Dopamine D3 Receptor Is Necessary for Ethanol Consumption: An Approach with Buspirone

Abstract

Mesolimbic dopamine (DA) controls drug- and alcohol-seeking behavior, but the role of specific DA receptor subtypes is unclear. We tested the hypothesis that D3R gene deletion or the D3R pharmacological blockade inhibits ethanol preference in mice. D3R-deficient mice (D3R−/−) and their wild-type (WT) littermates, treated or not with the D3R antagonists SB277011A and U99194A, were tested in a long-term free choice ethanol-drinking (two-bottle choice) and in a binge-like ethanol-drinking paradigm (drinking in the dark, DID). The selectivity of the D3R antagonists was further assessed by molecular modeling. Ethanol intake was negligible in D3R−/− and robust in WT both in the two-bottle choice and DID paradigms. Treatment with D3R antagonists inhibited ethanol intake in WT but was ineffective in D3R−/− mice. Ethanol intake increased the expression of RACK1 and brain-derived neurotrophic factor (BDNF) in both WT and D3R−/−; in WT there was also a robust overexpression of D3R. Thus, increased expression of D3R associated with activation of RACK1/BDNF seems to operate as a reinforcing mechanism in voluntary ethanol intake. Indeed, blockade of the BDNF pathway by the TrkB selective antagonist ANA-12 reversed chronic stable ethanol intake and strongly decreased the striatal expression of D3R. Finally, we evaluated buspirone, an approved drug for anxiety disorders endowed with D3R antagonist activity (confirmed by molecular modeling analysis), that resulted effective in inhibiting ethanol intake. Thus, DA signaling via D3R is essential for ethanol-related reward and consumption and may represent a novel therapeutic target for weaning.

Neuronal circuitry underlying the impact of D3 receptor ligands in drug addiction

“…In another study, increases in BDNF and D3 receptor expression were found in the NAcc of rats that received sensitizing doses of morphine in a distinct environment (Liang et al, 2011). Increased of D3 receptor have been reported also following alcohol exposure (Leggio et al, 2014; Vengeliene et al, 2006) and nicotine exposure (Le Foll et al, 2003a; Le Foll et al, 2003b). …”

Genes and Alcohol Consumption

“…Overexpression of D 2 transiently increased intake in D 2 receptor knockout mice and decreased intake in wild-type mice (Thanos, Rivera, et al, 2005). Effects of D 3 and D 4 dopamine receptor deletion are less well studied, but there is a report of substantially decreased alcohol consumption in 2BC and DID tests in D 3 knockout mice (Leggio et al, 2014). An example of the complex role of sex and genetic background is illustrated by the DAT knockout, which decreased drinking in females but not males on a B6 background and increased drinking in males but not females on a mixed genetic background (Table 3).…”

Imaging the D3 dopamine receptor across behavioral and drug addictions: Positron emission tomography studies with [11C]-(+)-PHNO

“…In this regard, the drug buspirone (Buspar s , a marketed anxiolytic mainly used for its serotonergic effects) was recently shown to have D 3 antagonist properties in vitro (Bergman et al, 2013;Kula et al, 1994). Studies in nonhuman primates showed buspirone to decrease cocaine selfadministration at acute doses that are clinically relevant in humans (Bergman et al, 2013;Czoty and Nader, 2015), and chronic dosing regimens also showed efficacy in reducing cocaine, ethanol and nicotine self-administration in primates and mice (Leggio et al, 2014;Mello et al, 2013aMello et al, , 2013bSkolnick, 2010). In humans, several studies have evaluated the efficacy of buspirone in clinical trials of addictions (with mixed results; reviewed in Paterson et al, 2014), and a recent pilot study of methamphetamine dependence suggested that buspirone may dampen subjective responses to methamphetamine (Paterson et al, 2014).…”