Dependence-induced increases in ethanol self-administration in mice are blocked by the CRF1 receptor antagonist antalarmin and by CRF1 receptor knockout

Abstract

Models of dependence-induced increases in ethanol self-administration will be critical in increasing our understanding of the processes of addiction and relapse, underlying mechanisms, and potential therapeutics. One system that has received considerable attention recently is the CRF 1 system that may mediate the link between anxiety states and relapse drinking. C57BL/6J mice were trained to lever press for ethanol, were made dependent and then were allowed to self-administer ethanol following a period of abstinence. The effect of the CRF 1 antagonist, antalarmin, was examined on this abstinence-induced self-administration in a separate group of mice. Finally, dependence-induced changes in ethanol self-administration were examined in CRF 1 knockout and wild type mice. The results indicated that ethanol self-administration was increased following the induction of dependence, but only after a period of abstinence. This increase in ethanol self-administration was blocked by antalarmin. Furthermore, CRF 1 knockout mice did not display this increased ethanol selfadministration following dependence and abstinence. These studies, using both a pharmacological and genetic approach, support a critical role for the CRF 1 system in ethanol self-administration following dependence. In addition, a model is presented that may be useful for studies examining underlying mechanisms of the ethanol addiction process as well as for testing potential therapeutics.

The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats

“…The first line of evidence is that antagonism of CRF 1 receptors attenuates both yohimbine-induced (present report) and dependence-induced increases in alcohol selfadministration (Chu et al 2007;Funk et al 2007;Gehlert et al 2007;Sabino et al 2006). Both in our study and in the study of Funk et al (2007) antalarmin only partially attenuated the increases in alcohol intake, and in neither study, an orderly dose-response curve was observed.…”

Effects of naltrexone, duloxetine, and a corticotropin-releasing factor type 1 receptor antagonist on binge-like alcohol drinking in rats

“…This result is consistent with the hypothesis that the activation of extra-hypothalamic CRF systems is more involved in alcohol drinking motivated by the negative reinforcing properties of the drug (i.e., dependence-induced drinking), but not drinking motivated by the positive reinforcing effects of the drug (i.e., binge-like alcohol drinking and nondependent alcohol drinking; Koob, 2003). Consistent with this notion, nondependent CRF 1 -receptor knockout mice have been observed to drink more alcohol than wild-type controls (Sillaber et al, 2002), but CRF 1 -receptor knockout mice do not exhibit the dependence-induced increases in alcohol drinking observed in wild-type controls (Chu et al, 2007). It remains to be determined if long-term binge-like drinking in a model such as the one used here is capable of eventually producing the motivational symptoms associated with alcohol dependence.…”

The Central Amygdala and Alcohol: Role of -Aminobutyric Acid, Glutamate, and Neuropeptides

“…Chronic treatment with a CRF 1 R antagonist abolishes dependence-induced escalation of drinking in rats chronically exposed to high doses of alcohol (Roberto et al 2010b). Likewise, (1) stressors and alcohol withdrawal increase CRF 1 R expression in limbic brain regions (Aguilar-Valles et al 2005;Sommer et al 2008); (2) rats bred for high alcohol preference show increased anxiety-like behavior and CRF 1 R levels (Ciccocioppo et al 2006); and (3) CRF 1 R knockout mice show decreased anxiety-like behavior (Muller et al 2003) and decreased drinking following withdrawal from chronic highdose alcohol (Chu et al 2007). …”