Nicotinic Mechanisms Modulate Ethanol Withdrawal and Modify Time Course and Symptoms Severity of Simultaneous Withdrawal from Alcohol and Nicotine

Abstract

Alcohol and nicotine are among the top causes of preventable death in the United States. Unfortunately, people who are dependent on alcohol are more likely to smoke than individuals in the general population. Similarly, smokers are more likely to abuse alcohol. Alcohol and nicotine codependence affects health in many ways and leads to poorer treatment outcomes in subjects who want to quit. This study examined the interaction of alcohol and nicotine during withdrawal and compared abstinence symptoms during withdrawal from one of the two drugs only vs both. Our results indicate that simultaneous withdrawal from alcohol and nicotine produces physical symptoms that are more severe and last longer than those experienced during withdrawal from one of the two drugs alone. In animals experiencing withdrawal after chronic ethanol treatment, acute nicotine exposure was sufficient to prevent abstinence symptoms. Similarly, symptoms were prevented when alcohol was injected acutely in mice undergoing nicotine withdrawal. These experiments provide evidence for the involvement of the nicotinic cholinergic system in alcohol withdrawal. Furthermore, the outcomes of intracranial microinfusions of mecamylamine, a nonselective nicotinic receptor antagonist, highlight a major role for the nicotinic receptors expressed in medial habenula and interpeduncular nucleus during withdrawal. Overall, the data support the notion that modulating the nicotinic cholinergic system might help to maintain long-term abstinence from alcohol.

Interactions between nicotine and drugs of abuse: a review of preclinical findings

“…Additionally, in studies investigating nicotine and alcohol withdrawal, mice that received simultaneous exposure to nicotine (P.O. in drinking water) and alcohol (daily injections) displayed more somatic withdrawal signs that lasted longer (i.e., >72 hrs) than either drug alone (i.e., <48 hrs; see [59]). Finally, acute nicotine prevented withdrawal symptoms from alcohol discontinuation and acute alcohol prevented withdrawal symptoms from nicotine discontinuation [59].…”

“…in drinking water) and alcohol (daily injections) displayed more somatic withdrawal signs that lasted longer (i.e., >72 hrs) than either drug alone (i.e., <48 hrs; see [59]). Finally, acute nicotine prevented withdrawal symptoms from alcohol discontinuation and acute alcohol prevented withdrawal symptoms from nicotine discontinuation [59]. Taken together, these findings may have important implications for treatment of comorbid nicotine and alcohol use disorders and suggest that the order of treatment may be an important consideration.…”

Mechanisms and genetic factors underlying co-use of nicotine and alcohol or other drugs of abuse

“…However, withdrawal from chronic concurrent exposure, which is more prolonged than withdrawal from either drug alone, can be attenuated by continued treatment with just one of the drugs (132). Furthermore, acute exposure to nicotine after chronic alcohol exposure, or vice versa, results in an attenuation of somatic withdrawal that is reversed by mecamylamine injections into the medial habenula or interpeduncular nucleus (132). …”

No evidence of a role of the β4 subunit of the nicotinic acetylcholine receptor in alcohol-related behaviors

“…Pharmacologic manipulation of nicotinic receptors have demonstrated their involvement in: ethanol consumption [42], ataxia [43], sedation [26], locomotion [34, 44], reward [45], and withdrawal [46, 47]. Moreover, the use of genetically modified animals has yielded additional information on which receptor subunits are important in these behaviors.…”

“…Both pharmacological and genetic manipulations have shown that nicotinic receptors are important for this behavior [46, 47, 50]. Recently, Perez and colleagues have shown that nicotinic acetylcholine receptors in the medial habenula are important in ethanol withdrawal [47]. Although this study did not examine the specific nicotinic receptors that mediate this response, α3β4 receptors are known to be abundant in this region [5].…”