Genetic linkage analysis of rats that were selectively bred for alcohol preference identified a chromosomal region that includes the neuropeptide Y (NPY) gene. Alcohol-preferring rats have lower levels of NPY in several brain regions compared with alcohol-non-preferring rats. We therefore studied alcohol consumption by mice that completely lack NPY as a result of targeted gene disruption. Here we report that NPY-deficient mice show increased consumption, compared with wild-type mice, of solutions containing 6%, 10% and 20% (v/v) ethanol. NPY-deficient mice are also less sensitive to the sedative/hypnotic effects of ethanol, as shown by more rapid recovery from ethanol-induced sleep, even though plasma ethanol concentrations do not differ significantly from those of controls. In contrast, transgenic mice that overexpress a marked NPY gene in neurons that usually express it have a lower preference for ethanol and are more sensitive to the sedative/hypnotic effects of this drug than controls. These data are direct evidence that alcohol consumption and resistance are inversely related to NPY levels in the brain.

Both in vitro and in vivo evidence indicate that cAMP-dependent protein kinase (PKA) mediates some of the acute and chronic cellular responses to alcohol. However, it is unclear whether PKA regulates voluntary alcohol consumption. We therefore studied alcohol consumption by mice that completely lack the regulatory IIbeta (RIIbeta) subunit of PKA as a result of targeted gene disruption. Here we report that RIIbeta knockout mice (RIIbeta-/-) showed incr eased consumption of solutions containing 6, 10, and 20% (v/v) ethanol when compared with wild-type mice (RIIbeta+/+). On the other hand, RIIbeta-/- mice showed normal consumption of solutions containing either sucrose or quinine. When compared with wild-type mice, the RIIbeta-/- mice were found to be less sensitive to the sedative effects of ethanol as measured by more rapid recovery from ethanol-induced sleep, even though plasma ethanol concentrations did not differ significantly from those of controls. Finally, both RIbeta- and catylatic subunit beta1-deficient mice showed normal voluntary consumption of ethanol, indicating that increased ethanol consumption is not a general characteristic associated with deletion of PKA subunits. These data demonstrate a role for the RIIbeta subunit of PKA in regulating voluntary consumption of alcohol and sensitivity to the intoxication effects that are produced by this drug.

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Several emerging theories of addiction have described how abused substances exploit vulnerabilities in decision-making processes. These vulnerabilities have been proposed to result from pharmacologically corrupted neural mechanisms of normal brain valuation systems. High alcohol intake in rats during adolescence has been shown to increase risk preference, leading to suboptimal performance on a decision-making task when tested in adulthood. Understanding how alcohol use corrupts decision making in this way has significant clinical implications. However, the underlying mechanism by which alcohol use increases risk preference remains unclear. To address this central issue, we assessed dopamine neurotransmission with fast-scan cyclic voltammetry during reward valuation and risk-based decision making in rats with and without a history of adolescent alcohol intake. We specifically targeted the mesolimbic dopamine system, the site of action for virtually all abused substances. This system, which continuously develops during the adolescent period, is central to both reward processing and risk-based decision making. We report that a history of adolescent alcohol use alters dopamine signaling to risk but not to reward. Thus, a corruption of cost encoding suggests that adolescent alcohol use leads to long-term changes in decision making by altering the valuation of risk.

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Children with neoplastic diseases were offered an unusual ice cream before their drug treatments. Patients experiencing gastrointestinal toxicity due to the drugs were subsequently less likely to choose that ice cream again than controls. This suggests that taste aversions induced by drug-associated symptoms may contribute to the appetite loss experienced by cancer patients.

Individuals who abused alcohol at an early age show decisionmaking impairments. However, the question of whether maladaptive choice constitutes a predisposing factor to, or a consequence resulting from, alcohol exposure remains open. To examine whether a causal link exists between voluntary alcohol consumption during adolescence and adult decision making the present studies used a rodent model. High levels of voluntary alcohol intake were promoted by providing adolescent rats with access to alcohol in a palatable gel matrix under nondeprivation conditions. A probability-discounting instrumental response task offered a choice between large but uncertain rewards and small but certain rewards to assess risk-based choice in adulthood either 3 weeks or 3 months following alcohol exposure. While control animals' performance on this task closely conformed to a predictive model of risk-neutral value matching, rats that consumed high levels of alcohol during adolescence violated this model, demonstrating greater risk preference. Evidence of significant risk bias was still present when choice was assessed 3 months following discontinuation of alcohol access. These findings provide evidence that adolescent alcohol exposure may lead to altered decision making during adulthood and this model offers a promising approach to the investigation of the neurobiological underpinnings of this link.adolescence ͉ probability discounting A dolescent alcohol use is a serious public health problem and is associated with an increased risk for development of chronic alcohol use disorders in adulthood (1). Furthermore, an association between a history of alcohol abuse and deficits in decision making has been documented (2-5). However, the question of whether maladaptive choices constitute a predisposing factor to, or a consequence resulting from, alcohol use remains open. Animal models allow for direct testing of causality and for examination of potential neural substrates underlying an association between alcohol use and risky decision making.Developing rodent models of alcohol abuse has been challenged by the fact that most rat strains do not freely consume significant amounts of ethanol in solution. A method for overcoming the reluctance of nondeprived rats to drink high levels of ethanol in solution was developed by Rowland et al. (6). It utilizes a palatable gel matrix containing ethanol and when made available to rats it stimulates robust and reliable selfadministration, without the need for fluid or food deprivation or any training period. Intake of these alcohol ''Jello Shots'' resulted in significant elevations of blood alcohol concentrations (6) in the range of 5 to 45 mg % with a linear relationship to amount consumed (r ϭ 0.94). Furthermore, alterations in brain chemistry in association with this administration protocol have also been documented (7-8). Since this delivery method does not require training to promote intake, it is particularly appropriate for developmental studies, such as those focused on adolescence, since, in ro...

Sensitization to drugs, such as amphetamine, is associated with alterations in the morphology of neurons in the nucleus accumbens, a brain region critical to motivation and reward. The studies reported here indicate that a strong natural motivator, sodium depletion and associated salt appetite, also leads to alterations in neurons in nucleus accumbens. Medium spiny neurons in the shell of the nucleus accumbens of rats that had experienced sodium depletions had significantly more dendritic branches and spines than controls. In addition, a history of sodium depletions was found to have cross-sensitization effects, leading to enhanced psychostimulant responses to amphetamine. Thus, neuronal alterations common to salt and drug sensitization may provide a general mechanism for enhanced behavioral responses to subsequent exposures to these challenges.