Sommer WH, Rimondini R, Hansson AC, Hipskind PA, Gehlert DR, Barr CS et al. Upregulation of voluntary alcohol intake, behavioral sensitivity to stress, and amygdala CRFr1 expression following a history of dependence. Biol Psychiatry 63: 139-145

Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism/National Institutes of Health, Bethesda, Maryland 20892-1108, USA.
Biological psychiatry (Impact Factor: 10.26). 02/2008; 63(2):139-45. DOI: 10.1016/j.biopsych.2007.01.010
Source: PubMed


A history of alcohol dependence recruits increased voluntary alcohol intake and sensitivity to stress. Corticotropin-releasing hormone (CRH) has been implicated in this transition, but underlying molecular mechanisms remain unclear.
A postdependent state was induced using intermittent alcohol exposure. Experiments were carried out following > or =3 weeks of recovery to eliminate contributions of acute withdrawal. Voluntary alcohol consumption was assessed in a two-bottle, free choice procedure. Behavioral sensitivity to stress was examined using fear suppression of behavior in a punished drinking (Vogel) conflict test. Effects of forced swim stress on voluntary alcohol intake were examined as a function of exposure history. Expression of Crh, Crhr1, and Crhr2 transcripts was analyzed by in situ hybridization histochemistry.
Alcohol drinking was upregulated long-term following a history of dependence. Fear suppression of behavior was selectively potentiated in postdependent animals. This persisted 3 months after alcohol exposure and was reversed by the selective CRH-R1 antagonist 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP) (10 mg/kg). Forced swim stress increased alcohol intake in postdependent animals but not in control animals. Behavioral changes were paralleled by an upregulation of Crhr1 transcript expression within basolateral (BLA) and medial (MeA) amygdala and Crh messenger RNA (mRNA) in central amygdala (CeA). In contrast, Crhr2 expression was down in the BLA.
Neuroadaptations encompassing amygdala CRH signaling contribute to the behavioral phenotype of postdependent animals.

