Biomedical subjects

L Lumeng

Publications and source records attributed to L Lumeng.

At least 19 recordsLinked to original sources

PubMed2006

Candidate genes, pathways and mechanisms for alcoholism: an expanded convergent functional genomics approach.

We describe a comprehensive translational approach for identifying candidate genes for alcoholism. The approach relies on the cross-matching of animal model brain gene expression data with human genetic linkage data, as well as human tissue data and biological roles data, an approach termed convergent functional genomics. An analysis of three animal model paradigms, based on inbred alcohol-preferring (iP) and alcohol-non-preferring (iNP) rats, and their response to treatments with alcohol, was used. A comprehensive analysis of microarray gene expression data from five key brain regions (frontal cortex, amygdala, caudate-putamen, nucleus accumbens and hippocampus) was carried out. The Bayesian-like integration of multiple independent lines of evidence, each by itself lacking sufficient discriminatory power, led to the identification of high probability candidate genes, pathways and mechanisms for alcoholism. These data reveal that alcohol has pleiotropic effects on multiple systems, which may explain the diverse neuropsychiatric and medical pathology in alcoholism. Some of the pathways identified suggest avenues for pharmacotherapy of alcoholism with existing agents, such as angiotensin-converting enzyme (ACE) inhibitors. Experiments we carried out in alcohol-preferring rats with an ACE inhibitor show a marked modulation of alcohol intake. Other pathways are new potential targets for drug development. The emergent overall picture is that physical and physiological robustness may permit alcohol-preferring individuals to withstand the aversive effects of alcohol. In conjunction with a higher reactivity to its rewarding effects, they may able to ingest enough of this nonspecific drug for a strong hedonic and addictive effect to occur.

Alcohol Drinking↗

PubMed2006

Protein expression changes in the nucleus accumbens and amygdala of inbred alcohol-preferring rats given either continuous or scheduled access to ethanol.

Chronic ethanol (EtOH) drinking produces neuronal alterations within the limbic system. To investigate changes in protein expression levels associated with EtOH drinking, inbred alcohol-preferring (iP) rats were given one of three EtOH access conditions in their home-cages: continuous ethanol (CE: 24h/day, 7days/week access to EtOH), multiple scheduled access (MSA: four 1-h sessions during the dark cycle/day, 5 days/week) to EtOH, or remained EtOH-naïve. Both MSA and CE groups consumed between 6 and 6.5g of EtOH/kg/day after the 3rd week of access. On the first day of EtOH access for the seventh week, access was terminated at the end of the fourth MSA session for MSA rats and the corresponding time point (2300h) for CE rats. Ten h later, the rats were decapitated, brains extracted, the nucleus accumbens (NAcc) and amygdala (AMYG) microdissected, and protein isolated for 2-dimensional gel electrophoretic analyses. In the NAcc, MSA altered expression levels for 12 of the 14 identified proteins, compared with controls, with six of these proteins altered by CE access, as well. In the AMYG, CE access changed expression levels for 22 of the 27 identified proteins, compared with controls, with 8 of these proteins altered by MSA, as well. The proteins could be grouped into functional categories of chaperones, cytoskeleton, intracellular communication, membrane transport, metabolism, energy production, or neurotransmission. Overall, it appears that EtOH drinking and the conditions under which EtOH is consumed, differentially affect protein expression levels between the NAcc and AMYG. This may reflect differences in neuroanatomical and/or functional characteristics associated with EtOH self-administration and possibly withdrawal, between these two brain structures.

Alcohol Drinking↗

PubMed2005

Gene expression in the hippocampus of inbred alcohol-preferring and -nonpreferring rats.

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-naive 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 < or = 0.01); 62 probesets differed at P < or = 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.

Alcohol Drinking↗

PubMed2004

Corticotropin-releasing factor gene expression is down-regulated in the central nucleus of the amygdala of alcohol-preferring rats which exhibit high anxiety: a comparison between rat lines selectively bred for high and low alcohol preference.

