Genetic and early environmental factors interact to influence ethanol's motivational effects. To explore these issues, a reciprocal cross-fostering paradigm was applied to Fischer and Lewis rats. The adult female offspring received vehicle or the kappa opioid antagonist nor-BNI (1 mg/kg) followed by assessments of conditioned taste aversion (CTA), blood alcohol concentrations (BACs) and hypothermia induced by 1.25 g/kg intraperitoneal ethanol. CTA acquisition in the in-fostered Fischer and Lewis animals did not differ;however, the Fischer maternal environment produced stronger acquisition in the cross-fostered Lewis rats versus their in-fostered counterparts. CTAs in the Fischer rats were not affected by cross-fostering. In extinction, the in-fostered Lewis animals displayed stronger aversions than the Fischer groups on two trials (of 12) whereas the cross-fostered Lewis differed from the Fischer groups on nine trials. Despite these CTA effects, Lewis rats exhibited higher BACs and stronger hypothermic responses than Fischer with no cross-fostering effects in either strain. No phenotypes were affected by nor-BNI. These data extend previous findings dissociating the aversive and peripheral physiological effects of ethanol in female Fischer and Lewis rats, and highlight the importance of genetic and early environmental factors in shaping subsequent responses to alcohol's motivational effects in adulthood. Our studies in the role of stress in alcohol abuse have continued. We and others have shown that stress can play an important role in promoting alcohol self-administration and relapse to drug abuse. The corticotropin releasing hormone receptor (CRHR1) plays a central role in initiation of the response to stress. Our studies suggest that CRHR1 antagonists such as antalarmin may be useful in the treatment of human alcohol dependence and relapse to other drugs of abuse, and that optimal treatment may vary between different subtypes of patients. We also tested the hypothesis that sigma receptors modulate ethanol reinforcement and contribute to excessive ethanol intake. We utilized the potent, selective sigma-1 receptor antagonist BD-1063 developed earlier in our laboratory in a number of rat models of alcohol self-administration. Our results also suggest that sigma receptor may contribute to innate or ethanol-induced increases in susceptibility to self-administer high ethanol levels, identifying a potential neuroadaptive mechanism contributing to excessive drinking and a therapeutic target for alcohol abuse and dependence.

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