Abstract
Addiction to major drugs of abuse, such as cocaine, has recently been linked to alterations in adult neurogenesis in the hippocampus. The endogenous cannabinoid system modulates this proliferative response as demonstrated by the finding that pharmacological activation/blockade of cannabinoid CB1 and CB2 receptors not only modulates neurogenesis but also modulates cell death in the brain. In the present study, we evaluated whether the endogenous cannabinoid system affects cocaine-induced alterations in cell proliferation. To this end, we examined whether pharmacological blockade of either CB1 (Rimonabant, 3 mg/kg) or CB2 receptors (AM630, 3 mg/kg) would affect cell proliferation [the cells were labeled with 5-bromo-2′-deoxyuridine (BrdU)] in the subventricular zone (SVZ) of the lateral ventricle and the dentate subgranular zone (SGZ). Additionally, we measured cell apoptosis (as monitored by the expression of cleaved caspase-3) and glial activation [by analyzing the expression of glial fibrillary acidic protein (GFAP) and Iba-1] in the striatum and hippocampus during acute and repeated (4 days) cocaine administration (20 mg/kg). The results showed that acute cocaine exposure decreased the number of BrdU-immunoreactive (ir) cells in the SVZ and SGZ. In contrast, repeated cocaine exposure reduced the number of BrdU-ir cells only in the SVZ. Both acute and repeated cocaine exposure increased the number of cleaved caspase-3-, GFAP- and Iba1-ir cells in the hippocampus, and this effect was counteracted by AM630 or Rimonabant, which increased the number of BrdU-, GFAP-, and Iba1-ir cells in the hippocampus. These results indicate that the changes in neurogenic, apoptotic and gliotic processes that were produced by repeated cocaine administration were normalized by pharmacological blockade of CB1 and CB2. The restorative effects of cannabinoid receptor blockade on hippocampal cell proliferation were associated with the prevention of the induction of conditioned locomotion but not with the prevention of cocaine-induced sensitization.
Highlights
Addiction is a chronic disorder in which contextual memories play important roles in drug-taking and drug-seeking (Koob and Volkow, 2010)
We examined whether pharmacological blockade of either CB1 (Rimonabant, 3 mg/kg) or CB2 receptors (AM630, 3 mg/kg) would affect cell proliferation [the cells were labeled with 5-bromo-2 -deoxyuridine (BrdU)] in the subventricular zone (SVZ) of the lateral ventricle and the dentate subgranular zone (SGZ)
EFFECT open field (OF) ACUTE AND REPEATED ADMINISTRATION OF COCAINE AND CO-ADMINISTRATION OF COCAINE AND RIMONABANT OR AM630 To study the interaction of the pharmacological blockade of CB1 and CB2 receptors and the acute stimulating effects of cocaine, we evaluated locomotor responses to acute doses of cannabinoid receptor antagonists (Rimonabant or AM630 at 3 mg/kg, i.p.) that were administered alone or in combination with cocaine (20 mg/kg, i.p.; Figure 2A)
Summary
Addiction is a chronic disorder in which contextual memories play important roles in drug-taking and drug-seeking (Koob and Volkow, 2010) These contextual memories associate specific environments/stimuli with the reinforcing properties of drugs. Sensitization is not linked to contextual associations; rather, sensitization is linked to plasticity in the dopaminergic signaling in the circuits of the ventral tegmental area, nucleus accumbens, and dorsal striatum (Pierce and Kalivas, 1997; Carlezon and Nestler, 2002).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
