Despite the pervasiveness of alcohol (ethanol) use, it is unclear how the multiple molecular targets for ethanol contribute to its many behavioral effects. The function of GABA type A receptors (GABA(A)-Rs) is altered by ethanol, but there are multiple subtypes of these receptors, and thus far, individual subunits have not been definitively linked with specific behavioral actions. The alpha1 subunit of the GABA(A)-R is the most abundant alpha subunit in the brain, and the goal of this study was to determine the role of receptors containing this subunit in alcohol action. We designed an alpha1 subunit with serine 270 to histidine and leucine 277 to alanine mutations that was insensitive to potentiation by ethanol yet retained normal GABA sensitivity and constructed knockin mice containing this mutant subunit. Hippocampal slice recordings from these mice indicated that the mutant receptors were less sensitive to ethanol's potentiating effects. Behaviorally, we observed that mutant mice recovered more quickly from the motor-impairing effects of ethanol and etomidate, but not pentobarbital, and showed increased anxiolytic effects of ethanol. No differences were observed in ethanol-induced hypnosis, locomotor stimulation, cognitive impairment, or in ethanol preference and consumption. Overall, these studies demonstrate that the postsynaptic effects of ethanol at GABAergic synapses containing the alpha1 subunit are important for specific ethanol-induced behavioral effects.

BACKGROUND: Tracking the dynamic course of human alcoholism brain pathology can be accomplished only through naturalistic study and without opportunity for experimental manipulation. Development of an animal model of alcohol-induced brain damage, in which animals consume large amounts of alcohol following cycles of alcohol access and deprivation and are examined regularly with neuroimaging methods, would enable hypothesis testing focused on the degree, nature, and factors resulting in alcohol-induced brain damage and the prospects for recovery or relapse. METHODS: We report the results of longitudinal magnetic resonance imaging (MRI) studies of the effects of free-choice chronic alcohol intake on the brains of 2 cohorts of selectively bred alcohol-preferring (P) rats. In the companion paper, we described the MRI acquisition and analysis methods, delineation of brain regions, and growth patterns in total brain and selective structures of the control rats in the present study. Both cohorts were studied as adults for about 1 year and consumed high doses of alcohol for most of the study duration. The paradigm involved a 3-bottle choice with 0, 15 (or 20%), and 30% (or 40%) alcohol available in several different exposure schemes: continuous exposure, cycles of 2 weeks on followed by 2 weeks off alcohol, and binge drinking in the dark. RESULTS: Brain structures of the adult P rats in both the alcohol-exposed and the water control conditions showed significant growth, which was attenuated in a few measures in the alcohol-exposed groups. The region with the greatest demonstrable effect was the corpus callosum, measured on midsagittal images. CONCLUSION: The P rats showed an age-alcohol interaction different from humans, in that normal growth in selective brain regions that continues in adult rats was retarded.

BACKGROUND: The alcohol-preferring (P) rat, a Wistar strain selectively bred to consume large amounts of alcohol voluntarily, has been used as an animal model of human alcoholism for 3 decades. Heretofore, knowledge about brain morphology has been confined to postmortem examination. Quantitative neuroimaging procedures make it feasible to examine the potential longitudinal effects of alcohol exposure in vivo, while controlling modifying factors, such as age, nutrition, and exercise. To date, few imaging studies have considered what morphological changes occur with age in the rodent brain, and none has systematically applied quantitative neuroimaging approaches to measure volume changes in regional brain structures over extended periods in the adult rat. METHODS: We used structural magnetic resonance imaging (MRI) in a longitudinal design to examine 2 cohorts of adult P rats, never exposed to alcohol: Cohort A included 8 rats, 7 of which survived the entire study (578 days) and 4 MRI sessions; Cohort B included 9 rats, all of which survived the study (452 days) and 5 MRI sessions. RESULTS: Growth in whole-brain volume reached maximal levels by about 450 days of age, whereas body weight continued its gain without asymptote. Growth was not uniform across the brain structures measured. Over the initial 12 months of the study, the corpus callosum area expanded 36%, cerebellum 17%, and hippocampus 10%, whereas ventricle size was unchanged. Factors affecting growth rate estimates included litter effects, MR image signal-to-noise ratio, and measurement error. CONCLUSION: Unlike longitudinal human reports of regional volume declines in aging brain tissue, several brain structures in adult rats continued growing, and some growth patterns were litter-dependent. Determining normal regional growth patterns of brain and of the substantial variance exerted by litter differences, even in selectively bred rats, is essential for establishing baselines against which normal and aberrant dynamic changes can be detected in animal models of aging and disease.

