κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats
Highlights
► Intermittent ethanol vapor exposure induced escalated responding for ethanol. ► Intra-accumbens nalmefene has increased potency in dependent animals. ► Intra-accumbens κ-opioid receptor antagonism selectively reduced escalated self-administration in dependent animals. ► Intra-accumbens μ- and δ-opioid receptor antagonists produce comparable effects in nondependent and dependent animals.
Introduction
Alcohol use disorders, comprising alcohol abuse and dependence, are a pervasive problem, with rates in the United States for person 18 years of age and older climbing from 7.41% in 1991–1992 to 8.5% in 2004 (Grant et al., 2004). Further, factors related to alcohol consumption have been shown to be the third leading cause of preventable death (Mokdad et al., 2004). Presently there are only three FDA-approved medications for the treatment of alcohol abuse and dependence (Heilig and Egli, 2006), none of which target the negative emotional states that accompany acute and protracted withdrawal from alcohol (Heilig and Koob, 2007). Clearly, an impetus exists to continue studying and developing effective pharmacotherapies to treat alcohol abuse and dependence, particularly those therapies targeting symptoms not addressed by current pharmacological strategies.
Acute ethanol stimulates the release of the endogenous opioid peptides β-endorphin (END), enkephalin (ENK), and dynorphin (DYN; Gianoulakis et al., 1996, Marinelli et al., 2003, Marinelli et al., 2004, Marinelli et al., 2005, Marinelli et al., 2006, Dai et al., 2005). Nonspecific opioid receptor antagonists can effectively reduce ethanol consumption in humans (Volpicelli et al., 1992, Mason et al., 1994) and reduce ethanol consummatory and self-administration behavior in rats (Gonzales and Weiss, 1998, Stromberg et al., 2001, Coonfield et al., 2002, Shoemaker et al., 2002, Walker and Koob, 2008, Walker and Ehlers, 2009). Subtype-selective antagonists of the μ- and δ-opioid receptor (MOR and DOR, for which the endogenous ligands are END and ENK, respectively) have been shown to reduce ethanol self-administration (Stromberg et al., 1998, Hyytia and Kiianmaa, 2001). Antagonists selective for the κ-opioid receptor (KOR, for which DYN is the endogenous ligand) generally show no effect on nondependent ethanol self-administration (Williams and Woods, 1998, Doyon et al., 2006, Walker and Koob, 2008, Logrip et al., 2008, Walker et al., 2011), but see Mitchell et al. (2005). Thus, evidence suggests that the MOR and DOR are viable targets to reduce the positive reinforcing effects of ethanol in nondependent cohorts, whereas DYN/KOR systems do not appear to be involved in the positive reinforcing effects of ethanol.
Recent evidence comparing the FDA-approved naltrexone to another opioid receptor antagonist, nalmefene, showed that nalmefene and naltrexone were comparably efficacious for reducing ethanol self-administration in nondependent animals, an effect that was attributed to their similar affinity for the MOR. However, in ethanol-dependent animals, nalmefene was more effective than naltrexone for attenuating ethanol self-administration (Walker and Koob, 2008). It was posited that nalmefene’s increased efficacy in dependent animals was due to KOR binding affinity differences between the two compounds. Nalmefene has equipotent binding affinity with naltrexone at the MOR, but unlike naltrexone, has a higher affinity for the KOR and DOR in rats (Michel et al., 1985) and the κ receptor in humans (Bart et al., 2005). Specifically, nalmefene had a two-fold increase in affinity at the KOR in rats compared to naltrexone (Michel et al., 1985) at low doses. Indeed, when nondependent and ethanol-dependent animals were pretreated with a selective KOR antagonist, ethanol-dependent animals showed significant reductions in self-administration, whereas nondependent animals were unaffected (Walker and Koob, 2008, Walker et al., 2011). Thus, KOR antagonists selectively impacted dependent animals which suggested that neuroadaptations in DYN/KOR systems occur during the transition to dependence and could be a viable target for pharmacotherapies to treat ethanol dependence. KORs are morphologically situated in a manner that enables them to oppose the effects of MOR agonists (Di Chiara and Imperato, 1988b) and directly inhibit motivationally-relevant mesolimbic dopamine neurons with terminal regions in the nucleus accumbens shell (AcbSh; Di Chiara and Imperato, 1988a). Furthermore, chronic ethanol exposure results in neuroadaptations in AcbSh DYN/KOR systems that are reflective of an upregulated state (Przewlocka et al., 1997, Lindholm et al., 2000, Lindholm et al., 2007) and increased DYN/KOR systems signaling produces behaviors indicative of a negative affective state (Todtenkopf et al., 2004, Carlezon et al., 2006).
