Much evidence from studies in humans and animals supports the hypothesis that alcohol addiction is a complex disease with both hereditary and environmental influences. Molecular determinants of excessive alcohol consumption are difficult to study in humans. However, several rodent models show a high or low degree of alcohol preference, which provides a unique opportunity to approach the molecular complexities underlying the genetic predisposition to drink alcohol. Microarray analyses of brain gene expression in three selected lines, and six isogenic strains of mice known to differ markedly in voluntary alcohol consumption provided >4.5 million data points for a meta-analysis. A total of 107 arrays were obtained and arranged into six experimental data sets, allowing the identification of 3,800 unique genes significantly and consistently changed between all models of high or low amounts of alcohol consumption. Several functional groups, including mitogen-activated protein kinase signaling and transcription regulation pathways, were found to be significantly overrepresented and may play an important role in establishing a high level of voluntary alcohol drinking in these mouse models. Data from the general meta-analysis was further filtered by a congenic strain microarray set, from which cis-regulated candidate genes for an alcohol preference quantitative trait locus on chromosome 9 were identified: Arhgef12, Carm1, Cryab, Cox5a, Dlat, Fxyd6, Limd1, Nicn1, Nmnat3, Pknox2, Rbp1, Sc5d, Scn4b, Tcf12, Vps11, and Zfp291 and four ESTs. The present study demonstrates the use of (i) a microarray meta-analysis to analyze a behavioral phenotype (in this case, alcohol preference) and (ii) a congenic strain for identification of cis regulation.alcoholism ͉ gene expression ͉ microarray

The Rescorla-Wagner model has been the most influential theory of associative learning to emerge from the study of animal behavior over the last 25 years. Recently, equivalence to this model has become a benchmark in assessing connectionist models, with such equivalence often achieved by incorporating the Widrow-Hoff delta rule. This article presents the Rescorla-Wagner model's basic assumptions, reviews some of the model's predictive successes and failures, relates the failures to the model's assumptions, and discusses the model's heuristic value. It is concluded that the model has had a positive influence on the study of simple associative learning by stimulating research and contributing to new model development. However, this benefit should neither lead to the model being regarded as inherently "correct" nor imply that its predictions can be profitably used to assess other models.

Many studies have used voluntary ethanol consumption by animals to assess the influence of genetic and environmental manipulations on ethanol drinking. However, the relationship between home cage ethanol consumption and more formal assessments of ethanol-reinforced behavior using operant and instrumental conditioning procedures is not always clear. The present review attempted to evaluate whether there are consistent correlations between mouse and rat home cage ethanol drinking on the one hand, and either operant oral self-administration (OSA), conditioned taste aversion (CTA) or conditioned place preference (CPP) with ethanol on the other. We also review literature on intravenous ethanol self-administration (IVSA). To collect data, we evaluated a range of genetic manipulations that can change both genes and ethanol drinking behavior including selective breeding, transgenic and knock-out models, and inbred and recombinant inbred strain panels. For a genetic model to be included in the analysis, there had to be published data resulting in differences on home cage drinking and data for at least one of the other behavioral measures. A consistent, positive correlation was observed between ethanol drinking and OSA, suggesting that instrumental behavior is closely genetically related to consummatory and ingestive behavior directed at ethanol. A negative correlation was observed between CTA and drinking, suggesting that ethanol's aversive actions may limit oral consumption of ethanol. A more modest, positive relationship was observed between drinking and CPP, and there were not enough studies available to determine a relationship with IVSA. That some consistent outcomes were observed between widely disparate behavioral procedures and genetic populations may increase confidence in the validity of findings from these assays. These findings may also have important implications when researchers decide which phenotypes to use in measuring alcohol-reward relevant behaviors in novel animal models.

Background-Repeated studies have shown that high impulsivity, when defined as the tendency to choose small immediate rewards over larger delayed rewards, is more prevalent in drug addicts and alcoholics when compared with nonaddicts. Assessing whether impulsivity precedes and potentially causes addiction disorders is difficult in humans because they all share a history of drug use. In this study, we address this question by testing alcohol-naïve mice from lines showing heritable differences in alcohol intake.

Identifying and characterizing brain regions regulating alcohol consumption is beneficial for understanding the mechanisms of alcoholism. To this aim, we first identified brain regions changing in expression of the inducible transcription factor c-Fos in the alcohol-preferring C57BL/6J (B6) and alcohol-avoiding DBA/2J (D2) mice after ethanol consumption. Drinking a 5% ethanol/10% sucrose solution in a 30 min limited access procedure led to induction of c-Fos immunoreactivity in urocortin (Ucn)-positive cells of the Edinger-Westphal nucleus (EW), suppression of c-Fos immunoreactivity in the dorsal portion of the lateral septum (LS) of both strains of mice, and strain-specific suppression in the intermediate portion of the LS and the CA3 hippocampal region. Because the EW sends Ucn projections to the LS, and B6 and D2 mice differ dramatically in EW Ucn expression, we further analyzed the Ucn EW-LS pathway using several genetic approaches. We find that D2 mice have higher numbers of Ucn-immunoreactive processes than B6 mice in the LS and that consumption of ethanol/sucrose in the F2 offspring of a B6D2 intercross positively correlates with Ucn immunoreactivity in the EW and negatively correlates with Ucn immunoreactivity in the LS. In agreement with these findings, we find that alcohol-avoiding male B6.D2 Alcp1 line 2.2 congenic mice have lower Ucn immunoreactivity in the EW than male B6.B6 mice. Finally, we also find that HAP mice, selectively bred for high alcohol preference, have higher Ucn immunoreactivity in EW, than LAP mice, selectively bred for low alcohol preference. Taken together, these studies provide substantial evidence for involvement of the EW-LS Ucn pathway in alcohol consumption.