BACKGROUND: Neurobiological studies have identified brain areas and related molecular mechanisms involved in alcohol abuse and dependence. Specific cell types in these brain areas and their role in alcohol-related behaviors, however, have not yet been identified. This study examined the involvement of cholinergic cells in inbred alcohol-preferring rats following 1 month of alcohol drinking. Cyclin-dependent kinase 5 (Cdk5) immunoreactivity (IR), a marker of neuronal plasticity, was examined in cholinergic neurons of the nucleus accumbens (NuAcc) and prefrontal cortex (PFC) and other brain areas implicated in alcohol drinking, using dual immunocytochemical (ICC) procedures. Single Cdk5 IR was also examined in several brain areas implicated in alcohol drinking. METHODS: The experimental group self-administered alcohol using a 2-bottle-choice test paradigm with unlimited access to 10% (v/v) alcohol and water for 23 h/d for 1 month. An average of 6 g/kg alcohol was consumed daily. Control animals received identical treatment, except that both bottles contained water. Rats were perfused and brain sections were processed for ICC procedures. RESULTS: Alcohol drinking resulted in a 51% increase in Cdk5 IR cholinergic interneurons in the shell NuAcc, while in the PFC there was a 51% decrease in the percent of Cdk5 IR cholinergic interneurons in the infralimbic region and a 46% decrease in Cdk5 IR cholinergic interneurons in the prelimbic region. Additionally, single Cdk5 IR revealed a 42% increase in the central nucleus of the amygdala (CNA). CONCLUSIONS: This study identified Cdk5 neuroadaptation in cholinergic interneurons of the NuAcc and PFC and in other neurons of the CNA following 1 month of alcohol drinking. These findings contribute to our understanding of the cellular and molecular basis of alcohol drinking and toward the development of improved region and cell-specific pharmacotherapeutic and behavioral treatment programs for alcohol abuse and alcoholism.

Behavioral studies show that the GABAergic system in the central amygdala (CeA) nucleus has a complex role in the reinforcing effects effects of ethanol and the anxiogenic response to ethanol withdrawal. Opioid peptides and nociceptin/orphanin FQ (nociceptin) within the CeA are implicated also in regulating voluntary ethanol consumption and ethanol relapse. Recently, we reported that basal GABAergic transmission was increased in ethanol-dependent rats, and that acute ethanol increases GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in CeA neurons from both naïve and ethanol-dependent rats to the same extent, suggesting lack of tolerance for the acute effect of ethanol. Here, we investigated the effect of nociceptin on IPSCs in CeA neurons and its interaction with ethanol effects on these GABA synapses. We found that nociceptin moderately decreased IPSC amplitudes, acting mostly presynaptically as it increased paired-pulse facilitation ratio of IPSCs and decreased miniature IPSC frequencies (but not amplitudes). Nociceptin also prevented the ethanol-induced augmentation of IPSCs in CeA of naïve rats. Interestingly, in CeA of ethanol-dependent rats, the nociceptin-induced inhibition of IPSCs was increased, indicating an enhanced sensitivity to nociceptin. Nociceptin also blocked the ethanol-induced augmentation of IPSCs in ethanol-dependent rats. Our data suggest that nociceptin has a role in regulating the GABAergic system and opposing the effect elicited by ethanol. Thus, nociceptin may represent a therapeutic target for alleviating alcohol dependence.

