Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor involved in synaptic differentiation, growth, and maintenance. Increases in BDNF have been shown in substance abuse and decreases in BDNF have been shown in response to stress and major depressive disorder (MDD). We analyzed the effects of BDNF upregulation via lentivirus on Pavlovian conditioned approach (PCA), behavioral sensitization, and nicotine self-administration in rats. Lentiviral-mediated expression cassettes, with dual promoters to drive the BDNF gene and the reporter gene were constructed according to the manufacturer’s instruction and surgically injected into the nucleus accumbens (Nac), the primary brain area that mediates drug reward and reinforcement. Rats were allowed to recover for three weeks before behavioral testing commenced. All rats were trained to associate the presentation of a lever and illumination of a stimulus light with delivery of 20% sucrose in a Pavlovian conditioned approach (PCA) task. Head entries into the receptacle where sucrose was delivered (goal tracking) and lever pressing (sign tracking) during the conditioned stimulus (CS) were measured to determine if BDNF over-expression (BDNF+) altered approach to the sign or goal location. Rats in the BDNF+ group made more goal directed behaviors during the CS than sham group. There were no differences in sign tracking and no differences in basal activity. This pattern suggests that BDNF over-expression may increase reward-related learning in a manner specific to goal tracking. Three days after completion of the PCA task, all animals were habituated to a locomotor arena followed by nicotine behavioral sensitization, and were administered nicotine (ip, 0.5 mg/kg free base) or saline every second day for seven days. Results revealed that the BDNF+ group demonstrated enhanced sensitivity to the hypoactive response to nicotine. At day 7, BDNF+ animals demonstrated enhanced behavioral sensitization to nicotine as compared to all other groups, and Sham NIC animals demonstrated sensitization compared to Sham SAL controls. Thus, it appears increasing NAc BDNF expression enhances the behavioral response to nicotine. Animals were then surgically implanted with a jugular catheter and commenced nicotine self-administration. Interestingly, BDNF+ rats demonstrated reduced nicotine self-administration and motivation to obtain nicotine. Global changes in BDNF expression could be a mediating variable in endophenotypes that are more or less susceptible to drug-taking and substance dependence.