Intermittent access ethanol consumption dysregulates CRF function in the hypothalamus and is attenuated by the CRF‐R1 antagonist, CP‐376395

Abstract

Corticotrophin-releasing factor (CRF) is a mediator of stress responses and a key modulator of ethanol-mediated behaviors. We report here that the CRF receptor 1 (CRF-R1) antagonist, CP-376395 reduces 20% ethanol consumption in animals trained to consume ethanol on an intermittent, but not a continuous, schedule. Furthermore, using [(35) S]GTPγS binding assays, we demonstrate that CRF-mediated G-protein signaling in the hypothalamus of the intermittent drinkers is decreased when compared to controls suggesting that the effects of CP-376395 are mediated by extrahypothalamic mechanisms. The present study provides further support for the use of CRF-R1 antagonists for the treatment of alcohol use disorders and suggests that ethanol consumption dysregulates CRF function in the hypothalamus.

Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse

“…Interestingly, Carnicella, Amamoto, and colleagues (2009) showed that about one-third of the total ethanol amount consumed throughout the 24-h session is consumed within the first 30 min, generating a BEC of > 80 mg%, which meets the criteria of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) for binge drinking in humans (National Institute on Alcohol Abuse and Alcoholism, 2004). Thus, this procedure is also used to model binge-like alcohol drinking in rats (Ahmadiantehrani et al, 2013; Barak, Ahmadiantehrani, et al, 2011; Ben Hamida et al, 2012; Carnicella, Amamoto, et al, 2009; George et al, 2012; Neasta, Ben Hamida, Yowell, Carnicella, & Ron, 2010, 2011; Nielsen et al, 2012; Simms, Nielsen, Li, & Bartlett, 2013). Moreover, in procedures that start the session in the light cycle, rats seem to consume lower levels of ethanol for several hours after the first 30 min of binge-like drinking (possibly until the dark cycle begins), and then consume high levels during the dark cycle (Barak, Ahmadiantehrani, et al, 2011; Carnicella, Amamoto, et al, 2009).…”

Voluntary ethanol consumption changes anticipatory ultrasonic vocalizations but not novelty response

“…Rats drink significantly more within the first 30 min and in a 24 h period when alcohol is available on intervening days compared to continuous access [3,4]. The IAE successfully models the binge and withdrawal cycles that contributes to dysregulation of hypothalamic-pituitary-adrenal axis, which may result in emotional or affective disorders [5]. The choice to drink ETOH is important in modeling binge drinking and AUD in rodents.…”

“…Higher ETOH drinking on an intermittent access schedule results in greater changes to plasma corticosterone levels, and is highly correlated with dysfunctional corticotropin-releasing factor regulation. [5]. Since the IEN test could be used to determine rats’ stress response, we aimed to understand how the IEN response changed after intermittent access to ETOH.…”

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).…”