Voluntary ethanol intake in the rat and the associated accumbal dopamine overflow are blocked by ventral tegmental mecamylamine

Ericson, Mia; Blomqvist, Ola; Engel, Jörgen A.; Söderpalm, Bo

doi:10.1016/s0014-2999(98)00602-5

Cited by 182 publications

(149 citation statements)

References 29 publications

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“…17). ACh levels in the ventral tegmental area are increased in highbut not low-ethanol consuming rats (28), and the nonselective nAChR antagonist mecamylamine decreases ethanol consumption in high-alcohol-preferring rats (20,21) and blocks ethanolinduced dopamine release (21,23,24).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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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.

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: Discussionmentioning

confidence: 99%

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confidence: 99%

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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.

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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“…Interestingly, only perfused mecamylamine in the VTA, but not in the NAc, prevented the accumbal DA overflow after systemic EtOH [38] . The voluntary EtOH self-administration demonstrated an increase in DAergic and cholinergic neurotransmission [39] , suggesting that VTA nAChRs may play an important role in mediating the mesolimbic activating and reinforcing properties of EtOH [40] . During in vitro preparations, EtOH potently modulates nAChRs at low concentrations (100 µmol/L-10 mmol/L), suggesting nAChRs as potential targets for EtOH action [41] .…”

Section: Cellular Mechanisms Of Nachr-mediated Etoh Reward and Dependmentioning

confidence: 99%

Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence

Gao

Taylor

2014

Acta Pharmacol Sin

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Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence. Alcoholism is a serious public health problem and has been identified as the third major cause of preventable mortality in the world. Worldwide, about 2 billion people consume alcohol, with 76.3 million having diagnosable alcohol use disorders. Alcohol is currently responsible for the death of 4% of adults worldwide (about 2.5 million deaths each year), and this number will be significantly increased by 2020 unless effective action is taken. Alcohol is the most commonly abused substance by humans. Ethanol (EtOH) is the intoxicating agent in alcoholic drinks that can lead to abuse and dependence. Although it has been extensively studied, the mechanisms of alcohol reward and dependence are still poorly understood. The major reason is that, unlike other addictive drugs (eg, morphine, cocaine or nicotine) that have specific molecular targets, EtOH affects much wider neuronal functions. These functions include phospholipid membranes, various ion channels and receptors, synaptic and network functions, and intracellular signaling molecules. The major targets in the brain that mediate EtOH's effects remain unclear. This knowledge gap results in a therapeutic barrier in the treatment of alcoholism. Interestingly, alcohol and nicotine are often co-abused, which suggests that neuronal nicotinic acetylcholine receptors (nAChRs), the molecular targets for nicotine, may also contribute to alcohol's abusive properties. Here, we briefly summarize recent lines of evidence showing how EtOH modulates nAChRs in the mesolimbic pathway, which provides a perspective that nAChRs are important targets mediating alcohol abuse.

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Voluntary ethanol intake in the rat and the associated accumbal dopamine overflow are blocked by ventral tegmental mecamylamine

Cited by 182 publications

References 29 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

Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence

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