Opposing actions of chronic stress and chronic nicotine on striatal function in mice.

Stress is a major risk factor in drug addiction development and relapse. Virtually all drugs of abuse act by increasing extracellular dopamine levels in the striatum. To gain an understanding of the interaction between stress and drug exposure, we studied the effects of concomitant chronic nicotine and chronic stress exposure on mouse striatal dopamine levels. C57Bl6/J mice were treated with nicotine in the drinking water or control solution for at least 6 weeks. Some mice were chronically stressed by daily exposure to cold, shaking or restrain. Nicotine-treated mice showed up-regulation of epibatidine binding in several brain regions. In mice treated with both chronic nicotine and stress, epibatidine binding was increased in all studied areas except the dorsal striatum. Therefore, microdialysis was used to measure extracellular dopamine levels in the dorsal striatum of mice chronically treated with nicotine, stress, or both. To have a measure of striatal response to different challenges, we performed microdialysis after acute injection of saline, nicotine, and cocaine. Chronic nicotine enhanced nicotine-dependent dopamine release, while chronic stress blunted the response to cocaine. When mice were subjected to both chronic nicotine and chronic stress, nicotine- and cocaine-dependent dopamine release was undistinguishable from that of control animals. In conclusion, our data suggest that chronic stress and chronic nicotine counteract each other's effect on dopamine release in the striatum. This effect might be mediated by changes in nicotinic acetylcholine receptor up-regulation. This "normalization" of striatal function when both nicotine and stress are present might help explain the comorbidity between stress-related disorders and drug abuse.