GDNF gene therapy for alcohol use disorder in male non-human primates.

Alcohol use disorder (AUD) exacts enormous personal, social and economic costs globally. Return to alcohol use in treatment-seeking patients with AUD is common, engendered by a cycle of repeated abstinence-relapse episodes even with use of currently available pharmacotherapies. Repeated ethanol use induces dopaminergic signaling neuroadaptations in ventral tegmental area (VTA) neurons of the mesolimbic reward pathway, and sustained dysfunction of reward circuitry is associated with return to drinking behavior. We tested this hypothesis by infusing adeno-associated virus serotype 2 vector encoding human glial-derived neurotrophic factor (AAV2-hGDNF), a growth factor that enhances dopaminergic neuron function, into the VTA of four male rhesus monkeys, with another four receiving vehicle, following induction of chronic alcohol drinking. GDNF expression ablated the return to alcohol drinking behavior over a 12-month period of repeated abstinence-alcohol reintroduction challenges. This behavioral change was accompanied by neurophysiological modulations to dopamine signaling in the nucleus accumbens that countered the hypodopaminergic signaling state associated with chronic alcohol use, indicative of a therapeutic modulation of limbic circuits countering the effects of alcohol. These preclinical findings suggest gene therapy targeting relapse prevention may be a potential therapeutic strategy for AUD.

Social preference in rats.

Rats were given repeated choices between social and nonsocial outcomes, and between familiar and unfamiliar social outcomes. Lever presses on either of 2 levers in the middle chamber of a 3-chamber apparatus opened a door adjacent to the lever, permitting 45-s access to social interaction with the rat in the chosen side chamber. In Experiment 1, rats preferred (a) social over nonsocial options, choosing their cagemate rat over an empty chamber, and (b) an unfamiliar over a familiar rat, choosing a non-cagemate over their cagemate. These findings were replicated in Experiment 2 with 2 different non-cagemate rats. Rats preferred both non-cagemate rats to a similar degree when pitted against their cagemate, but were indifferent when the 2 non-cagemates were pitted against each other. Similar preference for social over nonsocial and non-cagemate over cagemate was seen in Experiment 3, with new non-cagemate rats introduced after every third session. Response rates (for both cagemate and non-cagemate rats) were elevated under conditions of nonsocial (isolated) housing compared to conditions of social (paired) housing, demonstrating a social deprivation effect. Together, the experiments contribute to an experimental analysis of social preference within a social reinforcement framework, drawing on methods with proven efficacy in the analysis of reinforcement more generally.

Mifepristone Decreases Chronic Voluntary Ethanol Consumption in Rhesus Macaques.

The efficacy of short-term treatment with mifepristone (MIFE), a high-affinity, nonselective glucocorticoid receptor antagonist, to reduce ethanol drinking was tested in a rhesus macaque model. Stable individual daily ethanol intakes were established, ranging from 1.6 to 4.0 g/kg per day (n = 9 monkeys). After establishment of chronic ethanol intake, a MIFE dosing regimen that modeled a study of rodent drinking and human alcohol craving was evaluated. Three doses of MIFE (17, 30, and 56 mg/kg per day) were each administered for four consecutive days. Both 30 and 56 mg/kg decreased ethanol intake compared with baseline drinking levels without a change in water intake. The dose of 56 mg/kg per day of MIFE produced the largest reduction in ethanol self-administration, with the average intake at 57% of baseline intakes. Cortisol was elevated during MIFE dosing, and a mediation analysis revealed that the effect on ethanol drinking was fully mediated through cortisol. During a forced abstinence phase, access to 1.5 g/kg ethanol resulted in relapse in all drinkers and was not altered by treatment with 56 mg/kg MIFE. Overall, these results show that during active drinking MIFE is efficacious in reducing heavy alcohol intake in a monkey model, an effect that was related to MIFE-induced increase in cortisol. However, MIFE treatment did not eliminate ethanol drinking. Further, cessation of MIFE treatment resulted in a rapid return to baseline intakes, and MIFE was not effective in preventing a relapse during early abstinence. SIGNIFICANCE STATEMENT: Mifepristone reliably decreases average daily ethanol self-administration in a nonhuman primate model. This effect was mediated by cortisol, was most effective during open-access conditions, and did not prevent or reduce relapse drinking.