The δ 2 -opioid receptor antagonist naltriben reduces motivated responding for ethanol

June, Harry L.; McCane, Shannan; Zink, Richard W.; Portoghese, Philip S.; Li, Ting Kai; Froehlich, Janice C.

doi:10.1007/s002130051145

Cited by 76 publications

(66 citation statements)

References 37 publications

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“…Previous research in EtOH preferring and/or high-drinking rats indicates that a DOR selective antagonist can either have no effect on EtOH consumption (Stromberg et al, 1998;Ingman et al, 2003) or can decrease EtOH consumption (Krishnan-Sarin et al, 1995a,b;June et al, 1999). The present data are consistent with the former findings.…”

Section: Discussionsupporting

confidence: 92%

“…DOR knock-out mice consume more EtOH than wild types (Roberts et al, 2001), yet pharmacologically blocking DOR signaling either attenuates EtOH consumption (Lê et al, 1993;Froehlich, 1995;Krishnan-Sarin et al, 1995a,b;June et al, 1999;Hyytiä and Kiianmaa, 2001;Ciccocioppo et al, 2002) or has no effect (Hyytiä, 1993;Ingman et al, 2003). The reasons for this variability are not known; however, one possibility is that DOR efficacy changes dynamically during EtOH exposure.…”

Section: Introductionmentioning

confidence: 99%

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δ-Opioid Receptor Expression in the Ventral Tegmental Area Protects Against Elevated Alcohol Consumption

Margolis¹,

Fields²,

Hjelmstad³

et al. 2008

J. Neurosci.

106

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Alcoholism is a complex and debilitating syndrome affecting ϳ140 million people worldwide. However, not everyone who consumes ethanol develops abuse, raising the possibility that some individuals have a protective mechanism that inhibits elevated alcohol consumption. We tested the hypothesis that the ␦-opioid receptor (DOR) plays such a protective role. Here we show that DOR activity in the ventral tegmental area (VTA) robustly decreases ethanol consumption in rats and that these effects depend on baseline ethanol consumption. Intra-VTA microinjection of the DOR agonist DPDPE decreases drinking, particularly in low-drinking animals. Furthermore, VTA microinjection of the DOR selective antagonist TIPP-⌿ increases drinking in low, but not high, drinkers and this increase is blocked by comicroinjection of the GABA A antagonist bicuculline. Using electrophysiological techniques we found that in VTA brain slices from drinking rats DPDPE presynaptically inhibits GABA A receptor mediated IPSCs in low drinkers, but not in high drinkers or naive animals, most likely through activation of DORs on GABA terminals. This DOR-mediated inhibition of IPSCs also correlates inversely with behavioral correlates of anxiety measured in the elevated plus maze. In contrast, presynaptic inhibition of VTA GABA A IPSCs by theopioid receptor agonist DAMGO is significantly reduced in both high-and low-drinking rats (Ͻ30%) compared with age-matched nondrinking controls (Ͼ70%). Together, our findings demonstrate the protective nature of VTA DORs and identify an important new target for therapeutic intervention for alcoholism.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

δ-Opioid Receptor Expression in the Ventral Tegmental Area Protects Against Elevated Alcohol Consumption

Margolis¹,

Fields²,

Hjelmstad³

et al. 2008

J. Neurosci.

106

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“…While a variety of neuronal systems have been shown to play a role in regulating EtOH-seeking behavior (McBride and Li, 1998;McBride et al, 1993) few have been linked as closely to the positive reinforcing properties of EtOH as the endogenous opioid systems (for a review, see Froehlich and Li, 1993;Herz, 1997;Reid and Hubbell, 1992). This conclusion is supported by pharmacological studies showing that selective (eg d and m) and nonselective (eg naloxone, naltrexone, nalmefene) opioid antagonists can decrease EtOH-seeking behaviors in a variety of preclinical animals models, suggesting that the endogenous opioid systems mediate in part, EtOH-reward processes (Herz, 1997;June et al, 1999;June et al, 1998;Krishnan-Sarin et al, 1995a). Similarly, it is also well established that the nonselective opioid antagonists naltrexone and nalmefene attenuate alcohol drinking behavior, control craving, and prevent relapse in alcohol-dependent humans (O'Malley et al, 1992;Volpicelli et al, 1992;Mason et al, 1994Mason et al, , 1999 albeit, the effectiveness of these agents has been limited by problems with compliance (Volpicelli et al, 1997;Johnson and Ait-Daoud, 2000;Kranzler, 2000).…”

Section: Introductionmentioning

confidence: 90%

“…After a period of stabilization on the concurrent FR1 schedule for EtOH and water, the response requirement was increased to a concurrent FR4 schedule. Following stabilization on the concurrent FR4 schedule, a series of preliminary studies were conducted to determine the saccharin concentration that produced response rates similar to that of EtOH (see June et al, 1998June et al, , 1999June, 2002). Of the saccharin concentrations tested, the 0.025 and 0.05% w/v concentrations produced rates of responding that were similar to EtOH in the rats tested.…”

Section: Behavioral Training and Testing Proceduresmentioning

confidence: 99%

“…Some researchers have argued that while both EtOH and other palatable reinforcers are affected by opioid antagonists, the relative magnitude of suppression is far less for water, sucrose, and saccharin solutions (see June et al, 1998June et al, , 1999Heyser et al, 1999). Still others contend that because the endogenous opioid systems mediate natural reinforcers (ie hunger, thirst, sex, etc) it is not realistic to expect a complete separation between EtOH intake and intake of other palatable reinforcers (Herz, 1997).…”

Section: Introductionmentioning

confidence: 99%

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

June

Cummings

Eiler

et al. 2003

Neuropsychopharmacol

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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.

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Association of a Functional Polymorphism in the μ-Opioid Receptor Gene With Alcohol Response and Consumption in Male Rhesus Macaques

Barr¹,

Schwandt²,

Lindell³

et al. 2007

Arch Gen Psychiatry

110

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These findings demonstrate that the rhesus macaques' equivalent of the OPRM1A118G variant is associated with increased alcohol response, consumption, and preference. Our results reveal effects of the OPRM1C77G genotype to be male-restricted or more marked among male macaques. This is of interest, given the fact that early-onset type II alcoholism is more common among men and that, among addicted individuals, men are more responsive to mu-opioid receptor blockade.

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The δ 2 -opioid receptor antagonist naltriben reduces motivated responding for ethanol

Cited by 76 publications

References 37 publications

δ-Opioid Receptor Expression in the Ventral Tegmental Area Protects Against Elevated Alcohol Consumption

δ-Opioid Receptor Expression in the Ventral Tegmental Area Protects Against Elevated Alcohol Consumption

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

Association of a Functional Polymorphism in the μ-Opioid Receptor Gene With Alcohol Response and Consumption in Male Rhesus Macaques

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