Although small molecules that act on cannabinoid CB1 receptor are known to modulate cocaine seeking behavior in rodents, the role of type 2 cannabinoid receptor (CB2R) in drug of abuse–related behavior is less clear. Here, Xi and colleagues demonstrate that a selective CB2R antagonist inhibits cocaine self-administration in mice by acting through central CB2Rs in the nucleus accumbens. The presence and function of cannabinoid CB2 receptors in the brain have been the subjects of much debate. We found that systemic, intranasal or intra-accumbens local administration of JWH133, a selective CB2 receptor agonist, dose-dependently inhibited intravenous cocaine self-administration, cocaine-enhanced locomotion, and cocaine-enhanced accumbens extracellular dopamine in wild-type and CB1 receptor knockout (CB1−/−, also known as Cnr1−/−) mice, but not in CB2−/− (Cnr2−/−) mice. This inhibition was mimicked by GW405833, another CB2 receptor agonist with a different chemical structure, and was blocked by AM630, a selective CB2 receptor antagonist. Intra-accumbens administration of JWH133 alone dose-dependently decreased, whereas intra-accumbens administration of AM630 elevated, extracellular dopamine and locomotion in wild-type and CB1−/− mice, but not in CB2−/− mice. Intra-accumbens administration of AM630 also blocked the reduction in cocaine self-administration and extracellular dopamine produced by systemic administration of JWH133. These findings suggest that brain CB2 receptors modulate cocaine's rewarding and locomotor-stimulating effects, likely by a dopamine-dependent mechanism.

Environmental enrichment (EE) increases dentate gyrus (DG) neurogenesis and brain-derived neurotrophic factor (BDNF) levels. However, running is considered an element of EE. To dissociate effects of physical activity and enrichment on hippocampal neurogenesis and BDNF levels, young female C57Bl/6 mice were housed under control, running, enrichment, or enrichment plus running conditions, and injected with bromodeoxyuridine. Cell genesis was assessed after 12 d and differentiation was analyzed 1 mo later. In addition, locomotor activity in the open field and hippocampal mature BDNF peptide levels were measured. Open-field adaptation was improved in all groups, compared to controls, but more so with running. New cell proliferation, survival, neuron number, and neurotrophin levels were enhanced only when running was accessible. We conclude that exercise is the critical factor mediating increased BDNF levels and adult hippocampal neurogenesis.