Viral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats.
Viral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats.
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DOI：
10.3389/fnbeh.2021.787362
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发表时间：
2021
影响因子：
3
通讯作者：
Sabino V
中科院分区：
文献类型：
--
作者：
Minnig MA;Park T;Echeveste Sanchez M;Cottone P;Sabino V
酒精使用障碍 (AUD) 是一种慢性、复发性疾病，其遗传和环境易感性因素尚不完全清楚。神经肽能信号传导反复与调节过量饮酒有关，尤其是在纹状体的亚区域内。在这里，我们研究了伏隔核壳 (NAcc Shell) 中垂体腺苷酸环化酶激活多肽 (PACAP) 选择性受体 PAC1R 在嗜酒大鼠过度饮酒中的潜在参与，这是一种已建立的酗酒遗传倾向的动物模型。 Scr:sP 酒精偏好大鼠经过训练可自行饮酒，然后将靶向敲除 PAC1R 的 AAV 病毒短发夹 RNA (shRNA) 或 AAV 对照病毒微量注入 NAcc 壳中。 NAcc Shell PAC1R shRNA 敲除病毒被证实可显着降低 NAcc Shell 中的 PAC1R 水平。使用固定比例 (FR) 1 和渐进比例 (PR) 强化方案研究了 NAcc Shell PAC1R shRNA 敲低对乙醇自我给药的影响。还评估了 PAC1R 敲低对自我施用替代强化剂糖精的影响。结果表明，NAcc Shell 中 PAC1R 的减少导致过量饮酒、对乙醇的偏好增加以及饮酒的动机更高。 NAcc Shell PAC1R shRNA 敲低并没有相对增加糖精的自我给药，表明作用的选择性。这些数据表明，NAcc Shell PAC1R可能充当饮酒的“刹车”，从而PAC1R功能的丧失导致过量饮酒。因此，PACAP/PAC1R系统可能代表治疗AUD的新靶点。
Alcohol use disorder (AUD) is a chronic, relapsing disorder whose genetic and environmental susceptibility components are not fully understood. Neuropeptidergic signaling has been repeatedly implicated in modulating excessive alcohol drinking, especially within sub-regions of the striatum. Here, we investigated the potential involvement of the selective receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), PAC1R, in the nucleus accumbens shell (NAcc Shell) in excessive alcohol drinking in alcohol-preferring rats, an established animal model of the genetic propensity for alcoholism. Scr:sP alcohol-preferring rats were trained to operantly self-administer alcohol and then either an AAV virus short-hairpin RNA (shRNA) targeted to knockdown PAC1R, or an AAV control virus were microinfused into the NAcc Shell. NAcc Shell PAC1R shRNA knockdown virus was confirmed to significantly decrease PAC1R levels in the NAcc Shell. The effects of NAcc Shell PAC1R shRNA knockdown on ethanol self-administration were investigated using a Fixed Ratio (FR) 1 and a Progressive Ratio (PR) schedule of reinforcement. The effect of PAC1R knockdown on self-administration of an alternative reinforcer, saccharin, was also assessed. The results showed that the reduction in PAC1R in the NAcc Shell led to excessive ethanol drinking, increased preference for ethanol, and higher motivation to drink. NAcc Shell PAC1R shRNA knockdown did not comparably increase saccharin self-administration, suggesting selectivity of action. These data suggest that NAcc Shell PAC1R may serves as a “brake” on alcohol drinking, and thereby the loss of function of PAC1R leads to excessive alcohol consumption. Therefore, the PACAP/PAC1R system may represent a novel target for the treatment of AUD.
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影响因子：
7.6
作者：
Dore, Riccardo;Iemolo, Attilio;Sabino, Valentina
通讯作者：
Sabino, Valentina
DOI：
10.1111/acer.13826
发表时间：
2018-09
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Gupta A;Gargiulo AT;Curtis GR;Badve PS;Pandey S;Barson JR
通讯作者：
Barson JR
影响因子：
7.6
作者：
Ferragud, Antonio;Velazquez-Sanchez, Clara;Cottone, Pietro
通讯作者：
Cottone, Pietro
影响因子：
3.4
作者：
Gargiulo AT;Pirino BE;Curtis GR;Barson JR
通讯作者：
Barson JR
影响因子：
4.7
作者：
George O;Hope BT
通讯作者：
Hope BT