Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Neuropharmacology. 2024 Nov 1;258:110081. doi: 10.1016/j.neuropharm.2024.110081. Epub 2024 Jul 15.
Synaptic plasticity in the mesolimbic dopamine (DA) system contributes to the neural adaptations underlying addictive behaviors and relapse. However, the specific behavioral relevance of glutamatergic excitatory drive onto dopamine D1 receptor (D1R)-expressing neurons in mediating the reinforcing effect of cocaine remains unclear. Here, we investigated how midbrain AMPAR and NMDAR function modulate cocaine reward-related behavior using mutant mouse lines lacking the glutamate receptor genes Gria1 or Grin1 in D1R-expressing neurons (GluA1 or GluN1, respectively). We found that conditional genetic deletion of either GluA1 or GluN1 within this neuronal sub-population did not impact the ability of acute cocaine injection to increase intracranial self-stimulation (ICSS) ratio or reduced brain reward threshold compared to littermate controls. Additionally, our data demonstrate that deletion of GluA1 and GluN1 receptor subunits within D1R-expressing neurons did not affect cocaine reinforcement in an operant self-administration paradigm, as mutant mice showed comparable cocaine responses and intake to controls. Given the pivotal role of glutamate receptors in mediating relapse behavior, we further explored the impact of genetic deletion of AMPAR and NMDAR onto D1R-expressing neurons on cue-induced reinstatement following extinction. Surprisingly, deletion of AMPAR and NMDAR onto these neurons did not impair cue-induced reinstatement of cocaine-seeking behavior. These findings suggest that glutamatergic activity via NMDAR and AMPAR in D1R-expressing neurons may not exclusively mediate the reinforcing effects of cocaine and cue-induced reinstatement.
中脑边缘多巴胺（DA）系统中的突触可塑性有助于成瘾行为和复发的神经适应。然而，介导可卡因强化效应的谷氨酸能兴奋性传入到多巴胺 D1 受体（D1R）表达神经元的具体行为相关性尚不清楚。在这里，我们使用在 D1R 表达神经元中缺乏谷氨酸受体基因 Gria1 或 Grin1 的突变小鼠系，研究了中脑 AMPAR 和 NMDAR 功能如何调节可卡因奖赏相关行为。我们发现，在这个神经元亚群中，条件性遗传缺失 GluA1 或 GluN1 都不会影响急性可卡因注射增加颅内自我刺激（ICSS）比率或降低大脑奖赏阈值的能力，与同窝对照相比。此外，我们的数据表明，D1R 表达神经元中 GluA1 和 GluN1 受体亚基的缺失不会影响操作式自我给药范式中的可卡因强化作用，因为突变小鼠表现出与对照相似的可卡因反应和摄入量。鉴于谷氨酸受体在介导复发行为中的关键作用，我们进一步探讨了 D1R 表达神经元中 AMPAR 和 NMDAR 的遗传缺失对消退后线索诱导复燃的影响。令人惊讶的是，这些神经元上 AMPAR 和 NMDAR 的缺失并没有损害可卡因寻求行为的线索诱导复燃。这些发现表明，D1R 表达神经元中的谷氨酸能活动通过 NMDAR 和 AMPAR 可能并不专门介导可卡因的强化效应和线索诱导复燃。
