Ryabinin AE, Yoneyama N, Tanchuck MA, Mark GP, Finn DA. Urocortin 1 microinjection into the mouse lateral septum regulates the acquisition and expression of alcohol consumption. Neuroscience 151: 780-790

Department of Behavioral Neuroscience, Oregon Health and Sciences University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
Neuroscience (Impact Factor: 3.36). 03/2008; 151(3):780-90. DOI: 10.1016/j.neuroscience.2007.11.014
Source: PubMed


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.

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Available from: Andrey E Ryabinin
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    • "Nonselective CRF antagonists like D-Phe-CRF 12-41 (Valdez et al. 2002), CRF 1 receptor antagonists, such as MTIP (Gehlert et al. 2007), MPZP (Gilpin et al. 2008), antalarmin, MJL-1-109-2, and R121919 (Funk et al. 2007) all reduced ethanol self-administration in animals that had been previously exposed to ethanol vapor. Moreover, urocortin 1, which has equal activity at CRF 1 and CRF 2 receptors, was injected directly into the lateral septum and attenuated alcohol self-administration during both the acquisition and expression phases of a limited-access alcohol drinking paradigm (Ryabinin et al. 2008) . Injections of D- Phe-CRF 12-41 in the CeA were able to replicate the behavioral results observed in studies using i.p. injections, while injections in the nucleus accumbens shell or in the bed nucleus of the stria terminalis were not (Funk et al. 2006a). "
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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.
    Full-text · Article · Mar 2015 · Psychopharmacology
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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.
    Full-text · Article · Jun 2013 · Alcoholism Clinical and Experimental Research
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    • "Because of its connections to mesolimbic reward pathways [4], [54], the septum has been associated with susceptibility to substance use disorders. The LS, in particular, has been shown to regulate ethanol consumption [8], [55]. Moreover, the LS showed greater neural activity following alcohol withdrawal [56]. "
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    ABSTRACT: The lateral septum has strong efferent projections to hypothalamic and midbrain regions, and has been associated with modulation of social behavior, anxiety, fear conditioning, memory-related behaviors, and the mesolimbic reward pathways. Understanding natural variation of lateral septal anatomy and function, as well as its genetic modulation, may provide important insights into individual differences in these evolutionarily important functions. Here we address these issues by using efficient and unbiased stereological probes to estimate the volume of the lateral septum in the BXD line of recombinant inbred mice. Lateral septum volume is a highly variable trait, with a 2.5-fold difference among animals. We find that this trait covaries with a number of behavioral and physiological phenotypes, many of which have already been associated with behaviors modulated by the lateral septum, such as spatial learning, anxiety, and reward-seeking. Heritability of lateral septal volume is moderate (h(2) = 0.52), and much of the heritable variation is caused by a locus on the distal portion of chromosome (Chr) 1. Composite interval analysis identified a secondary interval on Chr 2 that works additively with the Chr 1 locus to increase lateral septum volume. Using bioinformatic resources, we identified plausible candidate genes in both intervals that may influence the volume of this key nucleus, as well as associated behaviors.
    Full-text · Article · Aug 2012 · PLoS ONE
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