Publications

2008
Margaret J. Rosenbloom and Adolf Pfefferbaum. “Magnetic Resonance Imaging of the Living Brain.” Alcohol Research & Health, 31, 4, Pp. 362–376. Publisher's Version Abstract
Magnetic resonance imaging (MRI) provides a safe, noninvasive method to examine the brain’s macrostructure, microstructure, and some aspects of how the living brain functions. MRI is capable of detecting abnormalities that can occur with alcoholism as well as changes that can occur with sobriety and relapse. The brain pathology associated with chronic excessive alcohol consumption is well documented with imaging of the living body (i.e., in vivo imaging). Consistent findings include shrinkage of the frontal cortex,1 underlying white matter, and cerebellum and expansion of the ventricles. Some of these changes are reversible with abstinence, but some appear to be enduring. Research showing correlations between brain structure and quantitative neuropsychological testing demonstrates the functional consequences of the pathology. In addition, functional imaging studies provide evidence that the brain compensates for cognitive deficits. The myriad concomitants of alcoholism, the antecedents, and the consumption patterns each may influence the observed brain changes associated with alcoholism, which tend to be more deleterious with increasing age. The multifaceted nature of alcoholism presents unique challenges and opportunities to understand the mechanisms underlying alcoholism-induced neuropathology and its recovery. Longitudinal MRI studies of animal models of alcoholism, however, can address questions about the development and course of alcohol dependence and the scope and limits of in vivo degeneration and recovery of brain structure and concomitant function that may not be readily addressed in clinical studies.
Yuri A. Blednov and R. Adron Harris. “Metabotropic glutamate receptor 5 (mGluR5) regulation of ethanol sedation, dependence and consumption: relationship to acamprosate actions.” The International Journal of Neuropsychopharmacology, 11, 6, Pp. 775–793. Abstract
Recent studies have demonstrated that metabotropic glutamate receptor 5 (mGluR5) antagonists decrease alcohol self-administration and suggest that the anti-craving medication, acamprosate, may also act to decrease mGluR5 function. To address the role of mGluR5 in behavioural actions of ethanol and acamprosate, we compared mutant mice with deletion of the mGluR5 gene and mice treated with a mGluR5 antagonist (MPEP) or acamprosate. Lack of mGluR5 or administration of MPEP reduced the severity of alcohol-induced withdrawal (AW), increased the sedative effect of alcohol (duration of loss of righting reflex; LORR), and increased basal motor activity. The motor stimulation produced by ethanol was blocked by deletion of mGluR5, but not by injection of MPEP. Both acamprosate and MPEP increased ethanol-induced LORR and reduced AW. Importantly, the protective effects of both MPEP and acamprosate on AW were found when the drugs were injected before, but not after, injection of ethanol. This indicates that the drugs prevented development of dependence rather than merely producing an anticonvulsant action. No effects of acamprosate or MPEP on ethanol-induced LORR and AW were found in mGluR5 knockout mice, demonstrating that mGluR5 is required for these actions. mGluR5 null mutant mice showed decreased alcohol consumption in some, but not all, tests. These data show the importance of mGluR5 for several actions of alcohol and support the hypothesis that some effects of acamprosate require mGluR5 signalling.
K. Befort, D. Filliol, A. Ghate, E. Darcq, A. Matifas, J. Muller, A. Lardenois, C. Thibault, D. Dembele, J. Le Merrer, J. J. a. Becker, O. Poch, and B. L. Kieffer. “Mu-opioid receptor activation induces transcriptional plasticity in the central extended amygdala.” The European Journal of Neuroscience, 27, 11, Pp. 2973–2984. Abstract
Addiction develops from the gradual adaptation of the brain to chronic drug exposure, and involves genetic reprogramming of neuronal function. The central extended amygdala (EAc) is a network formed by the central amygdala and the bed nucleus of the stria terminalis. This key site controls drug craving and seeking behaviors, and has not been investigated at the gene regulation level. We used Affymetrix microarrays to analyze transcriptional activity in the murine EAc, with a focus on mu-opioid receptor-associated events because these receptors mediate drug reward and dependence. We identified 132 genes whose expression is regulated by a chronic escalating morphine regimen in the EAc from wild-type but not mu-opioid receptor knockout mice. These modifications are mostly EAc-specific. Gene ontology analysis reveals an overrepresentation of neurogenesis, cell growth and signaling protein categories. A separate quantitative PCR analysis of genes in the last of these groups confirms the dysregulation of both orphan (Gpr88) and known (DrD1A, Adora2A, Cnr1, Grm5, Gpr6) G protein-coupled receptors, scaffolding (PSD95, Homer1) and signaling (Sgk, Cap1) proteins, and neuropeptides (CCK, galanin). These transcriptional modifications do not occur following a single morphine injection, and hence result from long-term adaptation to excessive mu receptor activation. Proteins encoded by these genes are classically associated with spine modules function in other brain areas, and therefore our data suggest a remodeling of EAc circuits at sites where glutamatergic and monoaminergic afferences interact. Together, mu receptor-dependent genes identified in this study potentially contribute to drug-induced neural plasticity, and provide a unique molecular repertoire towards understanding drug craving and relapse.
