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 4 male rhesus monkeys, with another 4 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.
Monthly (c) and weekly (d) group means of BECs (milligrams per deciliter) from individual subjects by treatment group (n = 4 each) across all 6 reintroduction periods (R1–R6; mean ± s.e.m., n = 4/group).
(e) Group means of latency to maximum alcohol intake bout (seconds) by treatment group (mean ± s.e.m., n = 4/group) on the day of onset for each reintroduction phase.
(f) Group means of the size of the maximum alcohol intake bout (milliliters) by treatment group on the day of onset for each alcohol reintroduction phase period (mean ± s.e.m., n = 4 /group…).