Department of Experimental and Clinical Pharmacology, Medical University of Lublin, 20-090 Lublin, Poland.
Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland.
Int J Mol Sci. 2021 Jul 26;22(15):7940. doi: 10.3390/ijms22157940.
The activation of the endocannabinoid system controls the release of many neurotransmitters involved in the brain reward pathways, including glutamate. Both endocannabinoid and glutamate systems are crucial for alcohol relapse. In the present study, we hypothesize that N-methyl-D-aspartate (NMDA) glutamate receptors regulate the ability of a priming dose of WIN 55,212-2 to cross-reinstate ethanol-induced conditioned place preference (CPP). To test this hypothesis, ethanol-induced (1.0 g/kg, 10% /, i.p.) CPP (unbiased method) was established using male adult Wistar rats. After CPP extinction, one group of animals received WIN 55,212-2 (1.0 and 2.0 mg/kg, i.p.), the cannabinoid receptor 1 (CB1) agonist, or ethanol, and the other group received memantine (3.0 or 10 mg/kg, i.p.), the NMDA antagonist and WIN 55,212-2 on the reinstatement day. Our results showed that a priming injection of WIN 55,212-2 (2.0 mg/kg, i.p.) reinstated (cross-reinstated) ethanol-induced CPP with similar efficacy to ethanol. Memantine (3.0 or 10 mg/kg, i.p.) pretreatment blocked this WIN 55,212-2 effect. Furthermore, our experiments indicated that ethanol withdrawal (7 days withdrawal after 10 days ethanol administration) down-regulated the CNR1 (encoding CB1), GRIN1/2A (encoding GluN1 and GluN2A subunit of the NMDA receptor) genes expression in the prefrontal cortex and dorsal striatum, but up-regulated these in the hippocampus, confirming the involvement of these receptors in ethanol rewarding effects. Thus, our results show that the endocannabinoid system is involved in the motivational properties of ethanol, and glutamate may control cannabinoid induced relapse into ethanol seeking behavior.
内源性大麻素系统的激活控制着许多参与大脑奖励途径的神经递质的释放，包括谷氨酸。内源性大麻素和谷氨酸系统对于酒精复发都至关重要。在本研究中，我们假设 N-甲基-D-天冬氨酸（NMDA）谷氨酸受体调节引发剂量的 WIN 55,212-2 交叉复燃乙醇诱导的条件性位置偏爱（CPP）的能力。为了验证这一假设，使用雄性成年 Wistar 大鼠建立了乙醇诱导的（1.0 g/kg，10% /，ip）CPP（无偏方法）。CPP 消退后，一组动物接受了 WIN 55,212-2（1.0 和 2.0 mg/kg，ip），大麻素受体 1（CB1）激动剂，或乙醇，另一组接受了美金刚（3.0 或 10 mg/kg，ip），NMDA 拮抗剂和 WIN 55,212-2 在重新激发日。我们的结果表明，WIN 55,212-2（2.0 mg/kg，ip）的引发注射（交叉引发）与乙醇具有相似的功效复燃了乙醇诱导的 CPP。美金刚（3.0 或 10 mg/kg，ip）预处理阻断了这种 WIN 55,212-2 效应。此外，我们的实验表明，乙醇戒断（10 天乙醇给药后 7 天戒断）下调了前额叶皮层和背侧纹状体中的 CNR1（编码 CB1）、GRIN1/2A（编码 NMDA 受体的 GluN1 和 GluN2A 亚基）基因表达，但在海马体中上调了这些基因的表达，证实了这些受体参与了乙醇的奖赏效应。因此，我们的结果表明，内源性大麻素系统参与了乙醇的动机特性，而谷氨酸可能控制大麻素诱导的复饮行为。
