Document Type


Degree Name



Dept. of Behavioral Neuroscience


Oregon Health & Science University


Excessive alcohol (ethanol) consumption or the use of nicotine-containing tobacco products have significant health risks and result in high costs to society. Of particular concern is that nicotine and ethanol share a high rate of co-abuse, although underlying reasons remain unclear. One hypothesis for the co-use of nicotine and tobacco is that these drugs in combination have enhanced rewarding and neuroadaptive effects, compared to either drug alone, which could potentially increase risk to develop dependence.

The first goal of this research was to examine the combined vs. independent effects of nicotine and ethanol, using mouse models of drug sensitivity, reward, and neuroadaptation. The behavioral measures used to model these factors relevant to addiction were acute locomotor stimulation, conditioned place preference (CPP), and locomotor sensitization. In addition, we measured changes in density of nicotinic acetylcholine receptors (nAChRs) after repeated exposure to these drugs, using autoradiography. We hypothesized that nicotine and ethanol in combination would have greater stimulating, rewarding and neuroadaptive effects compared to either drug alone. Analysis of combined vs independent drug effects on these traits could provide information that will help to understand why these drugs are co-abused.

In FAST and DBA/2J mice, genotypes of mice sensitive to ethanol-induced stimulation, doses of nicotine, without stimulant effects, accentuated the locomotor stimulant response to ethanol. These data indicate that genetically-determined sensitivity to the stimulant effect of ethanol is necessary to see this accentuating effect of nicotine. In DBA/2J inbred strain mice, neither dose of nicotine alone produced CPP, whereas ethanol did, using a standard CPP procedure. The magnitude of ethanol-induced CPP was not affected by co-administration of 1 mg/kg nicotine tartrate, but 2 mg/kg nicotine tartrate interfered with the development of ethanol-induced CPP. Using a reference dose-like procedure, there was no significant preference or aversion for cues paired with nicotine + ethanol versus those paired with ethanol alone. These data suggest that nicotine does not enhance the conditioned rewarding effect of ethanol. Behavioral sensitization is a model of the neuroadaptations caused by repeated drug exposure that are thought to contribute to the development of persistent drug taking and relapse. The combined effects of nicotine and ethanol on locomotor sensitization were dependent on the dose of ethanol and whether testing was performed with the drugs in combination (during the acquisition phase) or after ethanol treatment alone (on the ethanol challenge day). Nicotine plus 1 g/kg ethanol had limited effects on the development of sensitization during the acquisition phase but resulted in a lack of sensitized response to the ethanol challenge. Nicotine plus 2 g/kg ethanol resulted in greater sensitization during the acquisition phase, when the drugs were administered in combination, but did not alter the response to the ethanol alone challenge. Our data do not support a role for nicotine + ethanol on the regulation of nAChR in the ventral tegmental area or nucleus accumbens in the combined effects of these drugs in the sensitization model.

The second goal of this research was to further evaluate varenicline as a potential treatment for ethanol dependence using several mouse models. Previous research has indicated that nAChRs are a potential target for novel pharmacotherapeutic treatment of ethanol dependence. Varenicline, a partial nAChR agonist and approved smoking cessation therapeutic, has previously been found to reduce ethanol consumption in humans and animal models of ethanol use. The current studies examined the effects of varenicline on non-consummatory traits relevant to ethanol addiction. We hypothesized that varenicline would attenuate the rewarding and locomotor sensitizing effects of ethanol, elucidating why varenicline might be an effective pharmacotherapy for ethanol dependence. Contrary to our hypothesis, varenicline did not attenuate the expression of ethanol-induced CPP. However, varenicline was found to attenuate ethanol-induced stimulation and the expression of ethanol-induced sensitization, in the absence of a significant effect on the acquisition of ethanol-induced sensitization. This suggests that varenicline may reduce not only acute ethanol effects, but also the effects of ethanol-established neuroadaptations that may encourage ethanol drinking. However, varenicline may not be effective at attenuating the response to ethanol-associated cues that may contribute to the continued use of ethanol or trigger relapse.




School of Medicine



To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.