Cocaine addiction is a serious health issue in Western countries. Despite the regular increase in cocaine consumption across the population, there is no specific treatment for cocaine addiction. Critical roles for glutamate neurotransmission in the rewarding effects of psychostimulants as well as relapse have been suggested and accumulating evidence indicates that targeting mGlu group III receptors could represent a promising strategy to develop therapeutic compounds to treat addiction. In this context, the aim of our study was to examine the effect of LSP2-9166, a mGlu4/mGlu7 receptor orthosteric agonist, on the motivation for cocaine intake. We used an intravenous self-administration paradigm in male Wistar rats as a reliable model of voluntary drug intake. We first evaluated the direct impact of cocaine on Grm4 and Grm7 gene expression. Voluntary cocaine intake under a fixed ratio schedule of injections induced an increase of both mGlu4 and mGlu7 receptor transcripts in nucleus accumbens and hippocampus. We then evaluated the ability of LSP2-9166 to affect cocaine self-administration under a progressive ratio schedule of reinforcement. We found that this compound inhibits the motivation to obtain the drug, although it induced a hypolocomotor effect which could biais motivation index. Our findings demonstrate that mGlu group III receptors represent new targets for decreasing motivation to self-administer cocaine.

可卡因成瘾在西方国家是一个严重的健康问题。尽管整个人口的可卡因消费量定期增加，但可卡因成瘾没有具体的治疗方法。已经提出谷氨酸神经传递在精神兴奋剂的奖励作用以及复发中的关键作用，并且越来越多的证据表明靶向mGlu III组受体可能代表开发治疗成瘾的治疗化合物的有希望的策略。在这种情况下，我们研究的目的是检查 LSP2-9166（一种 mGlu4/mGlu7 受体正构激动剂）对可卡因摄入动机的影响。我们在雄性 Wistar 大鼠中使用静脉内自我给药模式作为自愿药物摄入的可靠模型。我们首先评估了可卡因对Grm4的直接影响和Grm7基因表达。在固定比例的注射计划下自愿摄入可卡因会导致伏隔核和海马中 mGlu4 和 mGlu7 受体转录物的增加。然后，我们评估了 LSP2-9166 在渐进比例强化计划下影响可卡因自我给药的能力。我们发现这种化合物抑制了获得药物的动机，尽管它诱导了一种运动迟缓效应，这可能会影响动机指数。我们的研究结果表明，mGlu III 组受体代表了降低自我服用可卡因动机的新目标。