Effects of naltrexone and LY255582 on ethanol maintenance, seeking, and relapse responding by alcohol-preferring (P) rats

Abstract

Research indicates opioid antagonists can reduce alcohol drinking in rodents. However, tests examining the effects of opioid antagonists on ethanol seeking and relapse behavior have been limited. The present study examined the effects of two opioid antagonists on ethanol maintenance, seeking, and relapse responding by alcohol-preferring (P) rats. Adult P rats were self-trained in two-lever operant chambers to self-administer 15% (vol/vol) ethanol on a fixed-ratio 5 (FR5) versus water on a FR1 concurrent schedule of reinforcement in daily 1-h sessions. After 10 weeks, rats underwent extinction training, followed by 2 weeks in their home cages. Rats were then returned to the operant chambers without ethanol or water to measure responses on the ethanol and water levers for four sessions. After a subsequent 2 weeks in the home cage, without access to ethanol, rats were returned to the operant chambers with ethanol and water available. Effects of antagonists on maintenance responding were tested after several weeks of daily 1-h sessions. Naltrexone (NAL; 1–10 mg/kg, subcutaneously [s.c.]; n = 8/dose), LY255582 (LY; 0.03–1 mg/kg, s.c.; n = 8/dose), or vehicle were injected 30 min before the first session (in the absence of ethanol), following 2 weeks in their home cages, and for four consecutive sessions of ethanol self-administration under maintenance and relapse conditions. Both NAL and LY reduced responses on the ethanol lever without any fluids present, and ethanol self-administration under relapse and on-going drinking conditions, with LY being more potent than NAL. Both NAL and LY were less effective in reducing responding in the absence of ethanol than in reducing ethanol self-administration. Overall, the results indicate that the opioid system is involved in mediating ethanol seeking, and ethanol self-administration under relapse and on-going alcohol drinking, but that different neurocircuits may underlie these behaviors.

Operant self-administration of alcohol and nicotine in a preclinical model of co-abuse

“…These doses used are based on previous reports (Corrigall and Coen 1991; Dhaher et al 2012; Le et al 1999). Vehicle and the two doses of naltrexone were administered in counterbalanced order with each test separated by at least 2 d, on which animals received daily dual access sessions.…”

“…Naltrexone is a non-selective opioid receptor antagonist most commonly used to treat alcohol dependence (Heilig and Egli 2006), but it also can reduce smoking (King and Meyer 2000). It reduces alcohol SA in laboratory rodents (Bienkowski et al 1999; Dhaher et al 2012; Le et al 1999), but does not affect nicotine SA except at very high doses, calling into question the specificity of its effects on nicotine SA (Corrigall and Coen 1991; Liu et al 2009). In heavy drinkers that smoke, naltrexone may be more effective in reducing alcohol intake (Fucito et al 2012; King et al 2009).…”

Rat animal models for screening medications to treat alcohol use disorders

“…Pharmacological studies evaluating the acquisition of ethanol intake have been conducted under both home-cage drinking and operant self-administration conditions. As seen in Table 3, roles for the adrenergic (Froehlich et al, 2013a,b), cannabinoid (Gessa et al, 2005; Serra et al, 2001), GABAergic (GABRB: Colombo et al, 2002a; Orrù et al, 2005), opioid (Dhaher et al, 2012b; Sable et al, 2006), and serotonergic (Rodd et al, 2010; Rodd-Henricks et al, 2000a) systems have been implicated in the acquisition of ethanol intake. Of the selectively bred rat lines discussed here, only the P and sP rat lines have been used to examine acquisition of ethanol intake.…”

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

“…Essentially, peripheral naltrexone, a pan-opioid antagonist, has been tested repeatedly (Coonfield, Kiefer, Ferraro, & Sinclair, 2004; Dhaher et al, 2012; June, Grey, et al, 1998; Sable, Bell, Rodd, & McBride, 2006) along with a study testing the effects of CeA microinjections (Foster et al, 2004). These publications all reported significant reductions in ethanol intake by male and female, adolescent and adult P rats using both home-cage and operant procedures.…”

“…Another study reported that nalmefene microinjections into the NAcb, Hipp and VTA significantly reduced operant alcohol self-administration by adult female P rats (June et al, 2004). A study examining the acquisition, maintenance and relapse operant self-administration of ethanol by adult female P rats found that the mu opioid receptor (MOR) antagonist LY255582 significantly reduced all of these behaviors (Dhaher et al, 2012). Other studies examined the role of the delta opioid receptor (DOR) in mediating ethanol intake by adult P rats.…”