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The incentive salience of alcohol: translating the effects of genetic variant in CNR1.

ABSTRACT: The gene that codes for cannabinoid receptor 1 (CNR1) represents an important target for investigations designed to elucidate individual differences in the etiology of alcohol dependence.To achieve a better understanding of the role of the CNR1 gene in the etiology and treatment of alcohol dependence.The present investigation spans multiple levels of analysis, including receptor binding in postmortem brain tissue, neuroimaging, human laboratory models, and analyses of treatment outcome data.Findings indicate that the C allele of rs2023239 is associated with greater CB1 binding in the prefrontal cortex, greater alcohol cue-elicited brain activation in the midbrain and prefrontal cortex, greater subjective reward when consuming alcohol, and more positive outcomes after treatment with a medication that targets the mesocorticolimbic neurocircuitry. In addition, there were strong correlations between cue-elicited brain activation and alcohol consumption measures in individuals with the C allele.Individuals with the C allele may be more susceptible to changes in the mesocorticolimbic neurocircuitry that is involved in the attribution of incentive salience after repeated exposure to alcohol.

SUBMITTER: Hutchison KE

PROVIDER: S-EPMC2856651 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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The incentive salience of alcohol: translating the effects of genetic variant in CNR1.

Hutchison Kent E KE Haughey Heather H Niculescu Michelle M Schacht Joe J Kaiser Alan A Stitzel Jerry J Horton William J WJ Filbey Francesca F

Archives of general psychiatry 20080701 7

<h4>Context</h4>The gene that codes for cannabinoid receptor 1 (CNR1) represents an important target for investigations designed to elucidate individual differences in the etiology of alcohol dependence.<h4>Objective</h4>To achieve a better understanding of the role of the CNR1 gene in the etiology and treatment of alcohol dependence.<h4>Design</h4>The present investigation spans multiple levels of analysis, including receptor binding in postmortem brain tissue, neuroimaging, human laboratory mo ...[more]

PMID: 18606956

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Project description:Background and aimsIn susceptible individuals, cues associated with drug use are theorized to take on incentive-motivational properties, including the ability to reinforce higher-order, drug-related associative learning. This study aimed to test this prediction among people varying in risk for alcohol use disorder.Design, setting and participantsRepeated-measures experiment with a measured individual difference variable at a University psychology laboratory in Missouri, USA. One hundred and six young adults (96 contributed complete data) were pre-selected to represent the upper and lower quartiles of self-reported sensitivity to alcohol's acute effects.MeasurementsParticipants completed a second-order Pavlovian conditioning paradigm in which an initially neutral visual cue (second-order conditional stimulus; CS2 ) predicted onset of an olfactory cue (first-order conditional stimulus; CS1 ). Olfactory cues were isolated from alcoholic beverages, sweets and non-comestible substances, each presumed to have a natural history of first-order conditioning. Event-related potential responses to the CS2 across its conditioning and extinction, and to the CS1 , provided neurophysiological indices of incentive salience (IS).FindingsThe IS of the alcohol CS1 was higher among participants low in alcohol sensitivity (LS), relative to their higher-sensitivity (HS) peers. The IS of the CS2 paired with the alcohol CS1 increased across the CS2 conditioning phase among LS but not HS participants. Also, LS (but not HS) individuals also experienced increases in alcohol craving following alcohol CS1 exposure, and this change was correlated with increases in the IS of the CS2 paired with the alcohol CS1 .ConclusionsAlcoholic beverage odor, a proximal cue for alcohol consumption, appears to reinforce conditioning of neurophysiological responses to a novel cue among low alcohol sensitivity (LS) individuals but not high alcohol sensitivity individuals, providing the first evidence that the LS phenotype may be associated with differences in the conditioned reinforcing properties of alcohol-related cues. These findings support the idea that the LS phenotype may increase alcohol use disorder risk via susceptibility to incentive salience sensitization.

Project description:BACKGROUND:Preclinical and emerging clinical evidence indicates that varenicline, a nicotinic partial agonist approved for smoking cessation, attenuates alcohol seeking and consumption. Reductions of alcohol craving have been observed under varenicline treatment and suggest effects of the medication on alcohol reward processing, but this hypothesis remains untested. METHODS:In this double-blind, placebo-controlled randomized experimental medicine study, 29 heavy drinkers underwent a functional magnetic resonance imaging scan after 2 weeks of varenicline (2mg/d) or placebo administration. During functional magnetic resonance imaging, participants performed the Alcohol-Food Incentive Delay task, where they could earn points for snacks or alcohol. At baseline and after 3 weeks of medication, participants underwent intravenous alcohol self-administration sessions in the laboratory. RESULTS:During the functional magnetic resonance imaging scan, participants in the varenicline group (N=17) reported lower feelings of happiness and excitement on subjective mood scales when anticipating alcohol reward compared with the placebo group (N=12). Linear mixed effects analysis revealed that anticipation of alcohol reward was associated with significant blood oxygen level dependent activation of the ventral striatum, amygdala, and posterior insula in the placebo group; this activation was attenuated in the varenicline group. The varenicline group showed no difference in intravenous alcohol self-administration relative to the placebo group for either session. Participants with higher insula activation when anticipating alcohol reward showed higher alcohol self-administration behavior across groups. CONCLUSIONS:Our findings suggest that varenicline decreases blood oxygen level dependent activation in striato-cortico-limbic regions associated with motivation and incentive salience of alcohol in heavy drinkers. This mechanism may underlie the clinical effectiveness of varenicline in reducing alcohol intake and indicates its potential utility as a pharmacotherapy for alcohol use disorders.

Dataset Information

The incentive salience of alcohol: translating the effects of genetic variant in CNR1.

Publications

The incentive salience of alcohol: translating the effects of genetic variant in CNR1.

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