Central Opioid Receptors Differentially Regulate the Nalmefene-Induced Suppression of Ethanol- and Saccharin-Reinforced Behaviors in Alcohol-Preferring (P) Rats

Abstract

The exact opioid-sensitive receptors participating in EtOH-seeking behaviors remains unclear. Previous studies have reported higher densities of m-opioid receptor binding in the nucleus accumbens (NACC) of P relative to NP rats; however, no differences were seen in d-receptor binding. In contrast to the NACC, substantially lower levels of m-receptor binding have been observed in the ventral tegmental area (VTA) of both P and NP rats, albeit no line differences have been observed. In the present study, opioid receptors in the NACC, VTA, and hippocampus were evaluated for their capacity to regulate both EtOH-and saccharin-motivated behaviors in the genetically selected alcohol-preferring (P) rat. To accomplish this, nalmefene, an opiate antagonist with preferential binding affinity for the m-opioid receptor was unilaterally or bilaterally infused during concurrent availability of 1 h daily EtOH (10% v/v) and saccharin (0.025 or 0.050% w/v) solutions. Rats performed under a two-lever fixed ratio (FR) schedule in which four responses on one lever produced the EtOH solution, and four on a second lever produced the saccharin solution. The results demonstrated that when responding maintained by both EtOH and saccharin are matched at basal levels, unilateral (1-60 mg) or bilateral (0.5-10 mg) microinjections of nalmefene into the NACC produced selective dose-dependent reductions on responding maintained by EtOH. Unilateral (40, 60 mg) and bilateral (10 mg) VTA infusions were also observed to selectively reduced EtOH responding; however, greater nalmefene doses were required and the magnitude of suppression on EtOH responding was markedly less compared with the NACC. The greater sensitivity of nalmefene to suppress EtOH responding in the NACC is likely due to the greater number of opioid receptors in the NACC relative to the VTA. Only bilateral infusion of the 40 mg dose in the NACC and VTA suppressed responding maintained by both EtOH and saccharin. In contrast, intrahippocampal infusions dose dependently suppressed EtOH-and saccharin-maintained responding over a range of doses (1-20 mg). The present study provides evidence that nalmefene suppresses EtOH-motivated behaviors via blockade of opioid receptors within the NACC and VTA, and under various dose conditions both reinforcer and neuroanatomical specificity can be observed.

Pharmacological Evidence for a Motivational Role of κ-Opioid Systems in Ethanol Dependence

“…Nor-BNI selectively attenuated ethanol self-administration in dependent animals (**po0.01, ***po0.001 compared to vapor-exposed vehicle dose). published literature which identifies that both nalmefene (June et al, 1998(June et al, , 2004 and naltrexone (Stromberg et al, 1998(Stromberg et al, , 2001Coonfield et al, 2002;Shoemaker et al, 2002;Stromberg, 2004) have the ability to attenuate ethanol consummatory behaviors.…”

Effects of acute ethanol on β-endorphin release in the nucleus accumbens of selectively bred lines of alcohol-preferring AA and alcohol-avoiding ANA rats

“…As well, local administration of an opioid antagonist into the nucleus accumbens (NAC) decreased alcohol consumption and operant responding for alcohol in both nonselected and selectively bred alcohol-preferring rats (Heyser et al 1999;Hyytiä and Kiianmaa 2001;June et al 2004). In addition, microdialysis studies have shown that acute alcohol treatment increased the extracellular concentration of β-endorphin in the NAC of nonselected lines of rats (Marinelli et al 2003;Olive et al 2001).…”

Prolonged Central μ-Opioid Receptor Occupancy after Single and Repeated Nalmefene Dosing

“…Nalmefene is a more potent antagonist at d-opioid receptors (DeHaven-Hudkins et al, 1990;Emmerson et al, 1994) that have been implicated in alcohol drinking (Ciccocioppo et al, 2002;June et al, 2004), and the plasma terminal half-life of oral nalmefene (Dixon et al, 1987;Gal et al, 1986) markedly exceeds that of naltrexone (Meyer et al, 1984). Single oral nalmefene doses of 20-300 mg and repeated doses of 10-40 mg twice a day have been well tolerated (Dixon et al, 1987;Mason et al, 1994), and there have been no reports of any serious adverse drug reactions on hepatic or other body systems.…”

“…Nalmefene reduces alcohol drinking in preclinical models (June et al, 1998;June et al, 2004). Recent findings indicate that nalmefene and naltrexone are equally effective in reducing subjective responses to alcohol in alcoholics (Drobes et al, 2004), and in clinical studies, nalmefene has been associated with significant decreases vs placebo in reducing relapse to heavy drinking (Mason et al, 1994;Mason et al, 1999).…”