Y. A. Blednov, D. Walker, M. Martinez, M. Levine, S. Damak, and R. F. Margolskee. “Perception of sweet taste is important for voluntary alcohol consumption in mice.” Genes, Brain, and Behavior, 7, 1, Pp. 1–13. Abstract
To directly evaluate the association between taste perception and alcohol intake, we used three different mutant mice, each lacking a gene expressed in taste buds and critical to taste transduction: alpha-gustducin (Gnat3), Tas1r3 or Trpm5. Null mutant mice lacking any of these three genes showed lower preference score for alcohol and consumed less alcohol in a two-bottle choice test, as compared with wild-type littermates. These null mice also showed lower preference score for saccharin solutions than did wild-type littermates. In contrast, avoidance of quinine solutions was less in Gnat3 or Trpm5 knockout mice than in wild-type mice, whereas Tas1r3 null mice were not different from wild type in their response to quinine solutions. There were no differences in null vs. wild-type mice in their consumption of sodium chloride solutions. To determine the cause for reduction of ethanol intake, we studied other ethanol-induced behaviors known to be related to alcohol consumption. There were no differences between null and wild-type mice in ethanol-induced loss of righting reflex, severity of acute ethanol withdrawal or conditioned place preference for ethanol. Weaker conditioned taste aversion (CTA) to alcohol in null mice may have been caused by weaker rewarding value of the conditioned stimulus (saccharin). When saccharin was replaced by sodium chloride, no differences in CTA to alcohol between knockout and wild-type mice were seen. Thus, deletion of any one of three different genes involved in detection of sweet taste leads to a substantial reduction of alcohol intake without any changes in pharmacological actions of ethanol.
Colin N. Haile, Therese A. Kosten, and Thomas R. Kosten. “Pharmacogenetic treatments for drug addiction: alcohol and opiates.” The American Journal of Drug and Alcohol Abuse, 34, 4, Pp. 355–381. Abstract
AIMS: Psychiatric pharmacogenetics involves the use of genetic tests that can predict the effectiveness of treatments for individual patients with mental illness such as drug dependence. This review aims to cover these developments in the pharmacotherapy of alcohol and opiates, two addictive drugs for which we have the majority of our FDA approved pharmacotherapies. METHODS: We conducted a literature review using Medline searching terms related to these two drugs and their pharmacotherapies crossed with related genetic studies. RESULTS: Alcohol's physiological and subjective effects are associated with enhanced beta-endorphin release. Naltrexone increases baseline beta-endorphin release blocking further release by alcohol. Naltrexone's action as an alcohol pharmacotherapy is facilitated by a putative functional single nucleotide polymorphism (SNP) in the opioid mu receptor gene (Al18G) which alters receptor function. Patients with this SNP have significantly lower relapse rates to alcoholism when treated with naltrexone. Caucasians with various forms of the CYP2D6 enzyme results in a 'poor metabolizer' phenotype and appear to be protected from developing opioid dependence. Others with a "ultra-rapid metabolizer" phenotype do poorly on methadone maintenance and have frequent withdrawal symptoms. These patients can do well using buprenorphine because it is not significantly metabolized by CYP2D6. CONCLUSIONS: Pharmacogenetics has great potential for improving treatment outcome as we identify gene variants that affect pharmacodynamic and pharmacokinetic factors. These mutations guide pharmacotherapeutic agent choice for optimum treatment of alcohol and opiate abuse and subsequent relapse.
