Brynildsen Julia K, Yang Kechun, Lemchi Crystal, Dani John A, De Biasi Mariella, Blendy Julie A
Department of Systems Pharmacology and Translational Therapeutics, USA.
Department of Neuroscience, USA.
Neuropharmacology. 2022 Nov 1;218:109218. doi: 10.1016/j.neuropharm.2022.109218. Epub 2022 Aug 13.
The single nucleotide polymorphism (SNP) D398N (rs16969968) in CHRNA5, the gene encoding the α5 subunit of the nicotinic acetylcholine receptors (nAChR), has been associated with both nicotine and opiate dependence in human populations. Expression of this SNP on presynaptic VTA dopaminergic (DA) neurons is known to cause a reduction in calcium signaling, leading to alterations in transmitter signaling and altered responses to drugs of abuse. To examine the impact of the Chrna5 SNP on opiate reward and underlying dopaminergic mechanisms, mice harboring two copies of the risk-associated allele (Chrna5 A/A) at a location equivalent to human rs16969968 were generated via CRISPR/cas9 genome editing. We sought to determine whether Chrna5 A/A mice show differences in sensitivity to rewarding properties of morphine using the conditioned place preference paradigm. When mice were tested two weeks after conditioning, female Chrna5 A/A mice showed significantly enhanced preference for the morphine-paired chamber relative to WT females, suggesting that this genotype may enhance opioid reward specifically in females. In contrast, Chrna5 genotype had no effect on locomotor sensitization in male or female mice. Relative to WT females, peak amplitude of ACh-gated currents recorded from VTA DA neurons in Chrna5 A/A females was potentiated 1 day after conditioning with morphine. Increased FOS expression was also observed in Chrna5 A/A mice relative to WT mice following exposure to the morphine CPP chamber. We propose that impaired α5 nAChR subunit function alters DA neuron response following repeated morphine exposures, and that this early cellular response could contribute to enhanced opiate reward two weeks after conditioning.
编码烟碱型乙酰胆碱受体（nAChR）α5亚基的基因CHRNA5中的单核苷酸多态性（SNP）D398N（rs16969968），已被证明与人类群体中的尼古丁和阿片类药物依赖有关。已知该SNP在突触前腹侧被盖区多巴胺能（DA）神经元上的表达会导致钙信号传导减少，进而导致递质信号改变以及对滥用药物的反应改变。为了研究Chrna5 SNP对阿片类药物奖赏及潜在多巴胺能机制的影响，通过CRISPR/cas9基因组编辑技术培育出在相当于人类rs16969968位点携带两个风险相关等位基因拷贝（Chrna5 A/A）的小鼠。我们试图使用条件性位置偏爱范式来确定Chrna5 A/A小鼠对吗啡奖赏特性的敏感性是否存在差异。在条件化训练两周后对小鼠进行测试时，雌性Chrna5 A/A小鼠相对于野生型雌性小鼠，对与吗啡配对的隔室表现出显著增强的偏爱，这表明该基因型可能特异性地增强雌性小鼠的阿片类药物奖赏。相比之下，Chrna5基因型对雄性或雌性小鼠的运动致敏没有影响。相对于野生型雌性小鼠，在吗啡条件化训练1天后，从Chrna5 A/A雌性小鼠的腹侧被盖区多巴胺能神经元记录到的乙酰胆碱门控电流的峰值幅度增强。在暴露于吗啡CPP隔室后，相对于野生型小鼠，Chrna5 A/A小鼠中也观察到FOS表达增加。我们提出，α5 nAChR亚基功能受损会在反复接触吗啡后改变多巴胺能神经元的反应，并且这种早期细胞反应可能导致条件化训练两周后阿片类药物奖赏增强。
