Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor

The mesolimbic dopamine (DA) system has been implicated in drug reward, loc omotor sensitization, and responding for reward-related stimuli [termed con ditioned reinforcers (CR)]. Here, we investigated the effect of brain-deriv ed neurotrophic factor (BDNF), which enhances the survival and function of dopaminergic neurons, on stimulant-induced locomotor sensitization and resp onding for CR. In experiment 1, BDNF was infused into the nucleus accumbens (NAc) or ventral tegmental area over 2 weeks via chronically implanted min ipumps (1-2.5 mu g/d), and the psychomotor stimulant effects of cocaine (5- 15 mg/kg, i.p.) were studied. We found that BDNF enhanced the initial stimu lant effects of cocaine and seemed to facilitate the development of sensiti zation to repeated cocaine doses. In experiment 2, we studied the effects o f intra-NAc BDNF infusions on responding for CR. BDNF-treated rats showed t wice as many CR responses compared with controls when saline was first admi nistered. BDNF enhanced responding on the CR lever more than four times tha t seen in control animals after a cocaine injection (10 mg/kg, i.p.). The e nhanced response to cocaine in BDNF-treated animals persisted for more than a month after the BDNF infusions had stopped, indicating longlasting chang es in the mesolimbic DA system caused by BDNF administration. In experiment 3, we examined locomotor sensitization to cocaine in heterozygous BDNF kno ck-out mice and found that the development of sensitization was delayed com pared with wild-type littermates. These results demonstrate the profound ef fects of BDNF on the enhancement of both cocaine-induced locomotion and fac ilitation of CR and suggest a possible role for BDNF in long-term adaptatio ns of the brain to cocaine.