Long-term CB1 receptor blockade enhances vulnerability to anxiogenic-like effects of cannabinoids

Abstract

Compelling evidence has documented the anxiolytic and mood-enhancing properties of cannabis. In susceptible users, however, consumption of this drug is conducive to panic, paranoia and dysphoria. We hypothesized that the up-regulation of CB1 receptors (CB1Rs) in select brain regions may enhance the vulnerability to cannabinoid-induced anxiety. To test this possibility, we assessed the behavioral impact of a potent cannabinoid agonist (CP55,940; 0.05–0.1 mg/kg, IP) on C57BL/6 male mice, respectively subjected to a prolonged pre-treatment of either the selective CB1R antagonist/inverse agonist AM251 (1 mg/kg/day IP, for 21 days, followed by a 3-day clearance period before testing) or its vehicle (VEH1). Anxiety-like responses were studied in the novel open field, elevated plus maze (EPM) and social interaction assays. While CP55,940 induced anxiolytic-like effects in the EPM in VEH1-exposed animals, it elicited opposite actions in AM251-exposed mice. In this last group, CP55,940 also reduced rearing and social interaction in comparison to its vehicle (VEH2). The divergent effects of CP55,940 in AM251- and VEH1-pretreated animals were confirmed in 129SvEv mice. Immunoblotting analyses on brain samples of C57BL/6 mice revealed that AM251 pre-treatment caused a significant up-regulation of CB1R expression in the prefrontal cortex and striatum, but also a down-regulation of these receptors in the hippocampus and midbrain. Notably, CB1R levels in the prefrontal cortex were negatively correlated with anxiolysis-related indices in the EPM; furthermore, midbrain CB1R expression was positively correlated with the total duration of social interaction. These results suggest that regional variations in brain CB1R expression may differentially condition the behavioral effects of cannabinoids with respect to anxiety-related responses.

Disruption of peri-adolescent endocannabinoid signaling modulates adult neuroendocrine and behavioral responses to stress in male rats

“…However, in contrast to the present findings, chronic adult AM-251 treatment has been previously reported to produce a negative correlation between PFC CB1R expression and time spent in the center of the elevated plus maze and stretch attend postures (Tambaro et al, 2013). Despite this, increased risk assessment following disruption of peri-adolescent eCB signaling in the current study is reminiscent of the effects of stress during adolescence, which has been shown to increase risk M A N U S C R I P T…”

“…Chronic treatment with AM-251 in adult mice induced region-dependent differences in CB1R expression, with an upregulation in the PFC and striatum and downregulation in the hippocampus and mid-brain (Tambaro et al, 2013).…”

Sex‐specific effects of CB1 receptor antagonism and stress in adolescence on anxiety, corticosterone concentrations, and contextual fear in adulthood in rats

“…Experiment 1: long-term effects of AM251 and stress exposures in adolescence 4.1.1. Anxiety-like behaviours Endocannabinoid regulation of anxiety-like behaviours is welldocumented, although most investigations have involved the effects of agonism or antagonism while the drugs were in the system (Bellocchio et al, 2013;Bitencourt et al, 2008;Griebel et al, 2005;Haller et al, 2002Haller et al, , 2004Litvin et al, 2013;Moreira et al, 2008;Navarro et al, 1997;Rey et al, 2012;Rubino et al, 2008a;Simone et al, 2015a, b;Tambaro et al, 2013). In general, acute administration of CB1 receptor agonists decrease, whereas antagonists increase, anxiety-like behaviour in adult rats (Lafenetre et al, 2007).…”

Blood–brain and blood–cerebrospinal fluid passage of BRICHOS domains from two molecular chaperones in mice

“…Mouse tissues were homogenized in 50 mM Tris-HCl (pH 7.4), 150 mM NaCl, 1.0% (v/v) Triton X-100, 0.1% (w/v) SDS, and 10 mM EDTA supplemented with protease inhibitors as described previously (55). Brain samples were centrifuged for 30 min at 14,000 rpm (4°C), and then the supernatant was collected and stored at Ϫ20°C.…”