Corticosteroid-Dependent Plasticity Mediates Compulsive Alcohol Drinking in Rats

Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2012; 32(22):7563-71. DOI: 10.1523/JNEUROSCI.0069-12.2012
Source: PubMed


Alcoholism is characterized by a compulsion to seek and ingest alcohol, loss of control over intake, and the emergence of a negative emotional state during abstinence. We hypothesized that sustained activation of neuroendocrine stress systems (e.g., corticosteroid release via the hypothalamic-pituitary-adrenal axis) by alcohol intoxication and withdrawal and consequent alterations in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation drive compulsive alcohol drinking. Our results showed that rats exposed to alcohol vapor to the point of dependence displayed increased alcohol intake, compulsive drinking measured by progressive-ratio responding, and persistent alcohol consumption despite punishment, assessed by adding quinine to the alcohol solution, compared with control rats that were not exposed to alcohol vapor. No group differences were observed in the self-administration of saccharin-sweetened water. Acute alcohol withdrawal was accompanied by downregulated GR mRNA in various stress/reward-related brain regions [i.e., prefrontal cortex, nucleus accumbens (NAc), and bed nucleus of the stria terminalis (BNST)], whereas protracted alcohol abstinence was accompanied by upregulated GR mRNA in the NAc core, ventral BNST, and central nucleus of the amygdala. No significant alterations in MR mRNA levels were found. Chronic GR antagonism with mifepristone (RU38486) prevented the escalation of alcohol intake and compulsive responding induced by chronic, intermittent alcohol vapor exposure. Chronic treatment with mifepristone also blocked escalated alcohol drinking and compulsive responding during protracted abstinence. Thus, the GR system appears to be involved in the development of alcohol dependence and may represent a potential pharmacological target for the treatment of alcoholism.

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Available from: Leandro F Vendruscolo,
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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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    • "System Compounds Mode of action Co PD Dose (mg/kg) Read out References Glutamate Acamprosate Modulator → ↓ ↓ 200 2BFC Rimondini et al. 2002 LY379268 mGluR2/3 agonist ↓↓ ↓↓ 3 cRI Sidhpura et al. 2010; own observations MTEP mGluR1/5 antagonist ↓ ↓ 3 SA, cRI Sidhpura et al. 2010 GABA Baclofen GABA-B agonist ↓ ↓ ↓ 2 SA Walker & Koob 2007; own observations Dihydromyricetin GABA-A agonist → ↓ ↓ 1 2BFC Shen et al. 2012 Dopamine SCH23390 D1 antagonist ↓ ↓ ↓ 0.05 cRI Liu & Weiss 2002b Eticlopride D2 antagonist ↓ ↓ ↓ 0.05 cRI Liu & Weiss 2002b Opiates Naltrexone Non-selective antagonist ↓ ↓ ↓ 1 2BFC, sRI Liu & Weiss 2002b; Walker & Koob 2008; Gilpin et al. 2008a Nalmefene Non-selective antagonist ↓ ↓ ↓ 0.1 2BFC Walker & Koob 2008 Nor-binaltorphimine κ-opioid antagonist → ↓ ↓ 5 SA Walker & Koob 2008 Walker et al. 2011 Stress MTIP MPZP Antalarmin MJL-1–109-2 R121919 CRH1 antagonists → ↓ ↓ 10 10 20 20 20 SA Gehlert et al. 2007 Gilpin, Richardson & Koob 2008b Funk et al. 2007 Mifepristone GR antagonist → ↓ 150 SA Vendruscolo et al. 2012 JNJ-31020028 NPYR2 antagonists → → 30 SA Kallupi et al. 2013 SSR149415 "
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    ABSTRACT: Rational development of novel therapeutic strategies for alcoholism requires understanding of its underlying neurobiology and pathophysiology. Obtaining this knowledge largely relies on animal studies. Thus, choosing the appropriate animal model is one of the most critical steps in pre-clinical medication development. Among the range of animal models that have been used to investigate excessive alcohol consumption in rodents, the postdependent model stands out. It was specifically developed to test the role of negative affect as a key driving force in a perpetuating addiction cycle for alcoholism. Here, we will describe our approach to make rats dependent via chronic intermittent exposure to alcohol, discuss the validity of this model, and compare it with other commonly used animal models of alcoholism. We will summarize evidence that postdependent rats fulfill several criteria of a ‘Diagnostic and Statistical Manual of Mental Disorders IV/V-like’ diagnostic system. Importantly, these animals show long-lasting excessive consumption of and increased motivation for alcohol, and evidence for loss of control over alcohol intake. Our conclusion that postdependent rats are an excellent model for medication development for alcoholism is underscored by a summary of more than two dozen pharmacological tests aimed at reversing these abnormal alcohol responses. We will end with open questions on the use of this model. In the tradition of the Sanchis-Segura and Spanagel review, we provide comic strips that illustrate the postdependent procedure and relevant phenotypes in this review.
    Addiction Biology 12/2014; 20(1). DOI:10.1111/adb.12187 · 5.36 Impact Factor
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    • "The limited data comparing individuals with comorbid PTSD and AD with those with either disorder have not found differences in stress response to various challenge procedures between patient groups (Brady et al. 2006; McRae et al. 2006). Given the animal data showing that glucocorticoid signaling contributes to alcohol seeking, e.g., Vendruscolo et al. (2012), it is possible that changes in glucocorticoid response among those with comorbid PTSD and alcoholism may offer a mechanistic explanation for the lack of efficacy of NK1 antagonism to suppress stress-induced craving in the present sample as compared to our prior findings (George et al. 2008). "
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    ABSTRACT: Rationale Posttraumatic stress disorder (PTSD) and alcoholism are frequently comorbid, suggesting the possibility of overlapping neural substrates. The neurokinin 1 (NK1) receptor for substance P (SP) has been implicated in both stress- and alcohol-related behaviors. The NK1 antagonist aprepitant, clinically available as a treatment for chemotherapy-induced nausea, offers a tool to probe a potential role of the SP/NK1 system in comorbid PTSD and alcoholism. Objectives The aim of this study is to evaluate the efficacy of aprepitant for treatment of comorbid PTSD and alcoholism. Methods Fifty-three patients with PTSD and alcoholism were admitted for 4 weeks to an inpatient unit at the NIH Clinical Center and randomized to double-blind aprepitant (125 mg/day; based on PET studies reporting >90 % central receptor occupancy at this dose) or placebo. After reaching steady state, subjects were assessed for PTSD symptom severity, behavioral and neuroendocrine responses to stress and alcohol cues, and functional magnetic resonance imaging (fMRI) responses to stimuli with positive or negative emotional valence. Results Aprepitant treatment had no effect on PTSD symptoms or subjective or physiological responses to stress or alcohol cues. However, aprepitant robustly potentiated ventromedial prefrontal cortex (mPFC) fMRI responses to aversive visual stimuli. Conclusions Despite the lack of effect on PTSD symptoms and responses to stress/alcohol cues, NK1 antagonism activated the ventral mPFC, an area considered hypoactive in PTSD, during exposure to aversive stimuli. Because this brain area is critically important for extinction of fear memories and in alcohol craving and relapse, our finding suggests that NK1 antagonism might be a useful pharmacological treatment to enhance extinction-based cue-exposure therapies.
    Psychopharmacology 07/2014; 232(1). DOI:10.1007/s00213-014-3665-4 · 3.88 Impact Factor
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