The role of amygdaloid corticotropin-releasing factor (CRF) in alcoholism is not clear. Alcohol-preferring (P) rats and high alcohol-drinking (HAD) rats are selectively bred for high alcohol preference, and have been considered suitable animal models for studying alcoholism. The CRF neurons in the central nucleus of the amygdala (CeA) of P rats and HAD rats were studied in comparison with those of their respective counterparts, namely, alcohol-nonpreferring (NP) rats and low alcohol-drinking (LAD) rats. Specifically, CRF-immunoreactivity (ir) in the CeA and paraventricular hypothalamic nucleus (PVN) was assessed using radioimmunohistochemical (RIH) assay in alcohol-naive P/NP rats, and HAD/LAD rats. Furthermore, CRF mRNA was examined using in situ hybridization in the CeA of P/NP rats. Anxiety levels were also evaluated using an elevated plus maze. Results of the present study showed that CRF-ir was significantly lower in the CeA of P rats than NP rats. Moreover, CRF mRNA in the CeA was also much lower in P rats than NP rats. Such differences were not seen in the PVN. Interestingly, those P rats exhibited higher anxiety than NP rats. In contrary, there were no innate differences of CRF-ir in both the CeA and PVN between HAD and LAD rats whose anxiety levels were similar. This study is consistent with the literature showing CRF knockout (KO) induces alcohol drinking, and central administrations of CRF reduce alcohol intake. Collectively, the present study suggests that reduced CRF gene expression in the CeA of P rats is associated with their alcohol preference and anxiety.

Alcohol Drinking↗

PubMed2004

Ethanol drinking and deprivation alter dopaminergic and serotonergic function in the nucleus accumbens of alcohol-preferring rats.

The alcohol deprivation effect is a temporary increase in the intake of, or preference for, ethanol after a period of deprivation that may result from persistent changes in key limbic regions thought to regulate alcohol drinking, such as the nucleus accumbens. The present study tested the hypothesis that chronic alcohol drinking under continuous 24-h free-choice conditions alters dopamine and serotonin neurotransmission in the nucleus accumbens and that these alterations persist in the absence of alcohol. Using the no-net-flux microdialysis method, the steady-state extracellular concentration (point of no-net-flux) for dopamine was approximately 25% higher in the adult female alcohol-preferring P rats given prior access to 10% ethanol, even after 2 weeks of ethanol abstinence, compared with the P rats gives access only to water. However, the extracellular concentration of serotonin was approximately 35% lower in animals given 8 weeks of continuous access to ethanol compared with water controls and animals deprived of ethanol for 2 weeks. The effect of local perfusion with 100 microM sulpiride (D(2) receptor antagonist) and 35 microM 1-(m-chlorophenyl)-biguanide (5-hydroxytryptamine(3) receptor agonist) on dopamine overflow were reduced approximately 33% in both groups of ethanol-exposed P rats compared with water controls. Free-choice alcohol drinking by P rats alters dopamine and serotonin neurotransmission in the nucleus accumbens, and many of these effects persist for at least 2 weeks in the absence of ethanol, suggesting that these underlying persistent changes may be in part responsible for increased ethanol drinking observed in the alcohol-deprivation effect.

Alcohol Drinking↗

PubMed2004

Low-dose stimulatory effects of ethanol during adolescence in rat lines selectively bred for high alcohol intake.

BACKGROUND: The low-dose stimulatory effect of ethanol (EtOH) in rats has been hypothesized to reflect its hedonic effects and to be associated with a genetic predisposition toward high alcohol preference. To test the hypothesis that phenotypes associated with high alcohol preference in adulthood are also present in adolescent rats at the time of onset of alcohol drinking, the current study examined the effects of EtOH on locomotor activity (LMA) during adolescence in lines of rats selectively bred for divergent alcohol intakes. METHODS: Subjects were adolescent (31-40 days of age) rats from the alcohol-preferring (P) and -nonpreferring (NP) lines and from the high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) replicate lines. On day 1, all subjects (n = 8-10/line/gender/dose) received intraperitoneal saline injections and were placed in the activity monitor for 30 min. On day 2, subjects received intraperitoneal saline or 0.25, 0.50, 0.75, 1.0, or 1.5 g EtOH/kg. RESULTS: The LMA of male and female P rats was increased with low doses (0.25-0.75 g/kg) and decreased at the highest dose (1.5 g/kg) of EtOH. Similar effects were observed with low doses of EtOH on the LMA of HAD-1 and HAD-2 rats. None of the EtOH doses stimulated LMA in the NP, LAD-1, or LAD-2 rats, although all of the low-alcohol-intake lines of rats showed decreased LMA at the highest dose of EtOH. Only the P rats among the high-alcohol-consuming lines of rats showed decreased LMA at the highest dose of EtOH. CONCLUSION: Selective breeding for high alcohol consumption seems to be associated with increased sensitivity to the low-dose stimulating effects of EtOH and reduced sensitivity to the high-dose motor-impairing effects of ethanol. The expression of these phenotypes emerges during adolescence by the age of onset of alcohol-drinking behavior.