Alcohol dependence is characterized by tolerance, physical dependence, and craving. The neuroadaptations underlying these effects of chronic alcohol abuse are likely due to altered gene expression. Previous gene expression studies using human post-mortem brain demonstrated that several gene families were altered by alcohol abuse. However, most of these changes in gene expression were small. It is not clear if gene expression profiles have sufficient power to discriminate control from alcoholic individuals and how consistent gene expression changes are when a relatively large sample size is examined. In the present study, microarray analysis (approximately 47,000 elements) was performed on the superior frontal cortex of 27 individual human cases (14 well characterized alcoholics and 13 matched controls). A partial least squares statistical procedure was applied to identify genes with altered expression levels in alcoholics. We found that genes involved in myelination, ubiquitination, apoptosis, cell adhesion, neurogenesis, and neural disease showed altered expression levels. Importantly, genes involved in neurodegenerative diseases such as Alzheimer's disease were significantly altered suggesting a link between alcoholism and other neurodegenerative conditions. A total of 27 genes identified in this study were previously shown to be changed by alcohol abuse in previous studies of human post-mortem brain. These results revealed a consistent re-programming of gene expression in alcohol abusers that reliably discriminates alcoholic from non-alcoholic individuals.

BACKGROUND: Serum treatment of quiescent human dermal fibroblasts induces proliferation, coupled with a complex physiological response that is indicative of their normal role in wound-healing. However, it is not known to what extent such complex transcriptional events are specific to a given cell type and signal, and how these global changes are coordinately regulated. We have profiled the global transcriptional program of human fibroblasts from two different tissue sources to distinct growth stimuli, and identified a striking conservation in their gene-expression signatures. RESULTS: We found that the wound-healing program of gene expression was not specific to the response of dermal fibroblasts to serum but was regulated more broadly. However, there were specific differences among different stimuli with regard to signaling pathways that mediate these transcriptional programs. Our data suggest that the PI3-kinase pathway is differentially involved in mediating the responses of cells to serum as compared with individual peptide growth factors. Expression profiling indicated that let7 and other miRNAs with similar expression profiles may be involved in regulating the transcriptional program in response to proliferative signals. CONCLUSION: This study provides insights into how different stimuli use distinct as well as conserved signaling and regulatory mechanisms to mediate genome-wide transcriptional reprogramming during cell proliferation. Our results indicate that conservation of transcriptional programs and their regulation among different cell types may be much broader than previously appreciated.

OBJECTIVE: Individual differences in subjective responses to alcohol are believed to have a genetic basis and have been associated with increased risk of alcohol-related problems. There are, however, conflicting results from past studies, perhaps owing to differences in subjective alcohol effects by limb of the blood alcohol curve and the passage of time. The current pilot study evaluated relations among serotonin transporter (SERT) genotype, subjective alcohol responses, and drinking behavior across both the ascending and descending limbs of the blood alcohol curve. METHOD: Participants (N=222; 68% male) were administered alcohol (target blood alcohol concentration of .06%) with a subsample (n=86) providing genetic data. Following a social stressor, participants were provided the opportunity to engage in ad libitum alcohol consumption. RESULTS: SERT transporter was not significantly associated with ad lib drinking or subjective alcohol effects at individual time points, although a trend toward a SERT by blood alcohol concentration limb interaction was observed for ad lib drinking. In addition, SERT genotype predicted acute tolerance to alcohol effects, with participants homozygous for the long SERT allele developing acute tolerance more rapidly than other genotypes. CONCLUSIONS: Although SERT genotype was not reliably associated with ad lib drinking behavior, the results suggest that individuals with the long-long (LL) genotype may develop acute tolerance to alcohol effects more rapidly than heterozygotes or individuals homozygous for the short SERT allele.

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.

Many studies suggest a role for endogenous opioid peptides and their receptors in regulation of ethanol intake. It is commonly accepted that the κ-opioid receptors and their endogenous ligands, dynorphins, produce a dysphoric state and therefore may be responsible for avoidance of alcohol. We used mutant mice lacking preprodynorphin in a variety of behavioral tests of alcohol actions. Null mutant female, but not male, mice showed significantly lower preference for alcohol and consumed lower amounts of alcohol in a two-bottle choice test as compared with wild-type littermates. In the same test, knockout mice of both sexes showed a strong reduction of preference for saccharin compared to control mice. In contrast, under conditions of limited (4 hours) access (light phase of the light/dark cycle), null mutant mice did not show any differences in consumption of saccharin but they showed significantly reduced intake of sucrose. To determine the possible cause for reduction of ethanol preference and intake, we studied other ethanol-related behaviors in mice lacking the preprodynorphin gene. There were no differences between null mutant and wild type mice in ethanol-induced loss of righting reflex, acute ethanol withdrawal, ethanol-induced conditioned place preference or conditioned taste aversion to ethanol. These results indicate that deletion of preprodynorphin leads to substantial reduction of alcohol intake in female mice, and suggest thath this is caused by decreased orosensory reward of alcohol (sweet taste and/or palatability).

