Involvement of neuronal nitric oxide synthase in cross-sensitization between chronic unpredictable stress and ethanol in adolescent and adult mice.

The peculiar neurochemical profile of the adolescent brain renders it differently susceptible to several stimuli, including stress and/or drug exposure. Among several stress mediators, nitric oxide (NO) has a role in stress responses. We have demonstrated that adolescent mice are less sensitive to ethanol-induced sensitization than adult mice. The present study investigated whether chronic unpredictable stress (CUS) induces behavioral sensitization to ethanol in adolescent and adult Swiss mice, and investigated the influence of Ca2+-dependent nitric oxide synthase (NOS) activity in the phenomenon. Adolescent and adult mice were exposed to repeated 1.8 g/kg ethanol or CUS and challenged with saline or ethanol. A neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7NI), was administered along with ethanol and CUS to test its effects on behavioral sensitization. Both adolescent and adult mice displayed cross-sensitization between CUS and ethanol in adult mice, with adolescents showing a lower degree of sensitization than adults. nNOS inhibition by 7NI reduced both ethanol sensitization and cross-sensitization. All age differences in the Ca2+-dependent NOS activity in the hippocampus and prefrontal cortex were in the direction of greater activity in adults than in adolescents. Adolescents showed lower sensitivity to cross-sensitization between CUS and ethanol, and the nitric oxide (NO) system seems to have a pivotal role in ethanol-induced behavioral sensitization and cross-sensitization in both adolescent and adult mice.

Environmental enrichment blocks ethanol-induced locomotor sensitization and decreases BDNF levels in the prefrontal cortex in mice.

The use of addictive drugs can lead to long-term neuroplastic changes in the brain, including behavioral sensitization, a phenomenon related to addiction. Environmental enrichment (EE) is a strategy used to study the effect of environment on the response to several manipulations, including treatment with addictive drugs. Brain-derived neurotrophic factor (BDNF) has been associated with behaviors related to ethanol addiction. The aim of the present study was to evaluate the effects of EE on ethanol-induced behavioral sensitization and BDNF expression. Mice were exposed to EE and then repeatedly treated with a low dose (1.8 g/kg) of ethanol. Another group of mice was first subjected to repeated ethanol treatment according to the behavioral sensitization protocol and then exposed to EE. Environmental enrichment prevented the development of ethanol-induced behavioral sensitization and blocked behavioral sensitization in sensitized mice. Both repeated ethanol and EE decreased BDNF levels in the prefrontal cortex but not in the hippocampus. However, BDNF levels were lower in ethanol-treated mice exposed to EE. These findings suggest that EE can act on the mechanisms implicated in behavioral sensitization, a model for drug-induced neuroplasticity and relapse. Additionally, EE alters BDNF levels, which regulate addiction-related behaviors.