Age Factors↗

PubMed2004

Long-lasting alterations of the mesolimbic dopamine system after periadolescent ethanol drinking by alcohol-preferring rats.

BACKGROUND: This study tested the hypothesis that ethanol consumption by alcohol-preferring (P) rats during the periadolescent period causes persistent alterations in the mesolimbic dopamine (DA) system. After ethanol drinking during periadolescence, P rats were examined for alterations in basal locomotor activity, changes in extracellular DA levels and extraction fraction in the nucleus accumbens (NAc) by using no-net-flux (NNF) microdialysis, and changes in the response of the mesolimbic DA system to ethanol. METHODS: Male P rat pups were given 24-hr free-choice access to 15% (v/v) ethanol from postnatal day (PD) 30 through PD 60. On PD 70, rats were assessed for locomotor activity. On PD 70 to 80, rats were implanted with bilateral guide cannulas aimed above the NAc. After at least 5 days, microdialysis probes were inserted bilaterally; on the following day, NNF microdialysis experiments were conducted. On the day after the NNF experiment, conventional microdialysis experiments were conducted to measure extracellular levels of DA in response to intraperitoneal injection of saline or ethanol 2.5 g/kg. RESULTS: Compared with the ethanol-naive group, ethanol drinking by P rats during periadolescence did not alter basal locomotor activity, nor did it alter the basal extracellular concentration of DA. There was, however, a significant increase in the extraction fraction of DA of ethanol-drinking animals relative to the controls (57.4 +/- 2.7% and 45.8 +/- 2.3%, respectively). Additionally, compared with controls, P rats with exposure to ethanol during the periadolescent period showed a prolonged increase in the extracellular levels of DA after a challenge dose of ethanol. CONCLUSIONS: The results of the microdialysis experiments suggest that periadolescent ethanol drinking by P rats increases basal DA neurotransmission (as indicated by higher DA clearance while maintaining the same extracellular DA concentrations) and prolongs the response of DA neurotransmission to ethanol.

Age Factors↗

PubMed2003

Amphetamine-modified acoustic startle responding and prepulse inhibition in adult and adolescent alcohol-preferring and -nonpreferring rats.

Selective breeding has been used to develop the alcohol-preferring (P) and -nonpreferring (NP) rats, with the P rat having lower CNS levels of dopamine (DA) and reduced DA innervation in the nucleus accumbens compared with the NP rat. The acoustic startle response (ASR) and prepulse inhibition (PPI) of the ASR are experimental behaviors altered by DA agonists. We examined whether functional differences in amphetamine (AMPH)-modified ASR and PPI exist between P and NP rats. AMPH [0.0 (saline), 1.0, 2.0, or 4.0 mg/kg] was injected 15 min prior to placement into a startle apparatus. After a 5-min habituation period, rats were given approximately twelve 95-, 105-, or 115-dB white-noise burst (ASR) and PPI trials. As adults, P rats were sensitive to AMPH potentiation of the ASR to a greater extent than NP rats. During adolescence, P and NP rats had similar levels of AMPH-potentiated ASR. As adults, NP rats displayed potentiated, rather than disrupted, PPI at the 1.0-mg/kg dose, whereas P rats displayed the expected disrupted PPI at the 4.0-mg/kg dose. As adolescents, NP rats did not display significant differences in PPI after AMPH, whereas P rats displayed dose-dependent disruption of PPI, which was significant at the 4.0-mg/kg dose. The limited effect of AMPH on increasing the ASR and the presence of AMPH-potentiated PPI at the lowest dose in the adult NP rat suggests reduced functioning of the interactions between DA circuits and the neurocircuitry mediating the ASR and PPI, compared with P rats. However, the neurocircuitry mediating PPI does not appear to be fully developed in the adolescent NP rat. The present findings also indicate that lower levels of DA content and immunoreactive fibers in the P rat may not reflect reduced DA neuronal activity, because the P rat displayed AMPH-potentiated ASR, and, at the highest dose, AMPH disruption of PPI during both adulthood and adolescence.