Michal Bajo, Maureen T. Cruz, George R. Siggins, Robert Messing, and Marisa Roberto. “Protein kinase C epsilon mediation of CRF- and ethanol-induced GABA release in central amygdala.” Proceedings of the National Academy of Sciences of the United States of America, 105, 24, Pp. 8410–8415. Abstract
In the central amygdala (CeA), ethanol acts via corticotrophin-releasing factor (CRF) type 1 receptors to enhance GABA release. Amygdala CRF mediates anxiety associated with stress and drug dependence, and it regulates ethanol intake. Because mutant mice that lack PKCepsilon exhibit reduced anxiety-like behavior and alcohol consumption, we investigated whether PKCepsilon lies downstream of CRF(1) receptors in the CeA. Compared with PKCepsilon(+/+) CeA neurons, PKCepsilon(-/-) neurons showed increased GABAergic tone due to enhanced GABA release. CRF and ethanol stimulated GABA release in the PKCepsilon(+/+) CeA, but not in the PKCepsilon(-/-) CeA. A PKCepsilon-specific inhibitor blocked both CRF- and ethanol-induced GABA release in the PKCepsilon(+/+) CeA, confirming findings in the PKCepsilon(-/-) CeA. These results identify a PKCepsilon signaling pathway in the CeA that is activated by CRF(1) receptor stimulation, mediates GABA release at nerve terminals, and regulates anxiety and alcohol consumption.
Susanne Hiller-Sturmhöfel, Josip Sobin, and R. Dayne Mayfield. “Proteomic approaches for studying alcoholism and alcohol-induced organ damage.” Alcohol Research & Health: The Journal of the National Institute on Alcohol Abuse and Alcoholism, 31, 1, Pp. 36–48. Abstract
Proteomics research is concerned with the analysis of all proteins found in an organism, tissue, cell type, or cellular structure. The shotgun proteomic approach, which involves two-dimensional gel electrophoresis or liquid chromatography combined with mass spectrometry (MS), is used to identify novel proteins affected by alcohol. More targeted analyses study protein-protein interactions using such techniques as the yeast two-hybrid system, affinity chromatography, or immunoprecipitation. Finally, proteomic strategies can be combined with genomic research findings using computer analyses (i.e., in silico). All of these approaches have been used in the alcohol field. These studies have identified proteins in various brain regions whose expression is affected by alcohol. Other investigators have used proteomic approaches to identify proteins that could serve as potential biomarkers of alcohol use. Finally, interaction proteomic analyses have begun to identify proteins involved in several nerve signaling networks in the brain, which then can serve as targets for further studies on alcohol's effects. Future proteomic studies likely will shed more light on the mechanisms underlying alcohol's actions on the body.
Tatiana Rojkovicova, Yehia Mechref, Jason A. Starkey, Guangxiang Wu, Richard L. Bell, William J. McBride, and Milos V. Novotny. “Quantitative chiral analysis of salsolinol in different brain regions of rats genetically predisposed to alcoholism.” Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, 863, 2, Pp. 206–214. Abstract
A method to determine the catecholamine content in putamen (CPU) and midbrain (MB) regions of the brain of alcohol-preferring rats (P) is presented with a focus on the low-level detection of S,R-salsolinol, a metabolite of dopamine and a putative alcoholism marker. The developed strategy allows both quantitative profiling of related catecholamines and the enantiomeric separation and quantification of the S- and R-salsolinol isomers and their ratios. The described LC/MS strategy simplifies the current methodology that typically employs GC-MS by eliminating the need for derivatization. The data also suggest an increase in the non-enzymatic formation of salsolinol as a consequence of ethanol exposure.
