Graduate Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
Department of Psychiatry & Human Behavior, University of Mississippi Medical Center, 2500 North State St., Jackson, MS, 39216, USA.
Psychopharmacology (Berl). 2019 Jun;236(6):1797-1806. doi: 10.1007/s00213-018-5163-6. Epub 2019 Jan 12.
GABA receptors containing the α5 subunit (i.e., α5GABA receptors) appear to be critically involved in the reinforcing and subjective effects of alcohol. Their role in alcohol relapse remains unknown.
Pharmacological approaches were used to probe the role of α5GABA receptors in alcohol seeking induced by re-exposure to a sweetened alcohol-paired cue, as well as in alcohol + sucrose vs. sucrose self-administration.
For reinstatement studies, rats were trained to self-administer alcohol under a fixed-ratio schedule in which responding was maintained by alcohol + sucrose deliveries and an alcohol-paired stimulus. Sweetened alcohol seeking was extinguished by eliminating solution deliveries and the sweetened alcohol-paired stimulus. During reinstatement tests, animals received pretreatments of an α5GABA inverse agonist (L-655,708) or an agonist (QH-ii-066) prior to sessions in which presentation of the sweetened alcohol-paired stimulus was restored, but no solution was delivered. For self-administration studies, rats were trained to self-administer alcohol + sucrose or sucrose under a fixed-ratio schedule. Once stable, animals received pretreatments of QH-ii-066, L-655,708, the inverse agonist RY-023, or naltrexone.
L-655,708 attenuated reinstatement of sweetened alcohol seeking by alcohol + sucrose-paired cues; whereas sweetened alcohol-seeking behavior was augmented by QH-ii-066, albeit at different doses in different rats. Both L-655,708 and RY-023 selectively reduced alcohol + sucrose vs. sucrose self-administration. In contrast, naltrexone reduced both alcohol + sucrose and sucrose self-administration; whereas QH-ii-066 enhanced sucrose self-administration only.
α5GABA receptors play a key role in the modulation of sweetened alcohol cue-induced reinstatement, as well as in alcohol + sucrose but not sucrose self-administration. Inverse agonist activity at α5GABA receptors may offer a novel strategy for both the reduction of problematic drinking and the prevention of relapse.
包含α5 亚单位的 GABA 受体（即α5GABA 受体）似乎在酒精的强化和主观效应中起着至关重要的作用。它们在酒精复发中的作用尚不清楚。
采用药理学方法探讨α5GABA 受体在重新暴露于加糖酒精配对线索引起的酒精寻找中的作用，以及在酒精+蔗糖与蔗糖自我给药中的作用。
对于重新激发研究，大鼠在固定比例方案下接受酒精自我给药训练，其中反应由酒精+蔗糖的输送和酒精配对的刺激维持。通过消除溶液输送和加糖酒精配对刺激来消除加糖酒精寻找的消退。在重新激发测试中，动物在呈现加糖酒精配对刺激之前接受 α5GABA 反向激动剂（L-655,708）或激动剂（QH-ii-066）的预处理，但没有输送溶液。对于自我给药研究，大鼠在固定比例方案下接受酒精+蔗糖或蔗糖的自我给药训练。一旦稳定，动物接受 QH-ii-066、L-655,708、反向激动剂 RY-023 或纳曲酮的预处理。
L-655,708 减弱了酒精+蔗糖配对线索引起的加糖酒精寻找的重新激发；而 QH-ii-066 则增强了加糖酒精寻找行为，尽管在不同的大鼠中使用了不同的剂量。L-655,708 和 RY-023 均选择性地降低了酒精+蔗糖与蔗糖的自我给药。相比之下，纳曲酮降低了酒精+蔗糖和蔗糖的自我给药；而 QH-ii-066 仅增强了蔗糖的自我给药。
α5GABA 受体在调节加糖酒精线索诱导的重新激发以及酒精+蔗糖但不是蔗糖自我给药中起着关键作用。α5GABA 受体的反向激动剂活性可能为减少问题性饮酒和预防复发提供一种新的策略。
