Role of different nicotinic acetylcholine receptors in mediating behavioral and neurochemical effects of ethanol in mice

Larsson, Åsa; Svensson, Lennart; Söderpalm, Bo; Engel, Jörgen A.

doi:10.1016/s0741-8329(02)00244-6

Cited by 118 publications

(103 citation statements)

References 52 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: 54%

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.

342

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: 54%

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.

342

370

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“…However, our focus on striatum is based in part on the known role this circuitry plays in these behavioral outcomes. Ethanol, via both direct and indirect activation of DAergic neurons in the ventral tegmental area (26)(27)(28)(29), increases dopamine release in the striatum, which is associated with both the motivational and locomotor properties of most abused drugs. In addition, our data are consistent with recent reports in c-elegans indicating a role for BK channels in depression of locomotor effects of alcohol (11).…”

Section: Discussionmentioning

confidence: 99%

Identification of a BK channel auxiliary protein controlling molecular and behavioral tolerance to alcohol

Martin

Hendrickson²,

Penta³

et al. 2008

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

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Tolerance, described as the loss of drug effectiveness over time, is an important component of addiction. The degree of acute behavioral tolerance to alcohol exhibited by a naïve subject can predict the likelihood of alcohol abuse. Thus, the determinants of acute tolerance are important to understand. Calcium-and voltage-gated (BK) potassium channels, consisting of pore forming ␣ and modulatory ␤ subunits, are targets of ethanol (EtOH) action. Here, we examine the role, at the molecular, cellular, and behavioral levels, of the BK ␤4 subunit in acute tolerance. Single channel recordings in HEK-293 cells show that, in the absence of ␤4, EtOH potentiation of activity exhibits acute tolerance, which is blocked by coexpressing the ␤4 subunit. BK channels in acutely isolated medium spiny neurons from WT mice (in which the ␤4 subunit is well-represented) exhibit little tolerance. In contrast, neuronal BK channels from ␤4 knockout (KO) mice do display acute tolerance. Brain slice recordings showed tolerance to EtOH's effects on spike patterning in KO but not in WT mice. In addition, ␤4 KO mice develop rapid tolerance to EtOH's locomotor effects, whereas WT mice do not. Finally, in a restricted access ethanol self-administration assay, ␤4 KO mice drink more than their WT counterparts. Taken together, these data indicate that the ␤4 subunit controls ethanol tolerance at the molecular, cellular, and behavioral levels, and could determine individual differences in alcohol abuse and alcoholism, as well as represent a therapeutic target for alcoholism.electrophysiology ͉ knockout mice ͉ striatum ͉ addiction ͉ plasticity A lcohol abuse is the third largest cause of preventable mortality in the world. Tolerance, described as the gradual loss of drug effectiveness over time, is a hallmark of abused drugs. This phenomenon is particularly important in the response to acute alcohol because the degree of tolerance exhibited by a naïve subject can predict the likelihood to develop alcohol abuse (1-4). Thus, identifying the mechanistic and molecular underpinnings of tolerance is essential for understanding the pathophysiology of alcoholism, as well as determining potential therapeutic targets for alcohol abuse. The neurobiology of tolerance is thought to involve several types of adaptation, ranging from alteration in membrane lipid composition (5) to neuroadaptative changes in target proteins (6, 7).In recent years, large conductance calcium-and voltage-gated potassium (BK) channels have emerged as one of the key targets of ethanol action, yet their role in the physiological and behavioral response to alcohol are unknown. Invertebrate studies suggest that BK channels may be important for the development of tolerance to ethanol (8, 9). In mammals, BK channels exist as a complex formed by the association of the pore-forming ␣ subunit with the auxiliary ␤ subunit. The ␣ subunit is encoded by only one gene (slo) with several splice variants (STREX, P27, insertless, etc.), whereas the ␤ subunit is the product of four distinct genes (␤1-␤4)...

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“…Nicotine acts primarily at nACh receptors, whereas ethanol acts on a wide variety of targets that include nAChRs (Bowers et al 2005;Escher and Mittleman 2004;Larsson et al 2002;Melia et al 1996;Meyerhoff et al 2006;Wehner et al 2004;White et al 2000). Thus, ethanol may directly interact with nicotine by altering nAChR function; in support, ethanol stabilizes the open state of nAChRs, producing a twofold leftward shift in the acetylcholine response curve (Forman and Zhou 1999).…”

Section: Discussionmentioning

confidence: 99%

Interactive effects of ethanol and nicotine on learning in C57BL/6J mice depend on both dose and duration of treatment

Gulick

Gould

2007

Psychopharmacology

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Objective and rationale-Alcohol and nicotine are commonly co-abused; one possible explanation for co-abuse is that each drug ameliorates the aversive effects of the other. Both drugs have dose-dependent effects on learning and memory. Thus, this study examined the interactive effects of acute ethanol and acute, chronic, or withdrawal from chronic nicotine on fear conditioning in C57BL/6J mice.Materials and methods-Conditioning consisted of auditory conditioned stimulus-foot-shock unconditioned stimulus pairings. For acute studies, saline or ethanol, then saline or nicotine was administered before training, and saline or nicotine was also administered before testing. For chronic and withdrawal studies, saline or nicotine was administered chronically, and ethanol or saline was administered before training.Results-Acute nicotine (0.09 mg/kg) reversed ethanol-induced deficits (1.0 and 1.5 g/kg) in contextual and cued fear conditioning, whereas a low dose of ethanol (0.25 g/kg) reversed nicotine (6.3 mg kg −1 day −1 ) withdrawal-induced deficits in contextual conditioning. Tolerance developed for the effects of nicotine on ethanol-induced deficits in conditioning and cross-tolerance between chronic nicotine and acute ethanol was seen for the enhancing effects of ethanol on conditioning.Conclusions-The complex and sometimes polar actions of ethanol and nicotine on behavior may contribute to co-abuse of these drugs. Specifically, smoking may initially reduce the aversive effects of ethanol, but tolerance develops for this effect. In addition, low doses of alcohol may lessen nicotine withdrawal symptoms.

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Role of different nicotinic acetylcholine receptors in mediating behavioral and neurochemical effects of ethanol in mice

Cited by 118 publications

References 52 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

Identification of a BK channel auxiliary protein controlling molecular and behavioral tolerance to alcohol

Interactive effects of ethanol and nicotine on learning in C57BL/6J mice depend on both dose and duration of treatment

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