Neuroscience Curriculum, School of Medicine, University of North Carolina - Chapel Hill, Chapel Hill, NC, United States of America; Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina, Chapel Hill, NC, United States of America.
Center for Drug Discovery, RTI International, Research Triangle Park, NC, United States of America.
Pharmacol Biochem Behav. 2024 Jun;239:173767. doi: 10.1016/j.pbb.2024.173767. Epub 2024 Apr 10.
The subjective effects of alcohol are associated with alcohol use disorder (AUD) vulnerability and treatment outcomes. The interoceptive effects of alcohol are part of these subjective effects and can be measured in animal models using drug discrimination procedures. The newly developed mGlu and mGlu negative allosteric modulators (NAMs) are potential therapeutics for AUD and may alter interoceptive sensitivity to alcohol.
To determine the effects of mGlu and mGlu NAMs on the interoceptive effects of alcohol in rats.
Long-Evans rats were trained to discriminate the interoceptive stimulus effects of alcohol (2.0 g/kg, i.g.) from water using both operant (males only) and Pavlovian (male and female) drug discrimination techniques. Following acquisition training, an alcohol dose-response (0, 0.5, 1.0, 2.0 g/kg) experiment was conducted to confirm stimulus control over behavior. Next, to test the involvement of mGlu and mGlu, rats were pretreated with the mGlu-NAM (VU6001966; 0, 3, 6, 12 mg/kg, i.p.) or the mGlu-NAM (VU6010572; 0, 3, 6, 12 mg/kg, i.p.) before alcohol administration (2.0 g/kg, i.g.).
In Pavlovian discrimination, male rats showed greater interoceptive sensitivity to 1.0 and 2.0 g/kg alcohol compared to female rats. Both mGlu-NAM and mGlu-NAM attenuated the interoceptive effects of alcohol in male and female rats using Pavlovian and operant discrimination. There may be a potential sex difference in response to the mGlu-NAM at the highest dose tested.
Male rats may be more sensitive to the interoceptive effects of the 2.0 g/kg alcohol training dose compared to female rats. Both mGluand mGluNAM attenuate the interoceptive effects of alcohol in male and female rats. These drugs may have potential for treatment of AUD in part by blunting the subjective effects of alcohol.
酒精的主观效应与酒精使用障碍（AUD）易感性和治疗结果有关。酒精的内感受效应是这些主观效应的一部分，可以使用药物辨别程序在动物模型中进行测量。新开发的 mGlu 和 mGlu 负变构调节剂（NAM）是 AUD 的潜在治疗药物，可能会改变对酒精的内感受敏感性。
确定 mGlu 和 mGlu NAM 对大鼠酒精内感受效应的影响。
长爪沙鼠通过操作性（仅雄性）和条件性（雄性和雌性）药物辨别技术训练，辨别酒精（2.0 g/kg，ig）的内感受刺激效应与水。在获得训练后，进行酒精剂量反应（0、0.5、1.0、2.0 g/kg）实验，以确认行为对刺激的控制。接下来，为了测试 mGlu 和 mGlu 的参与，大鼠在给予酒精（2.0 g/kg，ig）之前预先给予 mGlu-NAM（VU6001966；0、3、6、12 mg/kg，ip）或 mGlu-NAM（VU6010572；0、3、6、12 mg/kg，ip）。
在条件性辨别中，雄性大鼠对 1.0 和 2.0 g/kg 酒精的内感受敏感性高于雌性大鼠。使用条件性和操作性辨别，两种 mGlu-NAM 和 mGlu-NAM 均减弱了雄性和雌性大鼠对酒精的内感受效应。在测试的最高剂量下，mGlu-NAM 的反应可能存在潜在的性别差异。
与雌性大鼠相比，雄性大鼠对 2.0 g/kg 酒精训练剂量的内感受效应可能更为敏感。两种 mGlu 和 mGluNAM 均减弱了雄性和雌性大鼠对酒精的内感受效应。这些药物可能通过减轻酒精的主观效应而具有 AUD 治疗的潜力。