Deborah A. Finn, Gregory P. Mark, Andrea M. Fretwell, Katherine R. Gililland, Moriah N. Strong, and Matthew M. Ford. “REINSTATEMENT OF ETHANOL AND SUCROSE SEEKING BY THE NEUROSTEROID ALLOPREGNANOLONE IN C57BL/6 MICE.” Psychopharmacology, 201, 3, Pp. 423–433. Publisher's Version Abstract
Rationale Recent work in our laboratory documented that the “sipper” method of operant ethanol self-administration produced high ethanol intake and blood ethanol concentrations as well as the typical extinction “burst” in responding under non-reinforced conditions in male C57BL/6 mice. However, the neurochemical basis for reinstatement of responding following extinction has not been examined in mice with this model. Objectives Based on findings that the GABAergic neurosteroid allopregnanolone (ALLO) significantly increased the consummatory phase of ethanol self-administration, the present study determined the effect of ALLO on reinstatement of extinguished ethanol-seeking behavior and compared this effect to reinstatement of responding for sucrose reward. Methods Separate groups of male C57BL/6 mice were trained to lever press for access to a 10% ethanol (10E) or a 5% sucrose (5S) solution. A single response requirement of 16 presses (RR16) on an active lever resulted in 30 min of continuous access to the 10E or 5S solution. After the animals responded on the RR16 schedule for 14 weeks, mice were exposed to 30 min extinction sessions where responding had no scheduled consequence. Once responding stabilized below the pre-extinction baseline, mice received an IP injection of ALLO (0, 3.2, 5.6, 10 or 17 mg/kg) 15 min prior to the extinction session in a within-subjects design. Results ALLO produced a dose-dependent increase in responding under non-reinforced conditions in both the 10E and 5S groups. Additional work documented the ability of a conditioned cue light or a compound cue (light+lever retraction) to reinstate non-reinforced responding on the previously active lever. Conclusions These findings definitively show that conditioned cues and priming with ALLO are potent stimuli for reinstating both ethanol and sucrose seeking behavior in C57BL/6 mice.
Meng Gu, Dong-Hyun Kim, Dirk Mayer, Edith V. Sullivan, Adolf Pfefferbaum, and Daniel M. Spielman. “Reproducibility study of whole-brain 1H spectroscopic imaging with automated quantification.” Magnetic Resonance in Medicine, 60, 3, Pp. 542–547. Abstract
A reproducibility study of proton MR spectroscopic imaging ((1)H-MRSI) of the human brain was conducted to evaluate the reliability of an automated 3D in vivo spectroscopic imaging acquisition and associated quantification algorithm. A PRESS-based pulse sequence was implemented using dualband spectral-spatial RF pulses designed to fully excite the singlet resonances of choline (Cho), creatine (Cre), and N-acetyl aspartate (NAA) while simultaneously suppressing water and lipids; 1% of the water signal was left to be used as a reference signal for robust data processing, and additional lipid suppression was obtained using adiabatic inversion recovery. Spiral k-space trajectories were used for fast spectral and spatial encoding yielding high-quality spectra from 1 cc voxels throughout the brain with a 13-min acquisition time. Data were acquired with an 8-channel phased-array coil and optimal signal-to-noise ratio (SNR) for the combined signals was achieved using a weighting based on the residual water signal. Automated quantification of the spectrum of each voxel was performed using LCModel. The complete study consisted of eight healthy adult subjects to assess intersubject variations and two subjects scanned six times each to assess intrasubject variations. The results demonstrate that reproducible whole-brain (1)H-MRSI data can be robustly obtained with the proposed methods.
Adele R. Blackler, Anna E. Speers, Mark S. Ladinsky, and Christine C. Wu. “A shotgun proteomic method for the identification of membrane-embedded proteins and peptides.” Journal of Proteome Research, 7, 7, Pp. 3028–3034. Abstract
Integral membrane proteins perform crucial cellular functions and are the targets for the majority of pharmaceutical agents. However, the hydrophobic nature of their membrane-embedded domains makes them difficult to work with. Here, we describe a shotgun proteomic method for the high-throughput analysis of the membrane-embedded transmembrane domains of integral membrane proteins which extends the depth of coverage of the membrane proteome.
