The main goal of this project is to evaluate the influence of a single-nucleotide polymorphism (SNP) on the brain-derived neurotrophic factor (BDNF) gene leading to a valine (Val) for methionine (Met) substitution (Val66Met) in the BDNF prodomain in a model of cross sensitization between stress and cocaine. This SNP has been associated with mood disorders, stress and drug abuse in the human carriers. However, the underlying circuitry and mechanisms involved remains cryptic. We will use male and female BDNF Val/Val and BDNF Met/Met knock-in mice to assess the impact of this SNP on the vulnerability to develop stress-induced cocaine addiction. First, we will evaluate relevant behavioral differences between genotypes generated in response to chronic restraint stress and cocaine. For these experiments, male and female mice will be restrained daily for 30 min, in acrylic tubes specifically designed for this purpose, during 5 consecutive days, while control animals are kept in their home cages. Two weeks after the last stress (day 19), the animals will be exposed to a challenge of cocaine or saline and behavioral sensitization will be evaluated in an open field. In these experiments, we will analyze the effect of stress on locomotor sensitization and anxiety-like behavior using different doses of cocaine. Then, we will evaluate molecular and structural changes in the two subdivisions of nucleus accumbens (NA), core and shell, in mice from both genotypes under this protocol.