Involvement of Nicotinic Receptors in Alcohol Self‐Administration

Lê, A. D.; Corrigall, William A.; Watchus, Jason; Harding, Shannon M.; Juzytsch, Walter; Li, T.-K.

doi:10.1111/j.1530-0277.2000.tb04585.x

Cited by 185 publications

(115 citation statements)

References 41 publications

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“…The ␣4␤2 nAChRs do not seem to have a major role in modulating acute responses to ethanol because the ␣4␤2 nAChR antagonist, dihydro-␤-erythroidine, did not decrease voluntary ethanol consumption in rats (22) and had no effect on ethanolinduced locomotor activity or ethanol-induced dopamine release in mice or rats (45,46). In contrast, in our work the animals were exposed to ethanol from 2 to 5 months before the varenicline treatment.…”

Section: Discussioncontrasting

confidence: 43%

“…The nAChRs are well characterized ligandgated ion channels that, in addition to mediating the rewarding properties of nicotine, also regulate several central functions, such as memory and attention, sleep and wakefulness, anxiety and pain (19). The nAChRs have received little attention despite evidence that they play a role in the development of alcohol dependence.Studies have shown that the nonselective nAChR antagonist, mecamylamine, decreases ethanol consumption in rats (20)(21)(22) and attenuates ethanol-induced dopamine release in the nucleus accumbens (21,23,24). Furthermore, mecamylamine has been reported to block the stimulant or euphoric subjective effects of alcohol and decreases the self-reported desire to consume more alcohol in healthy human volunteers (25-27).…”

mentioning

confidence: 99%

“…Studies have shown that the nonselective nAChR antagonist, mecamylamine, decreases ethanol consumption in rats (20)(21)(22) and attenuates ethanol-induced dopamine release in the nucleus accumbens (21,23,24). Furthermore, mecamylamine has been reported to block the stimulant or euphoric subjective effects of alcohol and decreases the self-reported desire to consume more alcohol in healthy human volunteers (25-27).…”

mentioning

confidence: 99%

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

Steensland

Simms

Holgate

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

344

370

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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...

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Section: Discussioncontrasting

confidence: 43%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Steensland

Simms

Holgate

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

344

370

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“…This result raises the question of whether adolescents that coabuse tobacco and ethanol end up consuming more ethanol in order to attain the desired level of anxiolysis. In this regard, experimental studies in rodents have shown that nicotine increases ethanol self-administration and that this response is suppressed by the nicotinic antagonist mecamylamine (Le et al, 2000), which provides evidence for the involvement of nicotinic receptors in the modulation of ethanol consumption.…”

Section: Anxiolytic Effects During Adolescent Exposurementioning

confidence: 93%

Combined Exposure to Nicotine and Ethanol in Adolescent Mice Differentially Affects Anxiety Levels during Exposure, Short-Term, and Long-Term Withdrawal

Abreu‐Villaça

Nunes

Queiroz-Gomes

et al. 2007

Neuropsychopharmacol

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Smoking and consumption of alcoholic beverages are frequently associated during adolescence. This association could be explained by the cumulative behavioral effects of nicotine and ethanol, particularly those related to anxiety levels. However, despite epidemiological findings, there have been few animal studies of the basic neurobiology of the combined exposure in the adolescent brain. In the present work we assessed, through the use of the elevated plus maze, the short-and long-term anxiety effects of nicotine (NIC) and/or ethanol (ETOH) exposure during adolescence (from the 30th to the 45th postnatal day) in four groups of male and female C57BL/6 mice: (1) Concomitant NIC (nicotine free-base solution (50 mg/ml) in 2% saccharin to drink) and ETOH (ethanol solution (25%, 2 g/kg) i.p. injected every other day) exposure; (2) NIC exposure; (3) ETOH exposure; (4) Vehicle. C57BL/6 mice were selected, in spite of the fact that they present slower ethanol metabolism, because they readily consume nicotine in the concentration used in the present study. During exposure (45th postnatal day: PN45), our results indicated that ethanol was anxiolytic in adolescent mice and that nicotine reverted this effect. Short-term drug withdrawal (PN50) elicited sex-dependent effects: exposure to nicotine and/or ethanol was anxiogenic only for females. Although neither nicotine nor ethanol effects persisted up to 1 month postexposure (PN75), the coadministration elicited an anxiogenic response. In spite of the fact that generalizations based on the results from a single strain of mice are prone to shortcomings, our results suggest that the deficient response to the anxiolytic effects of ethanol in adolescents co-exposed to nicotine may drive higher ethanol consumption. Additionally, increased anxiety during long-term smoking and drinking withdrawal may facilitate relapse to drug use.

