Novel models and neurochemical correlates of social and environmental influences on drug reward and drug-seeking behavior.

摘要

Social and environmental factors have a strong influence on the development and maintenance of addiction. Using animal models, two hypotheses were tested regarding the influence of social/environmental factors at different stages of addiction: 1) During initial exposure, drug and social rewards interact synergistically resulting in more robust reward than either component alone; 2) In contrast, during forced abstinence from drug self-administration, social/environmental stimulation decreases motivation for drug. To test the first hypothesis, the effects of cocaine, dextromethorphan, or nicotine on social reward-conditioned place preference (CPP) were examined using sub-threshold parameters for establishing social reward- and drug-CPP. Two pairings of a low dose of either cocaine (2 mg/kg, intraperitoneal) or nicotine (0.1 mg/kg, subcutaneous) or 2 pairings with another rat each failed to produce CPP when examined alone; however, robust CPP was observed with 2 pairings of either drug together with another rat, demonstrating a synergistic interaction between these rewards. In contrast, the non-rewarding drug, dextromethorphan (30 mg/kg, intraperitoneal), failed to enhance social reward-CPP, suggesting that enhancement of social reward-CPP may be specific to rewarding drugs. To test the second hypothesis, rats trained to self-administer cocaine while housed in isolated conditions were then assigned to live in either isolated, pair-housed, or environmental enrichment (EE) conditions during a period of forced abstinence. EE attenuated cocaine-seeking behavior elicited by stimuli paired previously with cocaine infusions, as well as functional activation (i.e., reduced Fos protein expression) throughout several brain regions associated with incentive motivation for cocaine. EE also blunted cocaine-seeking behavior relative to isolation during both short- and long-term abstinence; however, EE did not prevent the time-dependent increases in cocaine-seeking behavior that occur during abstinence (i.e., incubation effect). Neurochemical correlates examined suggested that the protective effects of EE may involve stress attenuation and neural plasticity. Finally, EE in combination with extinction training during abstinence afforded greater protection against cue-elicited cocaine-seeking behavior than either treatment alone; however, these protective effects did not persist once the treatments were discontinued. The findings are among the first to demonstrate preclinically the impact of social/environmental factors on initiation and withdrawal-induced motivation for drug. Consideration of these factors in future research will aide in developing more efficacious prevention and intervention treatment strategies.