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

Abstract

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.

The Role of Delta Opioid Receptors in Ethanol Consumption and Seeking: Implications for New Treatments for Alcohol Use Disorders

“…Furthermore, both naltrindole and CTOP suppressed responding in non-ethanol preferring Wistar rats suggesting that the DOP-R may play a greater role than the MOP-R in suppressing responding in high drinking rats, regardless of strain. This is further supported by other studies using models of low to moderate ethanol or limited access paradigms in which DOP-R antagonists do not reduce ethanol consumption (Ingman et al, 2003;Margolis et al, 2008;Stromberg et al, 1998a).…”

“…However, DOP-R antagonists also have been shown to not affect (Ingman et al, 2003;Stromberg et al, 1998a) or increase ethanol intake (Margolis et al, 2008) (Table 1). Factors likely contributing to these disparities include the length of ethanol exposure, the route of drug administration, different types of drinking models that induce low, moderate and high ethanol consumption, the rodent strains used (such as alcohol-preferring rats) and potential different roles of subtypes of the DOP-R on ethanol-mediated behaviors.…”

“…Similarly, the effects of DALA administered into the HPN were selective for ethanol over food and water consumption (Barson et al, 2010). DOP-R agonists have also been shown to reduce ethanol consumption in rats (Margolis et al, 2008) and mice (van Rijn & Whistler, 2009). Systemic administration of the selective DOP-R agonist, TAN67, reduced voluntary ethanol intake in mice using a 4 hr limited ethanol access paradigm (van Rijn & Whistler, 2009).…”

“…Systemic administration of the selective DOP-R agonist, TAN67, reduced voluntary ethanol intake in mice using a 4 hr limited ethanol access paradigm (van Rijn & Whistler, 2009). Following administration of the DOP-R agonist, DPDPE (10 mM), into the ventral tegmental area (VTA) of rats using continuous access to 10% ethanol paradigm, ethanol intake was reduced in low but not high ethanol consuming rats (Margolis et al, 2008). It is hypothesized that DOP-Rs in the VTA play a protective role against elevated ethanol consumption (Margolis et al, 2008).…”

Using iPSC‐derived human DA neurons from opioid‐dependent subjects to study dopamine dynamics

“…While DOR and KOR gene variants and expression have been associated with vulnerability to addiction (Margolis et al. 2008; Mendez and Morales‐Mulia 2008; Nielsen et al. 2013), some of the mechanisms involved were suggested to be acting through regulation of dopamine dynamics in vivo (Nielsen et al.…”