Acoustic Stimulation↗

PubMed2002

Mapping of QTL influencing saccharin consumption in the selectively bred alcohol-preferring and -nonpreferring rat lines.

The inbred preferring (iP) and nonpreferring (iNP) rat strains were derived from the selectively bred alcohol-preferring (P) and alcohol-nonpreferring (NP) lines. Previously, 381 iP x iNP F2 progeny were generated to identify quantitative trait loci (QTLs) influencing alcohol consumption and preference. Saccharin consumption (ml/48 h) and saccharin intake (ml/kg/day) were also measured in the F2 sample and were significantly correlated with both alcohol consumption and preference (all r > or = .20, p < .0001), suggesting that there might be some QTLs influencing both saccharin and alcohol phenotypes. We have performed a genome screen using F2 animals with extreme saccharin or alcohol consumption to identify QTLs contributing to saccharin-related phenotypes. Lod scores greater than 2.0 were found on chromosomes 3, 16 and 18 in this sample. Additional genotyping was performed in these regions in the full sample of 381 F2 progeny to further characterize these putative QTLs. On chromosome 3, the maximum lod score in the full sample was 2.7 with saccharin consumption. This QTL appears to overlap with a QTL identified for alcohol consumption in the iP and iNP lines and has pleiotropic effects on both phenotypes. Interestingly, this region of rat chromosome 3 is syntenic with mouse chromosome 2, where a QTL influencing alcohol preference has been previously reported. The QTL on chromosome 16 has a maximum lod score of 4.0 with saccharin intake and 2.6 with saccharin consumption. The QTL on chromosome 18 has a maximum lod score of 2.7 with saccharin consumption. Taken together, these data provide the first results of a genome screen for QTLs contributing to saccharin phenotypes in the rat.

Alcohol Drinking↗

PubMed2001

Alcohol place preference conditioning in high- and low-alcohol preferring selected lines of mice.

High- and low-alcohol preferring (HAP and LAP) selected lines of mice diverge greatly in free-choice alcohol consumption. This study investigated whether the lines differ in a measure of alcohol reward not dependent on drinking, specifically place conditioning. Mice were subjected to a differential conditioning procedure in which four alcohol-paired CS+ trials on one floor cue (0, 1.5, 3, or 4 g/kg; ns=20-24) alternated with four saline-paired CS- trials on a different floor cue. Testing was on a split floor, half CS+ and half CS-. HAP and LAP mice showed no preference at 0 g/kg, and equivalent, moderate preference at 1.5 and 3 g/kg alcohol. At 4 g/kg, LAP, but not HAP mice showed an increase in preference. The present findings imply greater efficacy of alcohol preference conditioning in LAP mice, but do not speak for line differences in sensitivity. Results do not support the hypothesis that selection for high drinking yields greater efficacy of alcohol as a reinforcer when reward is measured using a technique that does not rely on drinking. Low drinking in LAP mice may emerge from innate taste avoidance of alcohol as a result of selective breeding for low preference, which prevents them from encountering alcohol's rewarding, pharmacological effects.

Alcohol Drinking↗

PubMed2001

Regional central nervous system densities of delta-opioid receptors in alcohol-preferring P, alcohol-nonpreferring NP, and unselected Wistar rats.

The densities of delta-opioid receptors in the central nervous system of alcohol-naive, adult, male, alcohol-preferring P, alcohol-nonpreferring NP, and Wistar rats were examined with the use of quantitative autoradiography. Slides with coronal 20-microm sections through the regions of interest were incubated in 5 nM [3H]-[D-Pen(2),D-Pen(5)]enkephalin (DPDPE) to label delta(1)-opioid receptor sites. Nonspecific binding was determined in the presence of 10 microM naloxone. Significant differences between the P and the NP rat lines were found in numerous cortical regions, the basolateral amygdala, and the posterior hippocampus, with 10%-20% lower [3H]-DPDPE binding found in the P line. In most regions examined, binding levels in the Wistar rats were intermediate between those of the P and the NP rats. Significantly lower [3H]-DPDPE binding levels in the P rat may indicate fewer delta(1)-opioid receptors or decreased binding affinity. The lower binding in certain limbic regions, such as the basolateral amygdala and posterior hippocampus, as well as cortical differences in the P rat may be associated with the divergent alcohol drinking behaviors found between the P and the NP lines.

