Modeling Aversion Resistant Alcohol Intake in Indiana Alcohol-Preferring (P) Rats.
Modeling Aversion Resistant Alcohol Intake in Indiana Alcohol-Preferring (P) Rats.
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DOI：
10.3390/brainsci12081042
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发表时间：
2022-08-05
期刊：
影响因子：
3.3
通讯作者：
Engleman, Eric A.
中科院分区：
文献类型：
--
作者：
Katner, Simon N.;Sentir, Alena M.;Steagall, Kevin B.;Ding, Zheng-Ming;Wetherill, Leah;Hopf, Frederic W.;Engleman, Eric A.
关键词：
随着成瘾的社会和医疗负担，人们对了解增加成瘾发展的风险因素有相当大的兴趣。酒精使用障碍（AUD）的一个关键特征是强迫性酒精（EtOH）饮酒，其中EtOH饮酒在慢性摄入后变得“不灵活”，并且动物，例如患有AUD的人类，尽管有令人厌恶的后果，仍继续饮酒。此外，由于AUD风险存在可遗传的成分，一些工作集中在遗传选择的EtOH偏好啮齿动物上，这可能有助于揭示驱动病理性摄入的关键机制。在这方面，远系繁殖的Wistar大鼠（可能还有Sardinian-P EtOH偏好大鼠）需要>1个月的时间才能形成厌恶性饮酒（ARD）。然而，ARD在印第安纳州P大鼠中的研究有限，这些大鼠被选择为高EtOH偏好，并表现出与人类AUD相似的因素（包括前负荷和冲动）。在这里，我们表明，P-大鼠迅速发展的强迫样反应乙醇; 0.4克/升奎宁乙醇显着减少女性和男性摄入量的第一天曝光，但没有影响后一周的乙醇饮用（15%乙醇，24小时自由选择范例）。此外，在4-5周的乙醇饮用后，男性而不是女性表现出对更高奎宁（0.5 g/L）的抗性。因此，P-大鼠对EtOH迅速产生ARD，但只有雄性大鼠在进一步摄入时产生更强的ARD。最后，大鼠强烈减少摄入奎宁掺杂的水后1或5周的乙醇饮用，这表明没有变化的基本奎宁的敏感性。因此，在P-大鼠中建立ARD模型可能有助于深入了解强迫性饮酒的遗传易感性机制，并为AUD提供新的治疗方法。
With the substantial social and medical burden of addiction, there is considerable interest in understanding risk factors that increase the development of addiction. A key feature of alcohol use disorder (AUD) is compulsive alcohol (EtOH) drinking, where EtOH drinking becomes “inflexible” after chronic intake, and animals, such as humans with AUD, continue drinking despite aversive consequences. Further, since there is a heritable component to AUD risk, some work has focused on genetically-selected, EtOH-preferring rodents, which could help uncover critical mechanisms driving pathological intake. In this regard, aversion-resistant drinking (ARD) takes >1 month to develop in outbred Wistar rats (and perhaps Sardinian-P EtOH-preferring rats). However, ARD has received limited study in Indiana P-rats, which were selected for high EtOH preference and exhibit factors that could parallel human AUD (including front-loading and impulsivity). Here, we show that P-rats rapidly developed compulsion-like responses for EtOH; 0.4 g/L quinine in EtOH significantly reduced female and male intake on the first day of exposure but had no effect after one week of EtOH drinking (15% EtOH, 24 h free-choice paradigm). Further, after 4–5 weeks of EtOH drinking, males but not females showed resistance to even higher quinine (0.5 g/L). Thus, P-rats rapidly developed ARD for EtOH, but only males developed even stronger ARD with further intake. Finally, rats strongly reduced intake of quinine-adulterated water after 1 or 5 weeks of EtOH drinking, suggesting no changes in basic quinine sensitivity. Thus, modeling ARD in P-rats may provide insight into mechanisms underlying genetic predispositions for compulsive drinking and lead to new treatments for AUDs.
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