mGlu2 and mGlu3 receptor negative allosteric modulators attenuate the interoceptive effects of alcohol in male and female rats

IF 3.3 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior Pub Date : 2024-04-10 DOI:10.1016/j.pbb.2024.173767

Ryan E. Tyler , Kalynn Van Voorhies , Bruce E. Blough , Antonio Landavazo , Joyce Besheer

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引用次数: 0

Abstract

Rationale

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 mGlu₂ and mGlu₃ negative allosteric modulators (NAMs) are potential therapeutics for AUD and may alter interoceptive sensitivity to alcohol.

Objectives

To determine the effects of mGlu₂ and mGlu₃ NAMs on the interoceptive effects of alcohol in rats.

Methods

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 mGlu₂ and mGlu₃, rats were pretreated with the mGlu₂-NAM (VU6001966; 0, 3, 6, 12 mg/kg, i.p.) or the mGlu₃-NAM (VU6010572; 0, 3, 6, 12 mg/kg, i.p.) before alcohol administration (2.0 g/kg, i.g.).

Results

In Pavlovian discrimination, male rats showed greater interoceptive sensitivity to 1.0 and 2.0 g/kg alcohol compared to female rats. Both mGlu₂-NAM and mGlu₃-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 mGlu₂-NAM at the highest dose tested.

Conclusions

Male rats may be more sensitive to the interoceptive effects of the 2.0 g/kg alcohol training dose compared to female rats. Both mGlu₂_-and mGlu₃_-NAM 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.

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mGlu2和mGlu3受体负异osteric调节剂可减轻酒精对雌雄大鼠的感知间效应

理由酒精的主观效应与酒精使用障碍（AUD）的易感性和治疗效果有关。酒精的互感效应是这些主观效应的一部分，可以在动物模型中使用药物辨别程序进行测量。新开发的 mGlu2 和 mGlu3 负异位调节剂（NAMs）是治疗 AUD 的潜在药物，可能会改变大鼠对酒精的感受性。方法使用操作性（仅雄性）和巴甫洛夫（雄性和雌性）药物辨别技术训练 Long-Evans 大鼠辨别酒精（2.0 克/千克，含服）和水的互感刺激效应。在习得训练之后，进行了酒精剂量反应（0、0.5、1.0、2.0 克/千克）实验，以确认刺激对行为的控制。接下来，为了测试 mGlu2 和 mGlu3 的参与情况，在给大鼠注射酒精（2.0 克/公斤）之前，用 mGlu2-NAM（VU6001966；0、3、6、12 毫克/公斤，静脉注射）或 mGlu3-NAM（VU6010572；0、3、6、12 毫克/公斤，静脉注射）预处理大鼠。结果在巴甫洛夫辨别法中，与雌性大鼠相比，雄性大鼠对 1.0 和 2.0 g/kg 酒精表现出更高的感知间敏感性。mGlu2-NAM和mGlu3-NAM都能减弱雄性和雌性大鼠在巴甫洛夫辨别法和操作辨别法中对酒精的感受效应。结论与雌性大鼠相比，雄性大鼠可能对 2.0 g/kg 酒精训练剂量的互感效应更敏感。mGlu2-NAM和mGlu3-NAM都能减弱雄性和雌性大鼠对酒精的感受效应。这些药物可能通过部分削弱酒精的主观效应而具有治疗 AUD 的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pharmacology Biochemistry and Behavior 医学-行为科学

CiteScore

6.40

自引率

2.80%

发文量

122

审稿时长

38 days

期刊介绍： Pharmacology Biochemistry & Behavior publishes original reports in the areas of pharmacology and biochemistry in which the primary emphasis and theoretical context are behavioral. Contributions may involve clinical, preclinical, or basic research. Purely biochemical or toxicology studies will not be published. Papers describing the behavioral effects of novel drugs in models of psychiatric, neurological and cognitive disorders, and central pain must include a positive control unless the paper is on a disease where such a drug is not available yet. Papers focusing on physiological processes (e.g., peripheral pain mechanisms, body temperature regulation, seizure activity) are not accepted as we would like to retain the focus of Pharmacology Biochemistry & Behavior on behavior and its interaction with the biochemistry and neurochemistry of the central nervous system. Papers describing the effects of plant materials are generally not considered, unless the active ingredients are studied, the extraction method is well described, the doses tested are known, and clear and definite experimental evidence on the mechanism of action of the active ingredients is provided.