Kramar Cecilia, Loureiro Michael, Renard Justine, Laviolette Steven R
Department of Anatomy and Cell Biology, The Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
Department of Psychiatry, The Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
Cannabis Cannabinoid Res. 2017 Jan 1;2(1):8-20. doi: 10.1089/can.2016.0030. eCollection 2017.
The GPR55 receptor has been identified as an atypical cannabinoid receptor and is implicated in various physiological processes. However, its functional role in the central nervous system is not currently understood. The presence of GPR55 receptor in neural regions such as the ventral hippocampus (vHipp), which is critical for cognition, recognition memory, and affective processing, led us to hypothesize that intra-vHipp GPR55 transmission may modulate mesolimbic activity states and related behavioral phenomena. The vHipp is involved in contextual memory and affective regulation through functional interactions with the mesolimbic dopamine system. Using a combination of electrophysiology and behavioral pharmacological assays in rats, we tested whether intra-vHipp activation of GPR55 receptor transmission with the fatty acid amide, palmitoylethanolamide (PEA), a lipid neuromodulator with agonist actions at the GPR55 receptor, may modulate mesolimbic dopaminergic activity states. We further examined the potential effects of intra-vHipp PEA in affective, cognitive and contextual memory tasks. We report that intra-vHipp PEA produces a hyper-dopaminergic state in the mesolimbic system characterized by increased firing and bursting activity of ventral tegmental area dopaminergic neuron populations. Furthermore, while PEA-induced activation of GPR55 transmission had no effects on opiate-related reward-related memory formation, we observed strong disruptions in social interaction and recognition memory, spatial location memory, and context-independent associative fear memory formation. Finally, the effects of intra-vHipp PEA were blocked by a selective GPR55 receptor antagonist, CID160 and were dependent upon NMDA receptor transmission, directly in the vHipp. The present results add to a growing body of evidence demonstrating important functional roles for GPR55 signaling in cannabinoid-related neuronal and behavioral phenomena and underscore the potential for GPR55 signaling in the mediation of cannabinoid-related effects independently of the CB1/CB2 receptor systems.
GPR55受体已被确认为一种非典型大麻素受体，并参与多种生理过程。然而，目前尚不清楚其在中枢神经系统中的功能作用。GPR55受体存在于对认知、识别记忆和情感加工至关重要的神经区域，如腹侧海马体（vHipp），这使我们推测vHipp内的GPR55传递可能调节中脑边缘活动状态及相关行为现象。vHipp通过与中脑边缘多巴胺系统的功能相互作用参与情境记忆和情感调节。我们在大鼠中结合使用电生理学和行为药理学分析方法，测试了用脂肪酸酰胺棕榈酰乙醇胺（PEA，一种对GPR55受体具有激动作用的脂质神经调节剂）对vHipp内GPR55受体传递的激活是否可能调节中脑边缘多巴胺能活动状态。我们进一步研究了vHipp内PEA在情感、认知和情境记忆任务中的潜在作用。我们报告称，vHipp内的PEA在中脑边缘系统产生一种高多巴胺能状态，其特征为腹侧被盖区多巴胺能神经元群体的放电和爆发活动增加。此外，虽然PEA诱导的GPR55传递激活对阿片类药物相关的奖赏相关记忆形成没有影响，但我们观察到社交互动、识别记忆、空间位置记忆以及与情境无关的联想恐惧记忆形成受到强烈干扰。最后，vHipp内PEA的作用被选择性GPR55受体拮抗剂CID160阻断，并且直接在vHipp中依赖于NMDA受体传递。目前的结果增加了越来越多的证据，证明GPR55信号在大麻素相关的神经元和行为现象中具有重要功能作用，并强调了GPR55信号在介导大麻素相关效应方面独立于CB1/CB2受体系统的潜力。