Zuzana Kapasova and Karen K. Szumlinski. “Strain differences in alcohol-induced neurochemical plasticity: a role for accumbens glutamate in alcohol intake.” Alcoholism, Clinical and Experimental Research, 32, 4, Pp. 617–631. Abstract
BACKGROUND: Repeated alcohol administration alters nucleus accumbens (NAC) basal glutamate content and sensitizes the capacity of alcohol to increase NAC extracellular glutamate levels. However, the relevance of alcohol-induced changes in NAC glutamate for alcohol drinking behavior is under-investigated. METHODS: To examine the relationship between genetic variance in alcohol consumption and alcohol-induced neuroadaptations within the NAC, in vivo microdialysis was conducted in the alcohol-preferring C57BL/6J (B6) and alcohol-avoiding DBA2/J (D2) mouse strains on injections 1 and 8 of repeated alcohol treatment (8 x 2 g/kg, IP). To confirm an active role for NAC glutamate in regulating alcohol drinking behavior, the glutamate reuptake inhibitor dl-threo-beta-benzyloxyaspartic acid (TBOA) (300 microM) and the Group 2 metabotropic glutamate autoreceptor agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) (50 microM) were infused into the NAC of B6 and D2 mice prior to alcohol consumption in a 4 bottle-choice test. RESULTS: While strain differences were not apparent for NAC basal levels of dopamine, serotonin or gamma-amino butyric acid (GABA), repeated alcohol treatment elevated NAC basal glutamate content only in B6 mice. Strain differences in both the acute and the sensitized neurochemical responses to 2 g/kg alcohol were observed for all neurotransmitters examined. While the alcohol-induced rise in NAC dopamine and glutamate levels sensitized in B6 mice, a sensitization was not observed in D2 animals. Moreover, B6 mice exhibited a sensitized serotonin and GABA response to alcohol followed repeated treatment, whereas neither tolerance nor sensitization was observed in D2 animals. An intra-NAC APDC infusion reduced alcohol intake in both B6 and D2 mice by approximately 50%. In contrast, TBOA infusion elevated alcohol intake selectively in B6 mice. CONCLUSIONS: These data indicate an active role for NAC glutamate in regulating alcohol consumption in mice and support the hypothesis that predisposition to high alcohol intake involves genetic factors that facilitate alcohol-induced adaptations in glutamate release within the NAC.
Sushma Shivaswamy and Vishwanath R. Iyer. “Stress-dependent dynamics of global chromatin remodeling in yeast: dual role for SWI/SNF in the heat shock stress response.” Molecular and Cellular Biology, 28, 7, Pp. 2221–2234. Abstract
Although chromatin structure is known to affect transcriptional activity, it is not clear how broadly patterns of changes in histone modifications and nucleosome occupancy affect the dynamic regulation of transcription in response to perturbations. The identity and role of chromatin remodelers that mediate some of these changes are also unclear. Here, we performed temporal genome-wide analyses of gene expression, nucleosome occupancy, and histone H4 acetylation during the response of yeast (Saccharomyces cerevisiae) to different stresses and report several findings. First, a large class of predominantly ribosomal protein genes, whose transcription was repressed during both heat shock and stationary phase, showed strikingly contrasting histone acetylation patterns. Second, the SWI/SNF complex was required for normal activation as well as repression of genes during heat shock, and loss of SWI/SNF delayed chromatin remodeling at the promoters of activated genes. Third, Snf2 was recruited to ribosomal protein genes and Hsf1 target genes, and its occupancy of this large set of genes was altered during heat shock. Our results suggest a broad and direct dual role for SWI/SNF in chromatin remodeling, during heat shock activation as well as repression, at promoters and coding regions.
Over a decade of in-vitro data support a critical role for members of the Homer family of postsynaptic scaffolding proteins in regulating the functional architecture of glutamate synapses. Earlier studies of Homer knockout mice indicated a necessary role for Homer gene products in normal mesocorticolimbic glutamate transmission and behaviours associated therewith. The advent of adeno-associated viral vectors carrying cDNA for, or short hairpin RNA against, specific Homer isoforms enabled the site-directed targeting of Homers to neurons in the brain. This approach has allowed our groups to address developmental issues associated with conventional knockout mice, to confirm active roles for distinct Homer isoforms in regulating glutamate transmission in vivo, as well as in mediating a variety of behavioural processes. This review summarizes the existing data derived from our studies using adeno-associated viral vector-mediated neuronal targeting of Homer in rodents, implicating this family of proteins in drug and alcohol addiction, learning/memory and emotional processing.