Alcohol Drinking↗

PubMed2001

Alcoholic liver disease.

Research has substantiated the role of several mechanisms responsible for alcohol-induced hepatotoxicity. These mechanisms include: oxidative stress and lipid peroxidation; immunogenic processes initiated by formation of protein adducts of acetaldehyde, other aldehydes and 1-hydroxyethyl radicals; and activation of Kupffer cells by endotoxin and subsequent cascade of events that involved cytokines, chemokines, and adhesion molecules. Increasing evidence implicates enhanced intestinal permeability caused by alcohol ingestion as the culprit that leads to endotoxemia. While oxidative stress is important, the principal source of reactive oxygen species that causes alcohol-induced liver injury is hotly debated. Potential sources may include cytochrome P450IIE1, activated Kupffer cells, and mitochondrial electron transfer chain. Apoptosis is likely an important pathway that culminates in hepatocyte cell death. Abstinence, corticosteroids, and enteral nutrition remain the cornerstones in the treatment of alcoholic hepatitis. The efficacies of medications such as S-adenosylmethionine and pentoxifylline will need further confirmation by additional randomized trials before they can be recommended as standard therapies for alcoholic hepatitis.

Journal Article↗

PubMed2001

Effects of acamprosate on sensitization to the locomotor-stimulant effects of alcohol in mice selectively bred for high and low alcohol preference.

Sensitization to the locomotor-stimulant effects of drugs is thought to play an important role in the development of drug-seeking behaviour. We hypothesized that the ability of acamprosate to reduce alcohol relapse rates in recovering alcoholics, and alcohol consumption in rodents, may be related to its ability to reduce sensitization to the locomotor-stimulant effects of alcohol. The purpose of the present study was to determine whether acamprosate reduces the expression of sensitization to the locomotor-stimulant effects of alcohol in lines of mice selectively bred for high (HAP) and low (LAP) alcohol preference. Mice were given six intraperitoneal (i.p.) injections of alcohol (3 g/kg) or saline at 48 h intervals. The test for sensitization to the locomotor-stimulant effects of alcohol consisted of a challenge dose of 2 g/kg i.p. alcohol followed immediately by assessment of locomotor activity for 20 min. Mice were pretreated with either saline or acamprosate (400 mg/kg) at 14 h and again at 2 h before the alcohol challenge. Both HAP and LAP mice showed sensitization to the locomotor-stimulant effects of alcohol. Acamprosate reduced the expression of sensitization to the locomotor-stimulant effects of alcohol in HAP but not LAP mice. These data suggest complex effects of acamprosate on alcohol-stimulated locomotor activity that depend on genotype.

Acamprosate↗

PubMed2001

Local cerebral glucose utilization rates in alcohol-naïve high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats.

BACKGROUND: The present study compared baseline local cerebral glucose utilization (LCGU) values within reward-relevant brain regions in alcohol-naïve, adult male high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats from replicate lines 1 and 2. METHODS: 2-[14C]Deoxyglucose ([14C]2-DG) was injected (125 microCi/kg) intravenously during the rats' dark cycle. Timed arterial blood samples were collected over 45 min and assayed for glucose as well as [14C]2-DG content. Rats were then decapitated; their brains quickly removed and frozen in isopentane at -50 degrees C. Coronal sections from each brain were apposed to film and exposed for 2 days. Image densities were analyzed using quantitative autoradiography. RESULTS: Data were collected from several key limbic (nucleus accumbens, ventral tegmental area, olfactory tubercle, amygdala, hippocampus, ventral pallidum, and septum), basal ganglia, cortical (medial prefrontal, frontal, parietal, temporal, occipital, entorhinal, pyriform, and cingulate), and subcortical (thalamus, habenula, and superior colliculus) structures. Because there were no significant differences between the replicates within each drinking line, data from the two replicates were combined to determine drinking line differences. When both replicate lines were combined, there were trends toward higher (approximately 15%) LCGU rates in HAD (n = 15) versus LAD (n = 16) rats within the parietal and occipital cortices, but neither of these line differences reached statistical significance (p < 0.01). CONCLUSIONS: The findings suggested that, within the HAD and LAD replicate rat lines, the selection for alcohol preference did not lead to differences in functional brain activity, as measured with the 2-DG method.

