Similar to drugs of abuse, the hedonic value of food is mediated, at least in part, by the mesostriatal dopamine (DA) system. Prolonged intake of either high calorie diets or drugs of abuse both lead to a blunting of the DA system. Most studies have focused on DAergic alterations in the striatum, but little is known about the effects of high calorie diets on ventral tegmental area (VTA) DA neurons.
View Article and Find Full Text PDFAlcohol and nicotine are often co-abused. As many as 80-95% of alcoholics are also smokers, suggesting that ethanol and nicotine, the primary addictive component of tobacco smoke, may functionally interact in the central nervous system and/or share a common mechanism of action. While nicotine initiates dependence by binding to and activating neuronal nicotinic acetylcholine receptors (nAChRs), ligand-gated cation channels normally activated by endogenous acetylcholine (ACh), ethanol is much less specific with the ability to modulate multiple gene products including those encoding voltage-gated ion channels, and excitatory/inhibitory neurotransmitter receptors.
View Article and Find Full Text PDFBackground: Nicotine and alcohol are the two most co-abused drugs in the world, suggesting a common mechanism of action might underlie their rewarding properties. Although nicotine elicits reward by activating ventral tegmental area dopaminergic (DAergic) neurons via high-affinity neuronal nicotinic acetylcholine receptors (nAChRs), the mechanism by which alcohol activates these neurons is unclear.
Methods: Because most high-affinity nAChRs expressed in ventral tegmental area DAergic neurons contain the α4 subunit, we measured ethanol-induced activation of DAergic neurons in midbrain slices from two complementary mouse models, an α4 knock-out (KO) mouse line and a knock-in line (Leu9'Ala) expressing α4 subunit-containing nAChRs hypersensitive to agonist compared with wild-type (WT).
Recently, we investigated the molecular mechanisms of the smoking cessation drug varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, in its ability to decrease voluntary ethanol intake in mice. Previous to our study, other labs had shown that this drug can decrease ethanol consumption and seeking in rat models of ethanol intake. Although varenicline was designed to be a high affinity partial agonist of nAChRs containing the α4 and β2 subunits (designated as α4β2*), at higher concentrations it can also act upon α3β2*, α6*, α3β4* and α7 nAChRs.
View Article and Find Full Text PDFRecently, the smoking cessation therapeutic varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, has been shown to reduce alcohol consumption. However, the mechanism and nAChR subtype(s) involved are unknown. Here we demonstrate that varenicline and alcohol exposure, either alone or in combination, selectively activates dopaminergic (DAergic) neurons within the posterior, but not the anterior, ventral tegmental area (VTA).
View Article and Find Full Text PDFRationale: Recent reports describe a restricted access ethanol consumption paradigm where C57Bl/6J mice drink until intoxicated. Termed "drinking in the dark" (DID), this paradigm has been used as a model of binge drinking. Although neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in alcohol drinking in rats pre-trained to self-administer ethanol, their role in binge-like ethanol consumption is unknown.
View Article and Find Full Text PDFTolerance, 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.
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