Jérôme A. J. Becker, Katia Befort, Clara Blad, Dominique Filliol, Aditee Ghate, Doulaye Dembele, Christelle Thibault, Muriel Koch, Jean Muller, Aurélie Lardenois, Olivier Poch, and Brigitte L. Kieffer. “Transcriptome analysis identifies genes with enriched expression in the mouse central Extended Amygdala.” Neuroscience, 156, 4, Pp. 950–965. Publisher's Version Abstract
The central Extended Amygdala (EAc) is an ensemble of highly interconnected limbic structures of the anterior brain, and forms a cellular continuum including the Bed Nucleus of the Stria Terminalis (BNST), the central nucleus of the Amygdala (CeA) and the Nucleus Accumbens shell (AcbSh). This neural network is a key site for interactions between brain reward and stress systems, and has been implicated in several aspects of drug abuse. In order to increase our understanding of EAc function at the molecular level, we undertook a genome-wide screen (Affymetrix) to identify genes whose expression is enriched in the EAc. We focused on the less-well known BNST-CeA areas of the EAc, and identified 121 genes that exhibit more than 2-fold higher expression level in the EAc compared to whole brain. Among these, forty-three genes have never been described to be expressed in the EAc. We mapped these genes throughout the brain, using non-radioactive in situ hybridization, and identified eight genes with a unique and distinct rostro-caudal expression pattern along AcbSh, BNST and CeA. Q-PCR analysis performed in brain and peripheral organ tissues indicated that, with the exception of one (Spata13), all these genes are predominantly expressed in brain. These genes encode signaling proteins (Adora2, GPR88, Arpp21 and Rem2), a transcription factor (Limh6) or proteins of unknown function (Rik130, Spata13 and Wfs1). The identification of genes with enriched expression expands our knowledge of EAc at a molecular level, and provides useful information to towards genetic manipulations within the EAc.
Natalie M. Zahr and Edith V. Sullivan. “Translational studies of alcoholism: bridging the gap.” Alcohol Research & Health: The Journal of the National Institute on Alcohol Abuse and Alcoholism, 31, 3, Pp. 215–230. Abstract
Human studies are necessary to identify and classify the brain systems predisposing individuals to develop alcohol use disorders and those modified by alcohol, while animal models of alcoholism are essential for a mechanistic understanding of how chronic voluntary alcohol consumption becomes compulsive, how brain systems become damaged, and how damage resolves. Our current knowledge of the neuroscience of alcohol dependence has evolved from the interchange of information gathered from both human alcoholics and animal models of alcoholism. Together, studies in humans and animal models have provided support for the involvement of specific brain structures over the course of alcohol addiction, including the prefrontal cortex, basal ganglia, cerebellum, amygdala, hippocampus, and the hypothalamic-pituitary-adrenal axis.
A. E. Ryabinin, N. Yoneyama, M. A. Tanchuck, G. P. Mark, and D. A. Finn. “Urocortin 1 microinjection into the mouse lateral septum regulates the acquisition and expression of alcohol consumption.” Neuroscience, 151, 3, Pp. 780–790. Abstract
Previous studies using genetic and lesion approaches have shown that the neuropeptide urocortin 1 (Ucn1) is involved in regulating alcohol consumption. Ucn1 is a corticotropin releasing factor (CRF) -like peptide that binds CRF1 and CRF2 receptors. Perioculomotor urocortin-containing neurons (pIIIu), also known as the non-preganglionic Edinger-Westphal nucleus, are the major source of Ucn1 in the brain and are known to innervate the lateral septum. Thus, the present study tested whether Ucn1 could regulate alcohol consumption through the lateral septum. In a series of experiments Ucn1 or CRF was bilaterally injected at various doses into the lateral septum of male C57BL/6J mice. Consumption of 20% volume/volume ethanol or water was tested immediately after the injections using a modification of a 2-h limited access sweetener-free "drinking-in-the-dark" procedure. Ucn1 significantly suppressed ethanol consumption when administered prior to the third ethanol drinking session (the expression phase of ethanol drinking) at doses as low as 6 pmol. Ethanol intake was differentially sensitive to Ucn1, as equivalent doses of this peptide did not suppress water consumption. In contrast, CRF suppressed both ethanol and water intake at 40 and 60 pmol, but not at lower doses. Repeated administration of Ucn1 during the acquisition of alcohol consumption showed that 40 pmol (but not 2 or 0.1 pmol) significantly attenuated ethanol intake. Repeated administration of Ucn1 also resulted in a decrease of ethanol intake in sham-injected animals, a finding suggesting that the suppressive effect of Ucn1 on ethanol intake can be conditioned. Taken together, these studies confirm the importance of lateral septum innervation by Ucn1 in the regulation of alcohol consumption.
