Siciliano Cody A, Locke Jason L, Mathews Tiffany A, Lopez Marcelo F, Becker Howard C, Jones Sara R
Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
College of Engineering, Pennsylvania State University, University Park, PA, USA.
Alcohol. 2017 Feb;58:25-32. doi: 10.1016/j.alcohol.2016.05.005. Epub 2016 Jun 11.
Alcoholism is a prevalent and debilitating neuropsychiatric disease, and much effort has been aimed at elucidating the neurobiological mechanisms underlying maladaptive alcohol drinking in an effort to design rational treatment strategies. In preclinical literature, the use of inbred mouse lines has allowed for the examination of ethanol effects across vulnerable and resistant phenotypes. C57BL/6J mice consistently show higher rates of ethanol drinking compared to most mouse strains. Conversely, DBA/2J mice display low rates of ethanol consumption. Given that the reinforcing and rewarding effects of ethanol are thought to be in part mediated by its actions on dopamine neurotransmission, we hypothesized that alcohol-preferring C57BL/6J and alcohol-avoiding DBA/2J mice would display basal differences in dopamine system function. By administering an L-aromatic acid decarboxylase inhibitor and measuring L-Dopa accumulation via high-performance liquid chromatography as a measure of tyrosine hydroxylase activity, we found no difference in dopamine synthesis between mouse strains in the midbrain, dorsal striatum, or ventral striatum. However, we did find that quinpirole-induced inhibition of dopamine synthesis was greater in the ventral striatum of C57BL/6J mice, suggesting increased presynaptic D2-type dopamine autoreceptor sensitivity. To determine whether dopamine synthesis or autoreceptor sensitivity was altered by a history of ethanol, we exposed C57BL/6J mice to one or two weekly cycles of chronic intermittent ethanol (CIE) exposure and withdrawal. We found that there was an attenuation of baseline dopamine synthesis in the ventral striatum after two cycles of CIE. Finally, we examined tissue content of dopamine and dopamine metabolites across recombinant inbred mice bred from a C57BL/6J × DBA/2J cross (BXD). We found that low dopaminergic activity, as indicated by high dopamine/metabolite ratios, was positively correlated with drinking. Together, these findings show differential autoreceptor effects on dopamine synthesis between C57BL/6J and DBA/2J mice, and suggest that decreased dopaminergic activity is associated with excessive drinking.
酒精中毒是一种普遍且使人衰弱的神经精神疾病，人们为阐明适应不良饮酒背后的神经生物学机制付出了诸多努力，旨在设计合理的治疗策略。在临床前文献中，近交系小鼠品系的使用使得人们能够研究乙醇对易感性和抗性表型的影响。与大多数小鼠品系相比，C57BL/6J小鼠一直表现出更高的乙醇饮用率。相反，DBA/2J小鼠的乙醇消费量较低。鉴于乙醇的强化和奖赏作用部分被认为是由其对多巴胺神经传递的作用介导的，我们推测偏好酒精的C57BL/6J小鼠和回避酒精的DBA/2J小鼠在多巴胺系统功能上会表现出基础差异。通过给予L-芳香酸脱羧酶抑制剂，并通过高效液相色谱法测量L-多巴积累量作为酪氨酸羟化酶活性的指标，我们发现中脑、背侧纹状体或腹侧纹状体中，小鼠品系之间的多巴胺合成没有差异。然而，我们确实发现喹吡罗诱导的多巴胺合成抑制在C57BL/6J小鼠的腹侧纹状体中更大，这表明突触前D2型多巴胺自身受体敏感性增加。为了确定多巴胺合成或自身受体敏感性是否因乙醇暴露史而改变，我们将C57BL/6J小鼠暴露于每周一或两个周期的慢性间歇性乙醇（CIE）暴露和戒断中。我们发现，经过两个周期的CIE后，腹侧纹状体中的基线多巴胺合成有所减弱。最后，我们检查了由C57BL/6J×DBA/2J杂交（BXD）培育的重组近交小鼠中多巴胺和多巴胺代谢物的组织含量。我们发现，以高多巴胺/代谢物比率表示的低多巴胺能活性与饮酒呈正相关。总之，这些发现表明C57BL/6J和DBA/2J小鼠之间自身受体对多巴胺合成的影响存在差异，并表明多巴胺能活性降低与过度饮酒有关
