Neutralization of neutrophin-3 in the ventral tegmental area or nucleus accumbens differentially modulates cocaine-induced behavioral plasticity in rats

These experiments were designed to assess the influence of neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) in the mesoaccumbens dopamine system on the initiation of behavioral sensitization to cocaine. A neutralizing antibody for NT-3, BDNF or their vehicle was administered into the ventral tegmental area (VTA) or nucleus accumbens prior to each of four daily injections of 15 mg/kg cocaine. Behavioral sensitization was operationally defined as a significant increase in the behavioral response to cocaine relative to the first daily injection. Results indicated that the NT-3 antibody had differential effects when administered into the VTA or nucleus accumbens. Intra-VTA microinjection of anti-NT-3 resulted in enhanced sensitization to repeated cocaine injections in that the cocaine-induced behavioral response in the anti-NT-3 group was significantly greater than the vehicle group following the second and third daily injections of cocaine. Administration of anti-NT-3 into the nucleus accumbens increased the behavioral response to cocaine over all 4 days of cocaine administration, with no sensitization of this behavioral response. In contrast, pretreatment with anti-BDNF into the VTA or nucleus accumbens had no influence on the initiation of behavioral sensitization to cocaine. Taken together, these data indicate that neutralization of NT-3 in the VTA enhances cocaine-induced behavioral sensitization, while administration of the NT-3 antibody into the nucleus accumbens increases the hyperactive behavioral response induced by cocaine but impairs the further development of behavioral sensitization.