被盖腹侧区
酒精使用障碍
伏隔核
多巴胺能
胶质细胞源性神经生长因子
神经营养因子
神经科学
多巴胺能途径
多巴胺
中边缘通路
医学
心理学
药理学
酒
内科学
生物
受体
生物化学
作者
Matthew M. Ford,Brianna George,Victor S. Van Laar,Katherine M. Holleran,Jerusha Naidoo,Piotr Hadaczek,Lauren Vanderhooft,Emily G. Peck,Monica H. Dawes,Kousaku Ohno,John D. Heiss,Jodi L. McBride,Lluı́s Samaranch,John Forsayeth,Sara R. Jones,Kathleen A. Grant,Krystof S. Bankiewicz
出处
期刊:Nature Medicine
[Springer Nature]
日期:2023-08-01
卷期号:29 (8): 2030-2040
被引量:6
标识
DOI:10.1038/s41591-023-02463-9
摘要
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. In a preclinical study, the delivery of an AAV-based gene therapy encoding GDNF in the brain prevented the return to alcohol use behaviors in a non-human primate model.
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