The present study was undertaken to examine the role of the dopamine (DA) D2 receptor in the ethanol-evoked DA response in the ventral striatum. We performed microdialysis experiments using the D2 null mutant and wild-type controls and measured the effect of an intraperitoneal (i.p.) injection of either saline or ethanol (2 g/kg) on dialysate DA concentrations in the ventral striatum. Dialysate ethanol concentrations were also determined in the samples from the ventral striatum. In addition, the effects of quinpirole, a D2/D3 agonist, were examined in both the ventral and dorsal striatum. Basal dialysate concentrations of DA were significantly reduced in both the ventral and dorsal striatum of the D2 knockouts compared with wild-type controls. Ethanol administration significantly enhanced ventral striatal DA in both groups, but the increase in dialysate DA concentration was 3.5-fold higher in the wild-type controls. The time course of dialysate ethanol concentrations was similar in the two groups. Saline injection did not alter DA concentrations in either the ventral or dorsal striatum. However, quinpirole (0.3 mg/kg) administration significantly depressed striatal dialysate DA concentrations in the wild-type mice, but not in the D2 knockouts. The results suggest that the D2 receptor is necessary for normal development and regulation of striatal extracellular DA concentrations, but the mechanism for this alteration is unclear. In addition, the blunted ethanol-evoked DA response in the D2 knockouts may contribute, in part, to some of the behavioral deficits previously observed in response to ethanol.

BACKGROUND: There is a scarcity of behavioral models that will reliably produce ethanol intakes in rodents at levels that induce or maintain dependence. The present experiments were designed to reestablish a model that uses passive intragastric (IG) infusion of ethanol to induce tolerance/dependence/withdrawal before allowing rats to self-infuse ethanol intragastrically. METHODS: Sprague-Dawley rats were surgically implanted with IG catheters and allowed to recover. During the passive infusion phase (3-6 days), rats in the experimental group were passively infused with 10% (v/v) ethanol (3.3-12.2 g/kg/d). Rats in the control group were not infused. During the self-infusion phase (5-6 days), all rats had access to 2 flavored solutions. Licks on 1 solution were paired with ethanol infusions (20%, v/v) whereas licks on the other solution were unpaired. Experiments differed in the specific passive infusion parameters and in the ethanol intake limit during self-infusion. RESULTS: Rats in the experimental groups self-infused more ethanol per day (means of 4-7 g/kg/d) than did rats in the control group (means of 0-2.6 g/kg/d). Across all 3 studies, individual total daily intakes exceeded 5 g/kg on 35% of the self-infusion days in ethanol-preexposed rats compared with \textless1% of the self-infusion days in the control rats. Ethanol-exposed rats also infused a substantially higher percentage (42%) of their total ethanol intake in relatively large bouts (\textgreater1.5 g/kg) compared with control rats (\textless10%). The addition of a daily 6-hour ethanol-free period during the passive infusion phase (in Experiments 2 and 3) led to higher ethanol intakes than in Experiment 1. Results of a control experiment showed that differences between experimental and control groups in Experiments 1 to 3 were a result of ethanol experience and not a general effect of differential infusion experience. CONCLUSIONS: Relatively short periods of passive IG infusion of ethanol induced levels of ethanol self-infusion in genetically heterogeneous rats that were comparable with drinking intakes previously reported in rats selectively bred for ethanol intake/preference. Although the induction of dependence/withdrawal may have played a role in this outcome, an alternative interpretation is that experimental rats self-infused more ethanol because passive exposure produced tolerance to aversive pharmacological effects that would otherwise limit intake of the paired flavor because of development of conditioned taste aversion. The current findings provide a strong basis for future work designed to identify parametric determinants of this form of self-administration, its sensitivity to genetic influences, and its neurobiological substrates.

