Cannabinoid receptor CB2 agonist attenuates cocaine-induced reinstatement of place preference in mice: Possible role for microglia immuno-metabolism

Abstract

Abstract Chronic exposure to cocaine alters inflammatory signalling pathways in the brain, activates microglia and induces cognitive and motivational behavioural impairments. The endocannabinoid system may mediate cocaine’s effects. In the present study, we investigated the modulatory effects of the cannabinoid CB2 receptor agonist JWH-133 on cocaine-induced inflammation and motivational behavioural changes in vivo, and the possible effects of fractalkine (CX3CL1) on primary microglia metabolic activity and its subsequent contribution to cocaine-induced neurotoxicity. Our findings show that the CB2-specific receptor agonist, JWH-133, significantly attenuated the reinstatement of cocaine-induced CPP, increased Δ-FOSB expression in the nucleus accumbens (Nac), increased CX3CL1 levels in the ventral tegmental area (VTA) and prefrontal cortex (PFC), and decreased IL-1β in the PFC and NAc of cocaine treated animals. On the other hand, stimulation of the cortical primary microglial cells with CX3CL1 induced a biphasic effect. At a low concentration of 50 nM, CX3CL1 decreased mitochondrial oxidative metabolism vs glycolysis, and decreased the release of the proinflammatory cytokine, IL-1β, but did not affect TNFα. However, a dose of 100 nM of CX3CL1 increased mitochondrial oxidative metabolism, and both, IL-1β and TNFα release. These findings demonstrate that CB2 cannabinoid receptor modulation alters cocaine-induced reward-seeking behaviour and related neurobiological changes and highlights a potential role for CX3CL1 in the modulation of microglial metabolic and inflammatory-mediated activities.