Alcohol Drinking↗

PubMed2001

Quantitative autoradiography of mu-opioid receptors in the CNS of high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats.

BACKGROUND: The binding of [3H]DAMGO to mu-opioid sites was measured in the CNS of selectively bred high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats to test the hypothesis that high alcohol preference is associated with higher densities of mu-opioid receptors. METHODS: Adult, alcohol-naïve male HAD and LAD rats from replicate line 1 were decapitated and their brains frozen in isopentane. Brain sections were incubated with 5 nM [3H]DAMGO, and nonspecific binding was determined in the presence of unlabeled DAMGO. Films were exposed for 60 days, then analyzed using quantitative autoradiography. RESULTS: The densities of [3H]DAMGO binding sites were measured within subregions of neocortex, limbic system, basal ganglia, diencephalon, and brainstem. LAD rats had significantly higher [3H]DAMGO binding (10-30%) than HAD rats within the anterior dorsal hippocampus (CA2), posterior hippocampus (dorsal CA1, and ventral CA1, CA3, and dentate gyrus), thalamus (medial dorsal, lateral, medial dorsal, central, ventral lateral, ventral medial, and ventral medial geniculate nuclei), habenula, and amygdala. No significant interline differences were found in the prefrontal, cingulate, frontal, parietal, temporal, occipital or entorhinal cortices, olfactory tubercle, nucleus accumbens, lateral septum, ventral tegmental area, hypothalamus, caudate-putamen, substantia nigra, claustrum, central gray, or superior colliculus. CONCLUSIONS: The present findings with the HAD and LAD lines do not support the hypothesis that high alcohol preference is associated with higher densities of CNS mu-opioid receptors. Instead, the present results, in combination with previously published findings, suggest that the mu-opioid system may play a complex role in regulating high-alcohol-drinking behavior.

Alcohol Drinking↗

PubMed2001

Responsivity and development of tolerance to the motor impairing effects of moderate doses of ethanol in alcohol-preferring (P) and -nonpreferring (NP) rat lines.

BACKGROUND: Research comparing the alcohol-preferring (P) and -nonpreferring (NP) rat lines has detected an apparent association between ethanol preference and lower responsivity to ethanol, as well as the capacity to develop and maintain tolerance to ethanol's effects. However, past studies of tolerance to ethanol's effects generally involved relatively high doses. The present study examined recovery from functional impairment induced by moderate doses of ethanol after a single dose (responsivity) and after multiple doses (development of tolerance) in the P and NP rat lines. METHOD: Adult female P and NP rats were trained, for 5 consecutive days, to stay on an oscillating bar for 120 sec. Rats were then assigned to one of three groups to receive 1.0, 1.25, or 1.5 g/kg ethanol for 5 consecutive test days. Rats were tested each day at 15-min intervals, following intraperitoneal injection, until recovery to the 120 sec criterion. RESULTS: On the first test day, NP rats took longer to recover to criterion than the P rats following the 1.0 and 1.25 g/kg doses, whereas at the 1.5 g/kg dose no line difference was evident. Trunk blood alcohol concentrations (BACs), associated with time to recovery, indicated higher values for the P than NP rat on day 1 following injection of the two lower doses. Compared to day 1, NP rats demonstrated significantly shorter times to recovery beginning on day 2 following injections of the 1.0 and 1.25 g/kg doses. However, NP rats did not show significantly different recovery times on days 2-5 compared to day 1 following injection of the 1.5 g/kg dose. The shorter recovery times at the 1.0 and 1.25 g/kg doses were associated with BACs at recovery on day 3 being equal to or greater than values obtained on day 1. In contrast, compared to day 1, P rats did not show shorter recovery times until days 3 and 5 following the 1.0 and 1.25 g/kg doses, respectively. However, P rats did demonstrate shorter recovery times on day 2 and higher BACs on day 3 compared to day 1 following the 1.5 g/kg dose. CONCLUSION: With regard to motor impairment, lower responsivity to moderate doses of ethanol may be a factor associated with high alcohol-seeking behavior. The present results confirm past research supporting an association between ethanol preference and low ethanol responsivity but at doses that are more reflective of those self-administered by P rats.

