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Phillips TJ1,2,3 and Gubner NR3,4

1VA Portland Health Care System, Portland, OR, USA
2Portland Alcohol Res Center, Oregon Health & Science University, Portland, OR, USA
3Department Behav Neurosci, Oregon Health & Science University, Portland, OR, USA
4Center for Tobacco Control Res and Ed, University of California, San Francisco, CA, USA

The co-use of tobacco and alcohol occurs at a high rate and binge drinking is predictive of smoking status. Individuals who smoke and drink have more severe alcohol dependence and reduced success when trying to stop taking either drug. Doses of nicotine without stimulant effects of their own enhance the acute stimulant effect of ethanol. This suggests a synergistic effect of the two drugs that could involve greater activation of brain pathways that are involved in drug reward than caused by either drug alone. Furthermore, nicotine could enhance the development of neuroadaptations that contribute to alcohol dependence. To examine these hypotheses, we examined the conditioned rewarding and sensitizing effects of nicotine and alcohol (ethanol) alone and in combination. DBA/2J mice were used, because they are particularly sensitive to both ethanol-induced conditioned place preference (CPP; reward) and locomotor sensitization (a measure of neuroadaptation). A well-established CPP procedure that utilizes tactile cues and a drug-free preference test was used to measure conditioned reward. In addition, the “reference dose” procedure was used to directly compare the conditioned rewarding effect of ethanol with that of nicotine plus ethanol. Locomotor sensitization was measured using an established procedure during which treatments occurred daily, drug response was measured every third day, and then a final sensitization test was administered. Nicotine alone (1 or 2 mg/kg nicotine tartrate) did not produce CPP, whereas ethanol (1 g/kg) did. Nicotine dose-dependently interfered with the development of ethanol-induced CPP. Using the reference dose procedure, there was no significant preference or aversion for nicotine plus ethanol versus ethanol alone. Nicotine (1 or 2 mg/kg) did not induce sensitization, whereas ethanol (2 g/kg) did. Enhanced sensitization occurred in response to some nicotine/ethanol dose combinations. Together, nicotine and ethanol can have neuroadaptive effects that differ from the independent effects of each drug. However, our data do not support the hypothesis that nicotine enhances the conditioned rewarding effects of ethanol and indicate that the combined effects of these drugs on locomotor behavior do not predict enhanced reward.
Supported by the Department of Veterans Affairs, NIH grants P60AA010760, T32AA007468, R24AA020245 and F31AA020732, the American Psychological Association, and a Tartar Trust Fellowship.