Stephen L. Boehm, Eileen M. Moore, Cherie D. Walsh, Carly D. Gross, Austin M. Cavelli, Eduardo Gigante, and David N. Linsenbardt. “Using drinking in the dark to model prenatal binge-like exposure to ethanol in C57BL/6J mice.” Developmental Psychobiology, 50, 6, Pp. 566–578. Abstract
Animal models of prenatal ethanol exposure are necessary to more fully understand the effects of ethanol on the developing embryo/fetus. However, most models employ procedures that may produce additional maternal stress beyond that produced by ethanol alone. We employed a daily limited-access ethanol intake model called Drinking in the Dark (DID) to assess the effects of voluntary maternal binge-like ethanol intake on the developing mouse. Evidence suggests that binge exposure may be particularly harmful to the embryo/fetus, perhaps due to the relatively higher blood ethanol concentrations achieved. Pregnant females had mean daily ethanol intakes ranging from 4.2 to 6.4 g/kg ethanol over gestation, producing blood ethanol concentrations ranging from 115 to 182 mg/dL. This level of ethanol intake produced behavioral alterations among adolescent offspring that disappeared by adulthood, including altered sensitivity to ethanol's hypnotic actions. The DID model may provide a useful tool for studying the effects of prenatal ethanol exposure in mice.
Adolf Pfefferbaum, Natalie M. Zahr, Dirk Mayer, Shara Vinco, Juan Orduna, Torsten Rohlfing, and Edith V. Sullivan. “Ventricular expansion in wild-type Wistar rats after alcohol exposure by vapor chamber.” Alcoholism, Clinical and Experimental Research, 32, 8, Pp. 1459–1467. Abstract
BACKGROUND: Structural magnetic resonance imaging (MRI) reveals widespread brain damage manifest as tissue shrinkage and complementary ventriculomegaly in human alcoholism. For an animal model to parallel the human condition, high alcohol exposure should produce similar radiologically detectable neuropathology. Our previous structural MRI study demonstrated only modest brain dysmorphology of the alcohol-preferring (P) rat with average blood alcohol levels(BALs) of 125 mg/dl achieved with voluntary consumption. Here, we tested the hypothesis that wild-type Wistar rats, exposed to vaporized alcohol ensuring higher BALs than typically achieved with voluntary consumption in rodents, would model MRI findings in the brains of humans with chronic alcoholism. METHODS: The longitudinal effects of vaporized alcohol exposure on the brains of 10 wild-type Wistar rats compared with 10 sibling controls were investigated with structural MRI, conducted before (MRI 1) and after (MRI 2) 16 of alcohol exposure and after an additional 8 weeks at a higher concentration of alcohol (MRI 3). RESULTS: Two rats in the alcohol group died prior to MRI 2. The remaining vapor-exposed rats(n = 8) achieved BALs of 293 mg/dl by MRI 2 and 445 mg/dl by MRI 3. Whereas the controls gained 17% of their body weight from MRI 1 to MRI 3, the alcohol-exposed group lost 6%.MRI, quantified with atlas-based parcellation, revealed a profile of significant ventricular expansion,after alcohol vapor exposure, in 9 contiguous slices, extending from the dorsolateral to ventrolateral ventricles. In particular, from MRI 1 to MRI 2, this ventricular volume expanded by an average of 6.5% in the controls and by 27.1% in the alcohol-exposed rats but only an additional 1.5% in controls and 2.4% in alcohol-exposed rats from MRI 2 to MRI 3. The midsagittal volume of the full anterior-to-posterior extent of the corpus callosum grew between the first 2 MRIs in both groups followed by regression in the alcohol group by MRI 3. Although group differences were statistically significant, among animals there was substantial variability of the effects of alcohol exposure on brain morphology; some animals showed profound effects, whereas others were essentially unaffected. CONCLUSIONS: The ventricular dilatation and callosal shrinkage produced in wild-type rats following involuntary alcohol exposure yielded a modestly successful model of neurodysmorphology phenotypes of human alcoholism. As is the case for the human condition, however, in which some individuals express greater alcoholism-related neuropathology than others, some rats maybe more susceptible than others to extreme alcohol exposure.

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