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Available from: Wolfgang H Sommer, Sep 04, 2014
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    • "In animal models, CRF release is increased in the central nucleus of the amygdala (CeA) by acute ethanol administration (Lam and Gianoulakis 2011) and during ethanol withdrawal in the CeA and bed nucleus of stria terminalis in rats exposed to ethanol vapor (Merlo-Pich et al. 1995; Olive et al. 2002). Sommer et al. (2008) showed that rats exposed to ethanol vapors for 7 weeks and then withdrawn for 3 weeks had increased CRF messenger RNA (mRNA) in the CeA and increased CRF 1 mRNA in the basolateral and medial nuclei of the amygdala. Roberto et al. (2010) reported that dependent rats exhibited heightened sensitivity to the effects of CRF and CRF 1 antagonists on GABA release and increased CRF and CRF 1 expression in the CeA. "
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    ABSTRACT: We hypothesized that the corticotropin-releasing factor (CRF) system is hyperresponsive in animals with high ethanol intake, which exhibits a reduction of ethanol intake when administered with a CRF1 receptor antagonist. Outbred Swiss mice were subjected to a long-term, three-bottle, free-choice paradigm (5 and 10 % [v/v] ethanol and water) that consisted of four phases: acquisition (AC; 10 weeks), withdrawal (W; 2 weeks), reexposure (RE; 2 weeks), and quinine-adulteration (AD; 2 weeks). Based on individual ethanol intake, the mice were classified into three groups: A group, preference for ethanol and persistently high consumption during AD phase; B group, preference for ethanol and a reduction of ethanol intake in the AD phase; and C group; preference for water during all phases. A control group only had access to water. CRF1 receptor messenger RNA (mRNA) levels in the amygdala and the effect of the CRF1 receptor antagonist CP-154,526 on ethanol and water intake in the subgroups were studied. CRF1 transcript levels were higher in the B group than in the control group. The highest dose of CP-154,526 reduced ethanol intake and preference, with no changes in water consumption, in the A group compared with vehicle. The B group exhibited a reduction of both ethanol and water intake, with no changes in preference. The C group exhibited no changes in response to the CRF1 antagonist. CRF1 receptors appear to be involved in ethanol consumption in mice with high ethanol consumption, and CRF system-mediated neuroadaptations depend on drinking profiles.
    Psychopharmacology 03/2015; 232(15). DOI:10.1007/s00213-015-3909-y · 3.88 Impact Factor
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    • "In this model, rats exhibit somatic withdrawal signs and negative emotional symptoms reflected by anxiety-like responses, hyperalgesia, and elevated brain reward thresholds (Schulteis et al., 1995; Roberts et al., 2000; Valdez et al., 2002; Rimondini et al., 2003; O'Dell et al., 2004; Zhao et al., 2007; Sommer et al., 2008; Edwards et al., 2012; Vendruscolo et al., 2012). Control rats were not exposed to alcohol vapor. "
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    ABSTRACT: Prolonged alcohol exposure has been previously shown to impair the structure and function of the hippocampus, although the underlying structural and biochemical alterations contributing to these deleterious effects are unclear. Also unclear is whether these changes persist into prolonged periods of abstinence. Previous work from our lab utilizing a clinically relevant rodent model of alcohol consumption demonstrated that alcohol dependence (induced by chronic intermittent ethanol vapor exposure or CIE) decreases proliferation and survival of neural stem cells in the hippocampal subgranular zone and hippocampal neurogenesis in the dentate gyrus, implicating this region of the cortex as particularly sensitive to the toxic effects of prolonged ethanol exposure. For this study, we investigated seven weeks of CIE-induced morphological changes (dendritic complexity and dendritic spine density) of dentate gyrus (DG) granule cell neurons, CA3, and CA1 pyramidal neurons and the associated alterations in biochemical markers of synaptic plasticity and toxicity (NMDA receptors and PSD-95) in the hippocampus in ethanol-experienced Wistar rats 3h (CIE) and 21days (protracted abstinence) after the last ethanol vapor exposure. CIE reduced dendritic arborization of DG neurons and this effect persisted into protracted abstinence. CIE enhanced dendritic arborization of pyramidal neurons and this effect did not persist into protracted abstinence. The architectural changes in dendrites did not correlate with alterations in dendritic spine density, however, they were associated with increases in the expression of pNR2B, total NR2B, and total NR2A immediately following CIE with expression levels returning to control levels in prolonged abstinence. Overall, these data provide the evidence that CIE produces profound changes in hippocampal structural plasticity and in molecular tools that maintain hippocampal structural plasticity, and these alterations may underlie cognitive dysfunction associated with alcohol dependence. In addition, the compensatory state concurrent with reduced plasticity during protracted abstinence could leave the hippocampus vulnerable to subsequent insult following chronic ethanol exposure. Copyright © 2015. Published by Elsevier Inc.
    Molecular and Cellular Neuroscience 03/2015; 65. DOI:10.1016/j.mcn.2015.03.008 · 3.84 Impact Factor
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    • "following chronic alcohol intake in a similar paradigm to this study (Lawrence et al., 2006); and increased CRF mRNA in PVN and CeA following chronic exposure to alcohol (Rivier et al., 1990; Sommer et al., 2008). "
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    ABSTRACT: Background Chronic alcohol intake produces multiple neuroadaptive changes, including up- and down-regulation of neuropeptides and receptors. There are widespread projections of relaxin-3 containing neurons to, and abundant relaxin family peptide 3 receptor (RXFP3) expression within, brain regions involved in modulating alcohol intake. Recently we demonstrated the involvement of relaxin-3/RXFP3 signalling in alcohol-seeking in rats, therefore in this study we examined whether relaxin-3 and/or RXFP3 expression were altered by chronic alcohol intake in alcohol-preferring iP rats. Methods Expression of relaxin-3 mRNA in the hindbrain nucleus incertus and RXFP3 radioligand binding levels in discrete forebrain regions were investigated following voluntary intake of alcohol or sucrose for 12 weeks, with a 2 day washout, using quantitative in situ hybridisation histochemistry and in vitro receptor autoradiography, respectively, in cohorts of adult, male iP rats. Results Levels of relaxin-3 mRNA in the hindbrain nucleus incertus were positively correlated with the level of intake of both alcohol (r(12) = 0.59, p = 0.03) and sucrose (r(7) = 0.70, p = 0.04) in iP rats. Dense binding of the RXFP3-selective radioligand, [125]-R3/I5, was detected in hypothalamic and extrahypothalamic sites, but no significant changes in the density of RXFP3 were observed in the brain regions quantified following chronic sucrose or ethanol intake. Conclusions Our findings suggest high endogenous relaxin-3 expression may be associated with higher intake of rewarding substances, rather than its expression being regulated in response to their intake; consistent with an active role for the relaxin-3/RXFP3 system in modulating ingestive and alcohol-related behaviours.
    Drug and Alcohol Dependence 07/2014; DOI:10.1016/j.drugalcdep.2014.04.017 · 3.42 Impact Factor
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