Central urocortin 3 administration decreases limited-access ethanol intake in nondependent mice

Department of Behavioral Neuroscience, The Portland Alcohol Research Center, Oregon Health & Science University, Portland, Oregon, USA.
Behavioural pharmacology (Impact Factor: 2.15). 08/2009; 20(4):346-51. DOI: 10.1097/FBP.0b013e32832f01ba
Source: PubMed


Stress and alcohol abuse are co-related. Acute alcohol is anxiolytic and stress is cited as a factor in relapse to alcohol use. A primary mediator of the stress response is the neuropeptide corticotropin-releasing factor (CRF). The CRF family of endogenous ligands includes urocortin 3 (Ucn 3), which binds selectively to the CRF type 2 receptor and has been implicated in ethanol consumption in dependent and withdrawing rats. The objective of this study was to examine the effect of Ucn 3, delivered centrally to nondependent mice, on limited-access ethanol consumption. Adult C57BL/6J mice were trained to self-administer 10% ethanol during daily, 2-h limited-access sessions, using lickometers to assess drinking patterns for both ethanol and water. Sterile saline or 0.3, 1, or 3 nmol of Ucn 3 was microinjected into the lateral ventricle immediately before the limited-access session in a within-subjects design. There was a significant decrease in ethanol (both ml and g/kg), but not water, intake following Ucn 3 treatment, explained by a change in size of the largest lick run. Food intake at both 2 h and 24 h after injection was statistically unaffected by Ucn 3 administration. These results establish a role for CRF type 2 receptors in a nondependent mouse model of ethanol self-administration.


