibitors of endocannabinoid inactivation counteract behavioural alterations induced by acute phencyclidine in rats through multiple mechanisms
Authors
Erica Zamberletti
Doctorate in Neurobiology, Doctorate school in Biological and Medical Sciences Dept. of Functional and Structural Biology, University of Insubria, Busto Arsizio (VA)
Abstract
Recent clinical and experimental studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia.
Since administration of phencyclidine to rodents has proven to be a useful model for studying schizophrenic-like psychosis, we investigated the effect of cannabinoid compounds on the behavioural disorganization induced by this NMDA receptor antagonist.
Acute PCP injections were used to induce hyperlocomotion, stereotyped behaviours and ataxia in rats. The natural cannabinoid agonist, delta-9-tetrahydrocannabinol, the FAAH inhibitor, URB597, and the anandamide uptake inhibitor, AM404, were systemically administered to test their efficacy against the behavioural disorganization induced by PCP injections, alone or in combination with the CB1 receptor antagonist, AM251, or the TRPV1 receptor antagonist, capsazepine. Endocannabinoid levels as well as FAAH activity were then evaluated in selected brain regions relevant to the behaviours under investigation.
Enhancement of the endocannabinoid tone through THC, URB597 and AM404 administration counteracted the increase in locomotor activity, stereotyped behaviours and ataxia induced by acute PCP in rats. Interestingly, the recovery following URB597 and AM404 administration was not entirely dependent upon CB1 receptor activation, but involved also the TRPV1 channel, since capsazepine was able to counteract part of the beneficial effects induced by cannabinoid “indirect” agonists, in particular on PCP-induced stereotyped behaviours and ataxia.
CB1 and TRPV1 receptors appear to be both involved in controlling positive schizophrenia-like symptoms induced by acute PCP therefore the pharmacological manipulation of endocannabinoid levels might have therapeutic consequences.
Since administration of phencyclidine to rodents has proven to be a useful model for studying schizophrenic-like psychosis, we investigated the effect of cannabinoid compounds on the behavioural disorganization induced by this NMDA receptor antagonist.
Acute PCP injections were used to induce hyperlocomotion, stereotyped behaviours and ataxia in rats. The natural cannabinoid agonist, delta-9-tetrahydrocannabinol, the FAAH inhibitor, URB597, and the anandamide uptake inhibitor, AM404, were systemically administered to test their efficacy against the behavioural disorganization induced by PCP injections, alone or in combination with the CB1 receptor antagonist, AM251, or the TRPV1 receptor antagonist, capsazepine. Endocannabinoid levels as well as FAAH activity were then evaluated in selected brain regions relevant to the behaviours under investigation.
Enhancement of the endocannabinoid tone through THC, URB597 and AM404 administration counteracted the increase in locomotor activity, stereotyped behaviours and ataxia induced by acute PCP in rats. Interestingly, the recovery following URB597 and AM404 administration was not entirely dependent upon CB1 receptor activation, but involved also the TRPV1 channel, since capsazepine was able to counteract part of the beneficial effects induced by cannabinoid “indirect” agonists, in particular on PCP-induced stereotyped behaviours and ataxia.
CB1 and TRPV1 receptors appear to be both involved in controlling positive schizophrenia-like symptoms induced by acute PCP therefore the pharmacological manipulation of endocannabinoid levels might have therapeutic consequences.