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“…In addition to metabolic cross-tolerance a variety of factors including genetic factors may contribute to the dependence on both nicotine and ethanol (Bierut et al, 2004;Goldman et al, 2005;Swan et al, 1997;True et al, 1999;Tyndale, 2003). Additionally, other physiological mechanisms could include the ability of nicotine and ethanol to induce dopamine release in the mesolimbic dopamine system, thereby potentiating each other's rewarding effects (Corrigall et al, 1994;Gonzales et al, 2004), as well as a possible role of activation of nicotinic acetylcholine receptors (Blomqvist et al, 1996;Le et al, 2000). Our study demonstrates that the higher levels of hepatic CYP2E1 after chronic nicotine pretreatment and ethanol self-administration were accompanied by an increase in ethanol consumption and it remains to be tested whether metabolic crosstolerance directly contributes to this.…”

Section: Discussionmentioning

confidence: 99%

Differential induction of ethanol-metabolizing CYP2E1 and nicotine-metabolizing CYP2B1/2 in rat liver by chronic nicotine treatment and voluntary ethanol intake

Yue

Khokhar

Miksys

et al. 2009

European Journal of Pharmacology

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Alcohol and nicotine are frequently co-used and co-abused, and use of both drugs alone can affect hepatic drug metabolism. We investigated the influences of chronic nicotine treatment and voluntary ethanol intake on the induction of rat hepatic cytochrome P450 (CYP) enzymes that metabolize ethanol and nicotine. Rats were trained to voluntarily drink ethanol (6% v/v, 1 h) with nicotine pretreatment for 10 days. Another group of rats were treated with the same nicotine doses alone. Hepatic CYP2E1, CYP2B1/2 and CYP2D1 proteins were assessed by immunoblotting. Nicotine pretreatment (0.4, 0.8 and 1.2 mg/kg) increased voluntary ethanol intake on day 10 by 1.8, 2.0, and 1.4 fold respectively compared to saline pretreatment (P<0.01-0.3). CYP2E1 was increased 1.7, 1.8, and 1.4 fold by the three doses of nicotine alone (P<0.02-0.21); CYP2E1 levels were increased by voluntary ethanol intake alone and a further 2.4, 2.2, and 1.8 fold by 0.4, 0.8, and 1.2 mg/kg nicotine respectively versus saline pretreatment (P<0.002-0.06). CYP2B1/2 proteins were not induced by nicotine alone, but were increased by 2.2-2.5 fold by ethanol drinking (P<0.05). CYP2E1 (r=0.67, P<0.001) and CYP2B1/2 levels (r=0.49, P=0.007) correlated with alcohol consumption on day 10. There was no change in CYP2D1. Chronic nicotine increased voluntary ethanol intake thereby enhancing CYP2E1 and CYP2B1/2 levels. Thus CYPs are regulated not only directly by nicotine and ethanol, but also indirectly via an increase in the ethanol consumption in the presence of nicotine pretreatment. Together this may contribute to the co-abuse of these drugs and alter the metabolism of clinical drugs and endogenous substrates.

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Involvement of Nicotinic Receptors in Alcohol Self‐Administration

Cited by 185 publications

References 41 publications

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

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

Combined Exposure to Nicotine and Ethanol in Adolescent Mice Differentially Affects Anxiety Levels during Exposure, Short-Term, and Long-Term Withdrawal

Differential induction of ethanol-metabolizing CYP2E1 and nicotine-metabolizing CYP2B1/2 in rat liver by chronic nicotine treatment and voluntary ethanol intake

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