Major depression represents a complex mental disorder. The identification of biological markers that define subtypes of major depressive disorder would greatly facilitate appropriate medical treatments, as well as provide insight into etiology. Reduced activity of the cAMP signaling system has been implicated in the etiology of major depression. Previous work has shown low adenylyl cyclase activity in platelets and postmortem brain tissue of depressed individuals. Here, we investigate the role of the brain type VII isoform of adenylyl cyclase (AC7) in the manifestation of depressive symptoms in genetically modified animals, using a combination of in vivo behavioral experiments, gene expression profiling, and bioinformatics. We also completed studies with humans on the association of polymorphisms in the AC7 gene with major depressive illness (unipolar depression) based on Diagnostic and Statistical Manual of Mental Disorders IV criteria. Collectively, our results demonstrate a sex-specific influence of the AC7 gene on a heritable form of depressive illness.

If we conduct the same experiment in two laboratories or repeat a classical study many years later, will we obtain the same results? Recent research with mice in neural and behavioral genetics yielded different results in different laboratories for certain phenotypes, and these findings suggested to some researchers that behavior may be too unstable for fine-scale genetic analysis. Here we expand the range of data on this question to additional laboratories and phenotypes, and, for the first time in this field, we formally compare recent data with experiments conducted 30–50 years ago. For ethanol preference and locomotor activity, strain differences have been highly stable over a period of 40–50 years, and most strain correlations are in the range of r = 0.85–0.98, as high as or higher than for brain weight. For anxiety-related behavior on the elevated plus maze, on the other hand, strain means often differ dramatically across laboratories or even when the same laboratory is moved to another site within a university. When a wide range of phenotypes is considered, no inbred strain appears to be exceptionally stable or labile across laboratories in any general sense, and there is no tendency to observe higher correlations among studies done more recently. Phenotypic drift over decades for most of the behaviors examined appears to be minimal.

This article summarizes the proceedings of a symposium presented at the 2005 annual meeting of the Research Society on Alcoholism in Santa Barbara, California, USA. The organizer and chair was L. Judson Chandler. The presentations were (1) Chronic Ethanol Exposure, N-Methyl-D-Aspartate (NMDA) Receptor Dynamics, and Withdrawal Hyperexcitability, by Adam Hendricson, Regina Maldve, and Richard Morrisett; (2) Ethanol-Induced Synaptic Targeting of NMDA Receptors Is Associated With Enhanced Postsynaptic Density-95 Clustering and Spine Size, by Judson Chandler and Ezekiel Carpenter-Hyland; (3) Presynaptic and Postsynaptic Alterations in the Nucleus Accumbens Following Chronic Alcohol Exposure, by Feng Zhou, Youssef Sari, and Richard Bell; and (4) An Active Role for Accumbens Homer2 Expression in Alcohol-Induced Neural Plasticity, by Karen Szumlinski.

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 \textgreater4.5 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.

GABAA receptors mediate the majority of inhibitory neurotransmission in the CNS. Genetic deletion of the alpha1 subunit of GABAA receptors results in a loss of alpha1-mediated fast inhibitory currents and a marked reduction in density of GABAA receptors. A grossly normal phenotype of alpha1-deficient mice suggests the presence of neuronal adaptation to these drastic changes at the GABA synapse. We used cDNA microarrays to identify transcriptional fingerprints of cellular plasticity in response to altered GABAergic inhibition in the cerebral cortex and cerebellum of alpha1 mutants. In silico analysis of 982 mutation-regulated transcripts highlighted genes and functional groups involved in regulation of neuronal excitability and synaptic transmission, suggesting an adaptive response of the brain to an altered inhibitory tone. Public gene expression databases permitted identification of subsets of transcripts enriched in excitatory and inhibitory neurons as well as some glial cells, providing evidence for cellular plasticity in individual cell types. Additional analysis linked some transcriptional changes to cellular phenotypes observed in the knock-out mice and suggested several genes, such as the early growth response 1 (Egr1), small GTP binding protein Rac1 (Rac1), neurogranin (Nrgn), sodium channel beta4 subunit (Scn4b), and potassium voltage-gated Kv4.2 channel (Kcnd2) as cell type-specific markers of neuronal plasticity. Furthermore, transcriptional activation of genes enriched in Bergman glia suggests an active role of these astrocytes in synaptic plasticity. Overall, our results suggest that the loss of alpha1-mediated fast inhibition produces diverse transcriptional responses that act to regulate neuronal excitability of individual neurons and stabilize neuronal networks, which may account for the lack of severe abnormalities in alpha1 null mutants.

