{"id":630,"date":"2017-04-21T04:11:46","date_gmt":"2017-04-21T09:11:46","guid":{"rendered":"http:\/\/www.bocsci.com\/blog\/?p=630"},"modified":"2017-04-21T04:11:46","modified_gmt":"2017-04-21T09:11:46","slug":"ethanol-and-corticotropin-releasing-factor","status":"publish","type":"post","link":"https:\/\/www.bocsci.com\/blog\/ethanol-and-corticotropin-releasing-factor\/","title":{"rendered":"Ethanol and Corticotropin-Releasing Factor"},"content":{"rendered":"<p>Converging evidence from numerous investigations suggests that the role of <a href=\"http:\/\/www.bocsci.com\/tag\/corticotropin-releasing-factor-crf-117.html\">corticotropin-releasing factor<\/a> (CRF) in modulating the neurobiological effects of ethanol is dependent on the duration of\u00a0exposure.\u00a0Generally, initial or acute exposures to ethanol activate CRF in the hypothalamus, which\u00a0activates the HPA axis stress response. Acute ethanol administration is accompanied by\u00a0increases in levels of CRF, CRF-like immunoreactivity (CRF-IR), CRF heteronuclear RNA (hnRNA) and CRF messenger RNA (mRNA), as well as increased\u00a0CRF1R mRNA expression in the hypothalamus. Notably, no alterations in extrahypothalamic\u00a0brain regions have been reported during the early stages of ethanol exposure.<\/p>\n<p>With chronic administration and withdrawal, ethanol induces further alterations in the CRF system, most of which are observed in limbic regions. Upregulation of CRF markers,\u00a0including extracellular CRF, pre-pro CRF mRNA, and CRF mRNA have been reported in the\u00a0amygdala, and more specifically, within the central nucleus of the\u00a0amygdala (CeA) in dependent, ethanol-withdrawn rats relative to non-dependent controls. Likewise,\u00a0increased levels of extracellular CRF have been observed in the bed nucleus of the stria\u00a0terminalis (BNST) and enhanced CRF mRNA expression has been\u00a0noted in the paraventricular nucleus of the hypothalamus (PVN) after chronic ethanol exposure. Additionally, increased CRF1R expression has been\u00a0observed in the basolateral amygdala (BLA) and the medial nucleus of the amygdala (MeA), as well as the hypothalamus\u00a0in dependent, ethanol-withdrawn rats. Decreases in CRF2R expression were observed in the\u00a0BLA of ethanol dependent rats, while increases have been\u00a0observed in the dorsal raphe of mice, and the hypothalamus of\u00a0rats\u00a0with a history of ethanol exposure.<\/p>\n<p>Such alterations appear to be functional, as marked changes in CRF-induced excitability\u00a0in the BNST and CRF-induced inhibition in the CeA have been observed following prolonged\u00a0exposure to ethanol. Indeed, long-term investigations show that some of these\u00a0neurobiological changes in CRFR signaling persist months into abstinence, which may\u00a0contribute to the enhanced anxiety-like behaviors and stress responsiveness that are observed\u00a0long after ethanol administration has ceased, and follow-up investigations show that some of these changes can be normalized through reinstatement of ethanol self-administration. Thus, the literature\u00a0suggests that chronic ethanol exposure and withdrawal promote alterations in <a href=\"http:\/\/www.bocsci.com\/tag\/corticotropin-releasing-factor-crf-117.html\">CRF<\/a> signaling in\u00a0extrahypothalamic regions of the amygdala, the lateral septum, and the dorsal raphe, as well as\u00a0the hypothalamus. These observations are consistent with the hypothesis that a dysregulation\u00a0of CRFR signaling emerges over the course of ethanol dependence, and that this dysregulation\u00a0may contribute to the excessive and uncontrolled ethanol intake associated with ethanol\u00a0dependence. The effects of ethanol on CRF activity lead to the prediction that\u00a0CRFR antagonists may protect against excessive ethanol drinking, including binge-like drinking,\u00a0in non-dependent animals because initial ethanol exposure augments CRF signaling.<\/p>\n<p>The current body of preclinical literature suggests that the role of CRF signaling in low or moderate ethanol intake in the early stages of ethanol drinking is limited. For example, central administration of non-selective CRFR antagonists, such as [<sub>D<\/sub>-Phe,Nle,C\u03b1MeLeu]-rCRF<sub>(12-41)<\/sub>\u00a0(<sub>D<\/sub>-Phe-CRF) and \u03b1-helical CRF<sub>(9-41)<\/sub>\u00a0(ahCRF), does not significantly alter ethanol\u00a0consumption or self-administration in non-dependent rats or mice with a history of ethanol\u00a0exposure akin to social drinking in humans. Similar results have been obtained using peripheral\u00a0administration of antagonists selective for the CRF1R, including (<em><i>N,N<\/i><\/em>-bis(2-methoxyethyl)-3-(4-methoxy-2-methylpheenyl)-2,5-dimethyl-pyrazolo[1,5-<em><i>a<\/i><\/em>]pyrimidin-7-amine (MPZP), 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethylimidazo[1,2-b]pyridazine (MTIP), (4-ethyl-[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7<em><i>H<\/i><\/em>-pyrrolo[2,3-<em><i>d<\/i><\/em>]pyrimidin-4-yl]amino-1-butanol (LWH-63), 2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylaminopyrazolo[1,5-<em><i>a<\/i><\/em>]pyrimidine (R121919, also called NBI 30775), and [8-(4-bromo-2-chlorophenyl)-2,7-dimethyl-pyrazolo[1,5-<em><i>a<\/i><\/em>][1,3,5]triazin-4-yl]-<em><i>bis<\/i><\/em>-(2-methyoxyethyl)amine (MJL-1-109-2). Though there are reports of\u00a0a role for CRF in stress-induced ethanol consumption by non-dependent animals, converging evidence indicates that CRFR\u00a0signaling does not modulate low or moderate levels of ethanol consumption in non-dependent animals under non-stressed conditions.<\/p>\n<p>&nbsp;<\/p>\n<p>Reference:<\/p>\n<p>Lowery-Gionta, Emily Geyer.\u00a0<em><i>The role of corticotropin-releasing factor in binge-like ethanol consumption<\/i><\/em>. The University of North Carolina at Chapel Hill, 2011.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Converging evidence from numerous investigations suggests that the role of corticotropin-releasing factor (CRF) in modulating the neurobiological effects of ethanol is dependent on the duration of\u00a0exposure.\u00a0Generally, initial or acute exposures [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[147],"tags":[420],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/630"}],"collection":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/comments?post=630"}],"version-history":[{"count":1,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/630\/revisions"}],"predecessor-version":[{"id":631,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/630\/revisions\/631"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=630"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=630"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=630"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}