Phencyclidine-Induced Social Withdrawal Results from Deficient Stimulation of Cannabinoid CB1 Receptors: Implications for Schizophrenia

Abstract

The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB 1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB 1 -dependent manner, whereas pharmacological blockade of CB 1 receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB 1 receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB 1 -mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP-and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB 1 receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission.

Simultaneous Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Shares Discriminative Stimulus Effects with Δ9-Tetrahydrocannabinol in Mice

“…Selectivity of the drugs for the respective enzymes was evidenced here by measurement of AEA and 2-AG. PF-3845 and URB597 increased AEA but not 2-AG, whereas JZL184 increased 2-AG but not AEA (our results; see also Ahn et al, 2009;Long et al, 2009a,b,c;Ramesh et al, 2013;Seillier et al, 2013Seillier et al, , 2014Wiley et al, 2014). In this study, administration of a selective FAAH inhibitor (PF-3845) in combination with a selective MAGL inhibitor (JZL184) fully substituted for the discriminative stimulus effects of D 9 -THC.…”

Early Development of Parvalbumin-, Somatostatin-, and Cholecystokinin-Expressing Neurons in Rat Brain following Prenatal Immune Activation and Maternal Iron Deficiency

“…CCK interneurons are the major cell type expressing endocannabinoid CB1 receptors in the rodent forebrain [50] . There is also evidence that CCK in the medial PFC plays a role in stress and anxiety-related behaviors and that CB1 modulation of CCK transmission can alter social interaction and withdrawal behavior [51][52][53] . Therefore one can speculate that alteration in CCK neuron function caused by prenatal immune activation could potentially alter the reactivity to stress and cannabinoid use, which are risk factors for the development of overt psychosis in adolescence [54,55] , as well as impact social interaction.…”

Interactions Between Cannabinoid Signaling and Anxiety: A Comparative Analysis of Intervention Tools and Behavioral Effects

“…In other cases, however, no effects were seen either after genetic [139] or pharmacological blockade of FAAH activity [138][139][140]. FAAH inhibition was anxiogenic in one study [50]. Strong dependence on environmental conditions was reported in two studies [138,139].…”

“…Low doses (0.3-3 mg/kg) reduced anxiety in several models, e.g. the elevated plus-maze [37-39], light/dark [40] and Vogel tests [38], while higher doses (3-10 mg/kg) exerted anxiogenic effects in the elevated plus-maze [28, [41][42][43][44][45][46][47], light/dark [48], open-field [28], novelty induced hypophagia [49], elevated T-maze [28], defensive withdrawal [45], social interaction [50] and footshock-induced ultra sound vocalization [51] tests. Such large doses also increased cue-induced conditioned fear after both acute [52] and chronic treatment [29]; in addition, rimonabant inhibited the extinction of this response [53][54][55].…”

“…For instance, the CB 1 R blocker AM251 did not show the biphasic effect seen with rimonabant. This antagonist proved to be anxiogenic over a wide range of doses (0.3-8 mg/kg) [21,25,50,[64][65][66][67][68]. In addition, AM251 reduced urocortin1 microinjection-and nicotine abstinence-induced anxieties [69,70].…”