The present experiment evaluated whether infusion of the opioid receptor antagonist nalmefene into the AcbSh could attenuate ethanol self-administration in ethanol-dependent animals as it has been shown to do previously in nondependent animals (June et al., 2004). Because of evidence suggesting ethanol-dependent animals showed increased sensitivity to nalmefene, when compared to naltrexone, for reducing ethanol self-administration, in part, due to a KOR mechanism of action (Walker and Koob, 2008) and evidence supporting chronic ethanol-induced neuroadaptations of the DYN/KOR receptor system in the nucleus accumbens (Przewlocka et al., 1997, Lindholm et al., 2000, Lindholm et al., 2007), it was hypothesized that nalmefene would show increased potency in dependent animals. Furthermore, to elucidate whether the effects of intra-AcbSh nalmefene could be linked to particular opioid receptor subtypes, antagonists selective for the MOR, DOR and KOR were infused into the AcbSh of nondependent and ethanol-dependent animals prior to self-administration sessions and compared for their ability to attenuate operant self-administration of ethanol.
Section snippets
Animals
Fifty-four adult male Wistar rats (bred from Charles River Laboratory stock) approximately 70 days old at the beginning of the study were communally housed (2–3 per cage) in a temperature (21 ± 2 °C) controlled vivarium on a 12-h reverse light cycle (lights off at 6 am) with ad libitum food and water available. Prior to operant training, animals were handled daily for a one-week period. This work adheres to the National Research Council Guide for the Care and Use of Laboratory Animals (National
Results
Two animals were removed because the injection sites of the internal cannulae were located outside the AcbSh (see analysis below) with one hemisphere in the nucleus accumbens core and the other hemisphere in between the AcbSh and the midline. Three other animals were lost due to head stages that were damaged/removed and one animal was removed prior to the onset of pharmacological challenges because of an inability to display stable responding. Thus, of the 54 animals that began the study, 48
Discussion
The primary purpose of this study was to evaluate the efficacy of intra-accumbens nalmefene infusion to attenuate ethanol self-administration in dependent rats. A secondary objective was to identify whether alterations in the potency of nalmefene that were observed in ethanol-dependent animals could be attributed to a specific opioid receptor mechanism of action. After one month of intermittent vapor exposure and prior to pharmacological challenges, the vapor-exposed groups displayed the
Conclusions
Intermittent ethanol vapor exposure produced excessive ethanol self-administration during acute withdrawal in dependent animals, an effect that was ameliorated by AcbSh infusions of nalmefene, CTOP/naltrindole and nor-BNI. Intra-AcbSh nalmefene was shown to be more potent in ethanol-dependent animals, an effect that was attributed to a KOR mechanism of action. These results highlight nalmefene as an effective pharmacotherapy for both nondependent and ethanol-dependent populations and the
Acknowledgments
Support for this research was provided, in part, by Lundbeck Research USA, Inc. and the WSU Alcohol and Drug Abuse Research Program according to the State of Washington Initiative Measure No. 171. The authors would like to thank Jessica Bilimoria, Allison Brown, Tricia Christensen and Hunter Hoglen for their technical assistance.
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