Department of Psychiatry, University of California, San Diego, USA.
School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.
Neuropharmacology. 2023 Dec 1;240:109694. doi: 10.1016/j.neuropharm.2023.109694. Epub 2023 Sep 1.
Environmental conditioning factors have a profound impact on alcohol-seeking behavior and the maintenance of alcohol use in individuals with alcohol dependence. Cues associated with alcohol, depending on the perceived value of the primary reinforcer, gain salience and can trigger relapse. This study investigates the correlation between the reward magnitude of the primary reinforcer and the reinstatement evoked by cues predictive of their availability in male rats. Rat self-administration procedures were used to test reinstatement, with reinforcers consisting of 10% alcohol, 10% sucrose, or 2% sodium chloride (NaCl) experienced under need-state conditions. The effect of MTEP ([(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine), a selective metabotropic glutamate receptor 5 (mGluR5) antagonist, on motivation and reinstatement behaviors was also evaluated. RESULTS: demonstrate that under Fixed Ratio 1 (FR1) schedule, the three reinforcers maintain operant responding with the following order of magnitude 10% sucrose >2% NaCl >10% alcohol > water. Under a progressive ratio (PR) schedule of reinforcement, rats exhibit a significantly higher breakpoint for 2% NaCl (under Na-depletion), followed by 10% sucrose and 10% alcohol. After extinction, a significant reinstatement is observed with the magnitude order of 10% sucrose >10% alcohol >2% NaCl. However, only re-exposure to alcohol-paired cues induced significant reinstatement of alcohol-seeking after 4 and 8 months. Treatment with MTEP significantly reduces reinstatement of responding across all reinforcers, with the strongest effect observed on alcohol-seeking. These findings suggest that mGluR5 plays a general role in controlling cue-reactivity, but the effect is prominent in the case of alcohol compared to natural rewards. In conclusion, the results demonstrate a remarkable dissociation between the rewarding magnitude of the primary reinforcer and its ability to trigger relapse upon presentation of a cue previously associated with it. Importantly, alcohol, despite having lower intrinsic motivational value compared to a natural reward (sucrose) or a consummatory stimulus experienced under need state conditions (NaCl), can elicit more robust and longer-term reinstatement of seeking responses. Finally, our data demonstrate a significant involvement of the mGluR5 system in the regulation of seeking behavior.
环境条件因素对有酒精依赖的个体的觅酒行为和维持饮酒行为有深远影响。与酒精相关的线索，取决于主要强化物的感知价值，会获得突显，并可能引发复饮。本研究旨在调查雄性大鼠中，主要强化物的奖赏值与线索诱发复饮之间的相关性，这些线索可预测其可用性。大鼠自身给药程序用于测试复饮，强化物由在需求状态下体验到的 10%酒精、10%蔗糖或 2%氯化钠（NaCl）组成。还评估了选择性代谢型谷氨酸受体 5（mGluR5）拮抗剂 MTEP([(2-甲基-1,3-噻唑-4-基)乙炔基]吡啶)对动机和复饮行为的影响。结果表明，在固定比率 1（FR1）时间表下，这三种强化物的操作反应保持一致，其量级顺序为 10%蔗糖>2%NaCl>10%酒精>水。在递增比率（PR）强化时间表下，大鼠在钠耗竭时表现出 2%NaCl 的显著较高的断点，其次是 10%蔗糖和 10%酒精。在消退后，观察到显著的复饮，量级顺序为 10%蔗糖>10%酒精>2%NaCl。然而，只有暴露于酒精配对线索后，才能在 4 个月和 8 个月后显著诱发觅酒行为。MTEP 治疗显著降低了所有强化物的反应复饮，对觅酒行为的影响最为明显。这些发现表明，mGluR5 在控制线索反应方面起着一般作用，但在酒精与天然奖赏相比时，其作用更为突出。总之，研究结果表明，主要强化物的奖赏量级与其在呈现先前与之相关的线索时引发复饮的能力之间存在显著分离。重要的是，尽管与天然奖赏（蔗糖）或在需求状态下体验到的消耗性刺激（NaCl）相比，酒精的内在动机价值较低，但它可以引发更强烈和更持久的觅酒行为复饮。最后，我们的数据表明，mGluR5 系统在调节觅酒行为方面具有重要作用。