Available from: Amanda L Sharpe, Aug 14, 2014
    • "However, this investigation identified suggestive results for genes in the glutamatergic pathway for BD with AUD comorbidity. Several of the identified genes have previously been implicated in the pathophysiology of BD and alcohol-use phenotypes, separately (Joslyn et al. 2010; Kim et al. 2006; Le-Niculescu et al. 2008; Sharpe and Phillips 2009; Smith et al. 2014; Vergara et al. 2014; Zhao et al. 2011). However, none of these genes have been associated with BD-AUD comorbidity before and should be investigated further. "
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    ABSTRACT: Glutamatergic neurotransmission has been shown to be dysregulated in bipolar disorder (BD), alcohol use disorder (AUD) and substance use disorder (SUD). Similarly, disruption in the hypothalamic-pituitary-adrenal (HPA)-axis has also been observed in these conditions. BD is often comorbid with AUD and SUD. The effects of the glutamatergic and HPA systems have not been extensively examined in individuals with BD-AUD and BD-SUD comorbidity. The aim of this investigation was to determine whether variants in the glutamatergic pathway and HPA-axis are associated with BD-AUD and BD-SUD comorbidity. The research cohort consisted of 498 individuals with BD type I from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). A subset of the cohort had comorbid current AUD and current SUD. A total of 1935 SNPs from both the glutamatergic and HPA pathways were selected from the STEP-BD genome-wide dataset. To identify population stratification, IBS clustering was performed using the program Plink 1.07. Single SNP association and gene-based association testing were conducted using logistic regression. A pathway analysis of glutamatergic and HPA genes was performed, after imputation using IMPUTE2. No single SNP was associated with BD-AUD or BD-SUD comorbidity after correction for multiple testing. However, from the gene-based analysis, the gene PRKCI was significantly associated with BD-AUD. The pathway analysis provided overall negative findings, although several genes including GRIN2B showed high percentage of associated SNPs for BD-AUD. Even though the glutamatergic and HPA pathways may not be involved in BD-AUD and BD-SUD comorbidity, PRKCI deserves further investigation in BD-AUD.
    Metabolic Brain Disease 11/2015; DOI:10.1007/s11011-015-9762-1 · 2.64 Impact Factor
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    • "Recent studies have suggested that the CRF system modulates binge-like EtOH drinking in mice (Kaur et al., 2012; Lowery et al., 2010; Lowery-Gionta et al., 2012; Ryabinin et al., 2008; Sharpe and Phillips, 2009; Sparta et al., 2008), although not in rats (Ji et al., 2008); however, this study noted that longer duration of intake might allow CRF regulation of binge intake in rats. Koob and colleagues have proposed that CRF function is increased within the " extended amygdala " after chronic EtOH administration and dependence (Koob, 2003), in particular the central amygdala (Funk et al., 2006), and recent work has shown that CRF "
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    ABSTRACT: Background: Corticotropin releasing factor (CRF) and urocortin play an important role in many stress responses and also can regulate ethanol (EtOH) intake. Adaptations in CRF signaling in the central amygdala promote EtOH consumption after long-term EtOH intake in dependent animals and also after brief periods of binge EtOH intake. Thus, even brief episodes of EtOH consumption can alter the function of the CRF system, allowing CRF to regulate EtOH intake. Here, we examined whether brief binge EtOH consumption leads to CRF receptor adaptations within the ventral tegmental area (VTA), a structure involved in signaling rewarding and aversive events and important in the development and expression of drug and alcohol addiction. Methods: We utilized a mouse model of binge drinking known as drinking in the dark (DID), where C57BL/6J mice drink approximately 6 g/kg in 4 hours and achieve blood EtOH concentrations of approximately 100 mg/dl, which is equivalent to binge drinking in humans. We used ex vivo whole-cell recordings from putative VTA dopamine (DA) neurons to examine CRF regulation of NMDA receptor (NMDAR) currents. We also examined the impact of CRF receptor antagonist injection in the VTA on binge EtOH intake. Results: Ex vivo whole-cell recordings from putative VTA DA neurons showed enhanced CRF-mediated potentiation of NMDAR currents in juvenile mice that consumed EtOH in the DID procedure. CRF-induced potentiation of NMDAR currents in EtOH-drinking mice was blocked by administration of CP-154,526 (3 μM), a selective CRF1 receptor antagonist. Furthermore, intra-VTA infusion of CP-154,526 (1 μg) significantly reduced binge EtOH consumption in adult mice. These results were not due to alterations of VTA NMDAR number or function, suggesting that binge drinking may enhance signaling through VTA CRF1 receptors onto NMDARs. Conclusions: Altered CRF1 receptor-mediated signaling in the VTA promotes binge-like EtOH consumption in mice, which supports the idea that CRF1 receptors may therefore be a promising pharmacological target for reducing binge drinking in humans.
    Alcoholism Clinical and Experimental Research 06/2013; 37(10). DOI:10.1111/acer.12153 · 3.21 Impact Factor
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    • "v . decreased consumption of 10% ethanol in a limited - access proce - dure similar to the DID model of binge drinking ( Sharpe & Phillips , 2009 ) . This study was performed using a lickometer system allowing the researchers to conclude that the decrease in intake was due to a decrease in the size of the largest bout of drinking . "
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    ABSTRACT: It is widely accepted that stress, anxiety, depression and alcohol abuse-related disorders are in large part controlled by corticotropin-releasing factor (CRF) receptors. However, evidence is accumulating that some of the actions on these receptors are mediated not by CRF, but by a family of related Urocortin (Ucn) peptides Ucn1, Ucn2 and Ucn3. The initial narrow focus on CRF as the potential main player acting on CRF receptors appears outdated. Instead it is suggested that CRF and the individual Ucns act in a complementary and brain region-specific fashion to regulate anxiety-related behaviors and alcohol consumption. This review, based on a symposium held in 2011 at the research meeting on "Alcoholism and Stress" in Volterra, Italy, highlights recent evidence for regulation of these behaviors by Ucns. In studies on stress and anxiety, the roles of Ucns, and in particular Ucn1, appear more visible in experiments analyzing adaptation to stressors rather than testing basal anxiety states. Based on these studies, we propose that the contribution of Ucn1 to regulating mood follows a U-like pattern with both high and low activity of Ucn1 contributing to high anxiety states. In studies on alcohol use disorders, the CRF system appears to regulate not only dependence-induced drinking, but also binge drinking and even basal consumption of alcohol. While dependence-induced and binge drinking rely on the actions of CRF on CRFR1 receptors, alcohol consumption in models of these behaviors is inhibited by actions of Ucns on CRFR2. In contrast, alcohol preference is positively influenced by actions of Ucn1, which is capable of acting on both CRFR1 and CRFR2. Because of complex distribution of Ucns in the nervous system, advances in this field will critically depend on development of new tools allowing site-specific analyses of the roles of Ucns and CRF.
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