The midbrain-localized Edinger-Westphal nucleus is a major site of production of urocortin 1. Urocortin 1 is a neuropeptide related to corticotropin-releasing factor that has high affinity for corticotropin-releasing factor type-1 and corticotropin-releasing factor type-2 receptors. In several mouse models, the amount of urocortin 1 neurons within the Edinger-Westphal nucleus is positively associated with ethanol preference. Central administration of urocortin 1 exerts potent anorectic actions, and implicates endogenous urocortin 1 in the regulation of food intake. It is possible that brain areas such as the dorsal raphe, which receives urocortin 1 from the Edinger-Westphal nucleus and highly expresses corticotropin-releasing factor type-2 receptors, mediate the actions of urocortin 1 on feeding and ethanol preference. In this study the amount of food, water and ethanol consumed over the dark cycle by ethanol-preferring C57BL/6J mice was measured after injection of artificial cerebrospinal fluid vehicle, urocortin 1, corticotropin-releasing factor and the corticotropin-releasing factor type-2 receptor-selective antagonist antisauvagine-30 onto the dorsal raphe. Compared with vehicle, corticotropin-releasing factor and antisauvagine-30, urocortin 1 induced a significant reduction in the amount of food consumed overnight. Also, compared with antisauvagine-30 treatment, urocortin 1 significantly reduced the amount of weight gained during this time. Urocortin 1 also significantly reduced the total amount of fluid consumed, but did not alter ethanol preference, which was high during all treatments. These results suggest that the dorsal raphe is a neuroanatomical substrate of urocortin 1-induced reductions in feeding, possibly through modulation of serotonergic activity from this nucleus. In addition, it is suggested that endogenous urocortin 1 in this area, such as from the Edinger-Westphal nucleus, does not regulate ethanol preference in C57BL/6J mice.

One of the hallmarks of alcoholism is continued excessive consumption of alcohol-containing beverages despite the negative consequences of such behavior. The neurocircuitry regulating alcohol consumption is not well understood. Recent studies have shown that the neuropeptide urocortin 1 (Ucn1), a member of the corticotropin-releasing factor (CRF) family of peptides, could be an important player in the regulation of alcohol consumption. This evidence is accumulated along three directions of research: (1) Ucn 1-containing neurons are extremely sensitive to alcohol; (2) the Ucn1 neurocircuit may contribute to the genetic predisposition to high alcohol intake in mice and rats; (3) manipulation of the Ucn1 system alters alcohol consumption and sensitivity. This paper reviews the current knowledge of the Ucn1 neurocircuit and the evidence for its involvement in alcohol-related behaviors, and proposes a mechanism for its involvement in the regulation of alcohol consumption.

This article summarizes the proceedings of a symposium presented at the 2004 annual meeting of the Research Society on Alcoholism in Vancouver, British Columbia, Canada. The organizers and chairs were William J. McBride and Michael F. Miles. The presentations were (1) Molecular Triangulation on Gene Expression Patterns in Behavioral Responses to Acute Ethanol, by Robnet T. Kerns; (2) Gene Expression in Limbic Regions After Ethanol Self-Infusion Into the Posterior Ventral Tegmental Area, by Zachary A. Rodd; (3) Microarray Analysis of CNS Limbic Regions of Inbred Alcohol-Preferring and -Nonpreferring rats and Effects of Alcohol Drinking, by Wendy N. Strother and Howard J. Edenberg; and (4) Microarray Analysis of Mouse Lines Selected for Chronic Ethanol Withdrawal Severity: The Convergence of Basal, Ethanol Regulated, and Proximity to Ethanol Quantitative Trait Loci to Identify Candidate Genes, by Joel G. Hashimoto and Kristine M. Wiren.