Pharmacological blockade of corticotropin-releasing hormone receptor 1 (CRH1R) reduces voluntary consumption of high alcohol concentrations in non-dependent Wistar rats

Abstract

Background A dysregulation of the corticotropin-releasing hormone (CRH) system has been implicated in the development of excessive alcohol consumption and dependence. The aim of the present study was to evaluate whether the CRH system is also recruited when non-dependent Wistar rats escalate to high alcohol intake in the intermittent (alternate days) model of drinking. Methods We compared intermittent and continuous access to 20% (v/v) alcohol in a two-bottle free choice drinking paradigm. Following a total of twenty 24-hour exposures for every experimental group, we assessed signs of alcohol withdrawal, including anxiety-like behavior and sensitivity to stress. The selective CRH1 receptor (CRH1R) antagonist antalarmin (0, 10, 20 mg/kg, i.p.) was tested on alcohol consumption. Results Intermittent access to 20% alcohol led non-selected Wistar rats to escalate their voluntary intake to a high and stable level, whereas continuously exposed animals maintained a lower consumption. These groups did not differ in physical withdrawal signs. In addition, no differences were found when anxiogenic-like behavior was studied, neither under basal conditions or following restraint stress. Nevertheless, sensitivity to the treatment with the CRH1R antalarmin was observed since a reduction of 20% alcohol intake was found in both groups of animals regardless of the regimen of alcohol exposure. In addition, antalarmin was effective when injected to animals exposed to intermittent 10% (v/v) alcohol whereas it failed to suppress 10% continuous alcohol intake. Conclusions Pharmacological blockade of CRH1R reduced alcohol drinking when sustained high levels of intake were achieved suggesting that the CRH system plays a key role when high doses of ethanol are consumed by non-dependent subjects. This supports the notion that CRH system not only maintains the dependent state but also engages the transition to dependence.

Corticotropin releasing factor: A key role in the neurobiology of addiction

“…Moreover, both CRF and CRF 1 knockout mice show reduced ethanol intake and blood ethanol concentrations in a murine model of scheduled, limited access to ethanol (“drinking-in-the-dark”) that can produce binge-like intake (Kaur et al, 2012), suggesting an early role for CRF in neuroadaptations associated with the binge/intoxication stage of the addiction cycle. Perhaps accordingly, systemic administration of small-molecule CRF 1 antagonists can reduce binge-like but not non-binge-like ethanol intake in C57BL/6J mice and outbred rats (Lowery et al, 2010;Cippitelli et al, 2012;Simms et al, 2013) (but see (Giardino and Ryabinin, 2013) for additional findings suggesting that these effects may not be specific for ethanol). Site-specific infusion of CRF 1 antagonists into the CeA or VTA likewise could reduce heightened ethanol intake under intermittent access schedules (Lowery-Gionta et al, 2012;Hwa et al, 2013).…”

Frameworks of Alcohol Addiction

“…CRF 1 -receptor knockout mice also drink less 20% v/v ethanol under basal conditions (Pastor et al, 2011), and both CRF and CRF 1 knockout mice show reduced ethanol intake and blood ethanol concentrations in the bingelike drinking-in-the-dark paradigm of limited ethanol access (Kaur, Li, Stenzel-Poore, & Ryabinin, 2012), suggesting an early role in neuroadaptations associated with the binge/intoxication stage. Consistent with this hypothesis, systemic administration of small-molecule CRF 1 antagonists can reduce binge-like, but not nonbinge-like, ethanol intake in C57BL/6 J mice and outbred rats (Cippitelli et al, 2012;Lowery et al, 2010;Simms, Nielsen, Li, & Bartlett, 2013; but see Giardino & Ryabinin, 2013, for a suggestion that these effects may not be specific for ethanol). Site-specific infusion of CRF 1 antagonists into the central nucleus of the amygdala or ventral tegmental area likewise reduced heightened ethanol intake under intermittent access schedules (Hwa, Debold, & Miczek, 2013;Lowery-Gionta et al, 2012).…”

NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking

“…However, here we found a novel, non-canonical postsynaptic mechanism by which Y1R activation increased the frequency of postsynaptic inhibitory currents, suggesting that Y1R signaling potentiates postsynaptic GABA A R responses, altering plasticity at inhibitory synapses on CRF neurons in the BNST. Given the extensive literature describing the roles of GABARs and CRF in alcohol drinking and dependence 16,18,35,[38][39][40][41][42][43] , strict modulation of the function and plasticity of GABARs on CRF neurons in the BNST by Y1R may be particularly important for maintaining homeostasis of CRF neuronal activity. Thus, alterations of normal NPY function, such as those after chronic binge alcohol drinking, may have profound consequences on long-term behavioral outcomes, including continued alcohol use that leads to dependence.…”