Animals↗

PubMed2001

Effects of concurrent access to multiple ethanol concentrations and repeated deprivations on alcohol intake of alcohol-preferring rats.

BACKGROUND: The alcohol deprivation effect (ADE) is a temporary increase in the voluntary intake of ethanol solutions following a period of alcohol deprivation. Multiple deprivations can prolong the expression of an ADE. This study examined the effects of initial deprivation length, concurrent exposure to multiple ethanol concentrations, and number of deprivation exposures on the magnitude and duration of the ADE in alcohol-preferring (P) rats. METHODS: Adult female P rats received 24-hr free-choice access to 10, 20, and 30% ethanol and water for 6 weeks. Rats were then randomly assigned to three groups; one group served as a nondeprived control, whereas the other two groups were initially deprived of ethanol for 2 or 8 weeks. The ethanol solutions were restored to both deprived groups for 2 weeks before the groups were deprived of ethanol for another 2 weeks. This cycle was repeated three times for a total of four deprivations. RESULTS: After the initial ethanol deprivation period, both deprived groups displayed a similar 2-fold increased ethanol intake (g/Kg/day) during the initial 24-hr period when ethanol was restored. Both deprived groups showed greater than 2-fold increases in intake of the 20 and 30% ethanol solutions after re-exposure. Ethanol consumption returned to baseline levels within 2 weeks, before the subsequent deprivation period. Multiple deprivations increased the magnitude of the ADE over that observed in the first deprivation during the initial 24-hr period of re-exposure and prolonged the duration of the ADE. In addition, repeated deprivations increased ethanol intake in the first 2-hr period of re-exposure and produced blood ethanol levels in excess of 150 mg/100 ml. CONCLUSIONS: Alterations in the reinforcing and/or aversive effects of alcohol occurred after a single prolonged deprivation and were enhanced with repeated deprivations.

Animals↗

PubMed2001

Alcohol-naïve alcohol-preferring (P) rats exhibit higher local cerebral glucose utilization than alcohol-nonpreferring (NP) and Wistar rats.

BACKGROUND: The present study determined local cerebral glucose utilization (LCGU) rates in alcohol-naïve alcohol-preferring (P), alcohol nonpreferring (NP), and outbred Wistar rats to test the hypothesis that innate differences in functional neuronal activity are present in limbic regions as a result of selective breeding for high-alcohol drinking behavior. METHODS: All procedures were conducted during the dark cycle. 2-[14C]deoxyglucose ([14C]2-DG; 125 microCi/kg) was injected intravenously and timed arterial blood samples were collected during the following 45 min and assayed for glucose and [14C]2-DG content. Rats were then decapitated, the brains removed and frozen to -70 degrees C, and 20 microm coronal sections were prepared for quantitative autoradiographic analysis. RESULTS: Rates of LCGU were determined in 55 regions and subregions, including limbic, cortical, and subcortical structures. LCGU rates were significantly (p < 0.01) higher in several limbic (e.g., ventral tegmental area, nucleus accumbens shell, olfactory tubercle, medial prefrontal cortex, and lateral hypothalamus), cortical (e.g., parietal, temporal, occipital, cingulate, piriform, and entorhinal), and subcortical (e.g., thalamus, habenula, preoptic area, and striatum) regions in P rats, compared with NP and Wistar rats, whereas rates in Wistar rats were higher in a few regions (e.g., CA1 and CA3 regions of the posterior hippocampus) than NP rats. CONCLUSIONS: The data suggest that selective breeding for high-alcohol drinking produces intrinsically higher functional neuronal activity in the central nervous system regions of the high-alcohol consuming P line compared with low-alcohol drinking NP or Wistar rats, although these differences may not generalize to other rat lines selectively bred for divergent alcohol drinking.

Alcoholism↗