Treatments that attenuate latent inhibition (U) were examined using conditioned suppression in rats. In Experiment 1, retarded conditioned responding was produced by nonreinforced exposure to the CS prior to the CS-US pairings used to assess retardation (Le., conventional U). In Experiment la, retarded conditioned responding was induced by preexposure to pairings of the CS and a weak US prior to retardation-test pairings of the CS with a strong US (Le., Hall-Pearce [1979] U). Both types of U were attenuated by extensive exposure to the training context (Le., context extinction) following the CS-US pairings of the retardation test. Experiment 2 examined the specificity of the attenuated U effect observed in Experiment 1. After preexposure to two different CSs in two different contexts, each CS was paired with a US in its respective preexposure context. One of the two contexts was then extinguished. This attenuated U to a greater degree for the CS that had been trained in the extinguished context. Experiment 3 differentiated the roles in 11 of CS-context associations and context-US associations. Following preexposure to the CS in the training context, U was reduced by further exposure to the CS outside the training context. This observation was interpreted as implicating the CS-context association as a factor in U. Thus, the results of these experiments suggest that U is a performance deficit mediated by unusually strong CS-context associations. Implications for Wagner's (1981) SOP model andMatzel's (1988) comparator hypothesis are discussed.Latent inhibition (Ll), also known as the CS-preexposure effect, is a deficit in Pavlovian responding to a reinforced conditioned stimulus (CS) observed when subjects are exposed to nonreinforced presentations of that CS prior to reinforced training (e.g., Lubow, 1973). Numerous theoretical explanations ofLl have been proposed, almost all of which have presumed that Ll results from a failure by subjects to acquire the CS-unconditionedstimulus (US) association (see, e.g., Lubow, Schnur, 8? Rifkin, 1976;Mackintosh, 1975;Pearce & Hall, 1980;Wagner, 1981). Typically, these theories propose that the nonreinforced pretraining exposure to the target CS decreases attentional or memorial processing of the CS, which impairs the subject's ability to associate the CS with a US when these elements are later paired.However, theories explaining Ll as solely the result of impaired acquisition have been challenged by recent findings which indicate that responding to the CS can be increased by various treatments administered after the retardation-test CS-US pairings. These include a "reminder treatment," which consists of the US administered alone outside the training context (Kasprow, Catterson, Schachtman, & Miller, 1984), and testing that is extensively delayed after the CS-US pairings (Kraemer, Randall, & Carbary, 1991). These observations suggest that CS preexposure produces a reversible performance failure, whereby subjects are slow to respond in accord with the novel contingency encount...

Selectively breeding lines of mice and rats to differ in alcohol intake has proven useful for defining which traits correlate with high alcohol drinking behavior, as well as for creating animal models of alcoholism. This study reports the derivation of two novel sets of selected lines, High Alcohol Preferring (HAP) and Low Alcohol Preferring (LAP) replicate 2 and 3 lines. Mice were mass-selected using the same procedure as in the replicate 1 lines: using HS/Ibg as a progenitor, mice were selected for differences in 2-bottle choice intake of 10% alcohol during a 4-week testing period. In addition, another high drinking line, the crossed HAP (cHAP) line was selectively bred from a progenitors that were a cross of replicate 1 (S27) X replicate 2 (S21) HAP lines. All lines were characterized for saccharin intake. Overall, the response to selection of the HAP and LAP replicate 2 and 3 lines was quite similar. As anticipated, following selection, the cHAP line drank more than either parent HAP line (consuming 26.0 g/kg per day of alcohol by S11), suggesting that this method of crossing replicate lines and selecting from that cross captures more alleles than any single selected line, as well as producing a line with exceptionally high voluntary alcohol intake. As expected, saccharin consumption was highly associated with alcohol consumption; data from all 8 lines (HAP 1, 2, and 3, LAP 1, 2, and 3, HS/Ibg, and cHAP) indicated a genetic correlation between 10% alcohol and 0.32% saccharin intake of 0.917. Overall, these findings show the practicality of developing replicate lines divergent in alcohol preference, and validate a novel procedure for generating very high-drinking mouse populations.

Multiple lines of High Alcohol Preferring (HAP) mice were selectively bred for their intake of 10% ethanol (v/v) during 24-h daily access over a four-week period, with the highest drinking lines exhibiting intakes in excess of 20 g/kg/day. We observed circadian drinking patterns and resulting blood ethanol concentrations in the HAP lines. We also compared the drinking rhythms and corresponding blood ethanol concentrations (BEC) of the highest drinking HAP lines to those of the C57BL/6J (B6) inbred strain. Adult male and female crossed HAP (cHAP), HAP replicate lines 1, 2, 3, and B6 mice had free-choice access to 10% ethanol and water for 3 weeks prior to bi-hourly assessments of intake throughout the dark portion of the light-dark cycle. All HAP lines reached and maintained a rate of alcohol intake above the rate at which HAP1 mice metabolize alcohol, and BECs were consistent with this finding. Further, cHAP and HAP1 mice maintained an excessive level of intake throughout the dark portion of the cycle, accumulating mean BEC levels of 261.5 ± 18.09 and 217.9 ± 25.02 mg/dl, respectively. B6 mice drank comparatively modestly, and did not accumulate high BEC levels (53.63 + 8.15 mg/dl). Free-choice drinking demonstrated by the HAP1 and cHAP lines may provide a unique opportunity for modeling the excessive intake that often occurs in alcohol-dependent individuals, and allow for exploration of predisposing factors for excessive consumption, as well as the development of physiological, behavioral, and toxicological outcomes following alcohol exposure.