The alcohol-deprivation effect (ADE) was examined under 4-hr operant and 24-hr free-choice alcohol access in the alcohol-preferring (P) rat after deprivation intervals from 2 to 4 weeks. Results indicated that adult male P rats responding for 6 weeks on a concurrent FR-5/FR-1 schedule of reinforcement for alcohol and water, respectively, and then deprived of alcohol for 2 weeks, demonstrated a 40% increase in alcohol responding during the first 60 min of alcohol reinstatement. The alcohol deprivation effect was temporary, however, as responding did not differ from baseline levels on the second day of reinstatement. In a second experiment, weanling male and female P rats received 7 weeks of continuous access to alcohol, beginning at 21 days of age, and were then deprived of alcohol for 4 weeks. On the first day of alcohol reinstatement, P rats exhibited a 40% to 45% increase from baseline alcohol drinking levels, with alcohol intake returning to baseline levels by the 3rd day of reinstatement. Although alcohol intake was higher in females than in males when adjustment was made for body weight, there were no gender differences in the magnitude of the alcohol deprivation effect. Taken together, these results indicate that the ADE is a long-lasting phenomenon that occurs under both operant and continuous access conditions in the P rat, and thus these rats may be useful models for the study of factors involved in relapse of alcohol drinking.

The reduction in ethanol intake seen with the P rats is consistent with the postulated negative relationship between NPY activity and ethanol intake. The lack of effect of NPY on ethanol intake in Wistar and NP rats may be related to the lower baseline levels of ethanol intake in these rats or to differential central nervous system basal NPY activity or sensitivity to the peptide.

The factors that govern blood and tissue concentrations of ethanol after its ingestion are the rate of absorption from the gastrointestinal tract, the space of distribution in the body, and the rate of elimination. Ethanol is absorbed rapidly by diffusion from the stomach and small intestines and is distributed in total body water. It is neither accumulated to any extent by specific organs nor preferentially bound to cellular components. It is eliminated almost entirely by oxidative metabolism in the liver. Consequently, after an initial equilibration phase, the primary determinant of the duration and extent of ethanol's pharmacologic and potentially pathologic effects is the rate of its oxidative metabolism. For this reason, the enzymatic pathways of ethanol metabolism and their control by genetic and environmental factors have been important areas for detailed study. This review focuses on recent gains in our knowledge of the biochemical genetics of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), the two principal enzymes of ethanol oxidation in liver, and discusses the relationship of the discovered genetic polymorphisms of these enzymes to individual differences in alcohol oxidizing capacity and to alcohol abuse liability. GENETIC INFLUENCE ON ETHANOL PHARMACOKINETICSIn the fasted state, ingested ethanol is absorbed principally from the duodenum and jejunum, owing to its rapid transit through an empty stomach.When ethanol is consumed with food or when the stomach is already full, substantial amounts of ethanol are absorbed from the stomach. As much as 70% of the ingested ethanol can be From the absorbed from the stomach under these conditions and absorption may not be completed until 4 to 5 hours after ingestion.' Foodstuffs such as fats and hypertonic solutions delay gastric emptying. Delayed absorption leads to a lesser amount of ethanol appearing in the systemic circulation, because there is more time for first-pass metabolism to occur.2 This is the metabolism of ethanol by enzymes in the gastric and intestinal mucosa and the liver, as ethanol is absorbed and passes via the portal circulation through the liver to the systemic circulation. The rate of ethanol absorption is partially determined by genetic factor^,^ although the mechanism for this effect is unknown.After the absorptive and distributive phases are complete, rates of ethanol elimination can be estimated by measuring ethanol concentrations in the blood or breath over time. There is still lack of general agreement on what are the best ways to perform such calculations, because ethanol can be metabolized by different enzyme systems that have different affinities for ethanol (vide infra). However, experimental studies in humans can be performed only over a limited range of ethanol concentrations with safety. Under these circumstances, the rate of disappearance from blood or breath in the postabsorption-distribution phase can usually be described adequately by a single compartment model with pseudozero order (Widmark) or single K, Mic...

The hippocampus is sensitive to the effects of ethanol and appears to have a role in the development of alcohol tolerance. The objective of this study was to test the hypothesis that there are innate differences in gene expression in the hippocampus of inbred alcohol-preferring (iP) and -nonpreferring (iNP) rats that may contribute to differences in sensitivity to ethanol and/or in the development of tolerance. Affymetrix microarrays were used to measure gene expression in the hippocampus of alcohol-naïve male iP and iNP rats in two experiments (n = 4 and 6 per strain in the two experiments). Combining data from the two experiments, there were 137 probesets representing 129 genes that significantly differed (P £ 0.01); 62 probesets differed at P £ 0.001. Among the 36% of the genes that were expressed more in the iP than iNP rat at this level of significance, many were involved in cell growth and adhesion, cellular stress reduction and anti-oxidation, protein trafficking, regulation of gene expression, synaptic function and metabolism. Among the 64% of the genes that had lower expression in the hippocampus of iP than iNP rats were genes involved in metabolic pathways, cellular signaling systems, protein trafficking, cell death and neurotransmission. Overall, the data indicate that there are significant innate differences in gene expression in the hippocampus between iP and iNP rats, some of which might contribute to the differences observed in the development of alcohol tolerance between the selectively bred P and NP lines. Selective breeding was used to develop lines of rats that differ dramatically in their preference for alcohol, demonstrating that preference for alcohol is in part under genetic control. The alcohol-preferring (P) and alcohol-nonpreferring (NP) lines of rats were derived from a randomly bred, closed colony of Wistar rats (Wrm:WRC(WI)BR) by mass selection using a two-bottle free-choice paradigm with access to 10% (v/v) ethanol and water ('Lumeng et al. 1977). P rats have a preference ratio of at least 2:1 for the ethanol solution over water, whereas NP rats have a preference ratio of less than 0.5:1.The P line of rats meets all criteria proposed (Cicero 1979) for an animal model of alcoholism Murphy et al. 2002). The P line of rats (1) consumes 5-8 g of ethanol/kg body weight/day and attains blood alcohol concentrations of 50-200 mg%, (2) works to obtain 10-40% ethanol solutions when food and water are freely available, (3) consumes ethanol for its central nervous system (CNS) pharmacological effects, and not solely for its taste, odor or caloric properties, (4) develops metabolic and functional tolerance, (5) develops signs of physical dependence upon withdrawal of alcohol and (6) demonstrates robust alcohol relapse drinking following prolonged abstinence.Innate differences between selectively bred P and NP lines have been reported in several neurotransmitters and receptors within the hippocampus Murphy et al. 2002). Compared to the NP line, the P line has a lower content (Murphy et al. 1982) ...