Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking

Abstract

Alcohol dependence is a disease that impacts millions of individuals worldwide. There has been some progress with pharmacotherapy for alcohol-dependent individuals; however, there remains a critical need for the development of novel and additional therapeutic approaches. Alcohol and nicotine are commonly abused together, and there is evidence that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in both alcohol and nicotine dependence. Varenicline, a partial agonist at the ␣4␤2 nAChRs, reduces nicotine intake and was recently approved as a smoking cessation aid. We have investigated the role of varenicline in the modulation of ethanol consumption and seeking using three different animal models of drinking. We show that acute administration of varenicline, in doses reported to reduce nicotine reward, selectively reduced ethanol but not sucrose seeking using an operant self-administration drinking paradigm and also decreased voluntary ethanol but not water consumption in animals chronically exposed to ethanol for 2 months before varenicline treatment. Furthermore, chronic varenicline administration decreased ethanol consumption, which did not result in a rebound increase in ethanol intake when the varenicline was no longer administered. The data suggest that the ␣4␤2 nAChRs may play a role in ethanol-seeking behaviors in animals chronically exposed to ethanol. The selectivity of varenicline in decreasing ethanol consumption combined with its reported safety profile and mild side effects in humans suggest that varenicline may prove to be a treatment for alcohol dependence.A lcohol dependence constitutes one of the most serious public health problems worldwide. There are only three medications available for the treatment of alcohol dependence; disulfiram, acamprosate, and naltrexone. The opioid antagonist, naltrexone, has demonstrated the most consistent effect in reducing alcohol consumption in the context of behavioral therapy (1). Naltrexone has been shown to decrease ethanol consumption in numerous animal (2-6) and clinical studies (7-10) and has been shown to be more effective in heavy or excessive drinkers (11). However, not all patients respond to naltrexone, which is partly explained by genetic variations in the opioid receptor gene (12). Furthermore, opioid receptor antagonists decrease both ethanol and sucrose intake in rodents (13,14). Alcohol dependence is a complex disorder that will require the use of different therapeutic approaches to treat the disease effectively.Environmental and genetic factors contribute to an individual's risk of becoming dependent on drugs of abuse such as ethanol and nicotine. Approximately 85% of alcoholics smoke, and it has been suggested that common genes control the development of both alcohol and nicotine dependence (15). Furthermore, heavy drinkers tend to be heavy smokers, and alcohol influences nicotine dependence (16). Both nicotine and ethanol can either directly or indirectly activate the brain reward system through neuronal nicotinic acetylcholine re...

Association of the CHRNA4 Neuronal Nicotinic Receptor Subunit Gene with Frequency of Binge Drinking in Young Adults

“…Further evidence is provided in recent animal studies of varenicline, an alpha4-beta2 nicotinic receptor partial agonist used in smoking cessation. This drug reduces not only nicotine dependence, but also alcohol consumption in rats (Steensland et al, 2007). Hendrickson et al (2010) showed this effect depends specifically on activation of alpha4 nicotinic receptors.…”

The role of the central ghrelin system in reward from food and chemical drugs

“…Interestingly, these subtypes also mediate the rewarding properties of alcohol, alcohol cues as well as alcohol intake in rodents (Ericson et al 2009;Jerlhag et al 2006b;Larsson and Engel 2004;Löf et al 2007;Steensland et al 2007). These data are verified in clinical tests; thus blocking these subtypes, by using varenicline, reduces the intake of alcohol in heavy drinking smokers (McKee et al 2009) and one haplotype of the 6* gene is associated with heavy alcohol use ).…”

Novel Therapeutic Strategies for Alcohol and Drug Addiction: Focus on GABA, Ion Channels and Transcranial Magnetic Stimulation

“…We also showed that chlorzoxazone, an FDA-approved SK activator used for decades as a centrally acting myorelaxant, significantly reduces excessive alcohol intake in rats with intermittent access to ethanol, but does not reduce the more moderate alcohol intake in rats with continuous access to alcohol (Hopf et al, 2011). Alcohol intake in intermittent-access rats shows a number of other features, which have been considered to perhaps model some aspects of human alcoholism, including escalation of intake, sensitivity to compounds that reduce alcohol intake in human alcoholics (Steensland et al, 2007; Novel therapeutic strategies for addiction G Addolorato et al ............................................................................................................................................................... Simms et al, 2008;McKee et al, 2009) and aversion-resistant and perhaps compulsive alcohol intake (Hopf et al, 2010b). Thus, the SK activator chlorzoxazone may represent a potent and immediately accessible treatment for human alcoholism.…”