Abstract
The transition from non-dependent alcohol use to alcohol dependence involves increased activity of the dorsal striatum. Interestingly, the dorsal striatum expresses a large number of inhibitory G-protein-coupled receptors (GPCRs), which when activated may inhibit alcohol-induced increased activity and can decrease alcohol consumption. Here, we explore the hypothesis that dorsal striatal Gi/o-protein activation is sufficient to reduce voluntary alcohol intake. Using a voluntary, limited-access, two-bottle choice, drink-in-the-dark model of alcohol (10%) consumption, we validated the importance of Gi/o signaling in this region by locally expressing neuron-specific, adeno-associated-virus encoded Gi/o-coupled muscarinic M4 designer receptors exclusively activated by designer drugs (DREADD) in the dorsal striatum and observed a decrease in alcohol intake upon DREADD activation. We validated our findings by activating Gi/o-coupled delta-opioid receptors (DORs), which are natively expressed in the dorsal striatum, using either a G-protein biased agonist or a β-arrestin-biased agonist. Local infusion of TAN-67, an in vitro-determined Gi/o-protein biased DOR agonist, decreased voluntary alcohol intake in wild-type and β-arrestin-2 knockout (KO) mice. SNC80, a β-arrestin-2 biased DOR agonist, increased alcohol intake in wild-type mice; however, SNC80 decreased alcohol intake in β-arrestin-2 KO mice, thus resulting in a behavioral outcome generally observed for Gi/o-biased agonists and suggesting that β-arrestin recruitment is required for SNC80-increased alcohol intake. Overall, these results suggest that activation Gi/o-coupled GPCRs expressed in the dorsal striatum, such as the DOR, by G-protein biased agonists may be a potential strategy to decrease voluntary alcohol consumption and β-arrestin recruitment is to be avoided.
Highlights
Alcoholism and alcohol abuse is a widespread health issue, placing a large burden at both the individual and societal level
SNC80 (10 μM) infusion into the dorsal striatum of β-arrestin-2 KO animals did not cause hyperlocomotion compared with vehicle infusion [Figures S4A,B in Supplementary Material, paired two-tailed Student's t-test: t(6) = 1.68, p = 0.14], the trend toward a decrease in locomotor activity suggests that there may be a potential influence of SNC80 on locomotor activity with respect to the decrease in alcohol intake observed upon SNC80 infusion in β-arrestin-2 KO animals. Through both chemogenetic and pharmacologic activation of Gi/o-protein signaling, we observed that activation of Gi/o-proteincoupled receptors in the dorsal striatum significantly decreases alcohol intake in male C57BL/6 mice by either inhibitory designer receptors exclusively activated by designer drugs (DREADD) activation or activation of endogenously expressed delta-opioid receptors (DORs) using a G-protein biased agonist
We targeted the dorsal striatum as it plays an important role in modulating habitual alcohol use [2, 3, 7, 9], has strong DOR expression [20], and, crucially, is a region where DOR agonist SNC80 has been shown to increase alcohol intake in rats [25]
Summary
Alcoholism and alcohol abuse is a widespread health issue, placing a large burden at both the individual and societal level. One potential AUD treatment approach is to increase inhibition of the dorsal striatum, a brain region with observed increasing activation upon alcohol tasting in heavy alcohol drinking human subjects [2]. Habitual alcohol self-administration increases habit-like responding with decreased sensitivity to alcohol devaluation [6]. This shift toward habit-like responding, as well as reports of increased hyperexcitability and altered glutamatergic and GABAergic transmission in the dorsomedial striatum upon alcohol exposure [7,8,9], suggests molecular alterations in this brain region lead to behavioral reinforcement of alcohol intake resulting in habitual, excessive alcohol intake [3, 7, 9]. We hypothesized that one conceivable strategy to inhibit this alcohol-induced neuronal excitability is by activation of metabotropic, inhibitory Gi/o-protein signaling pathways via G-protein-coupled receptors (GPCRs) expressed on neurons in this region
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