Molecular and Behavioral Neuroscience Institute, University of Michigan, 205 Zina Pitcher Place, Ann Arbor, MI 48109, USA; Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA; Neuroscience Program, University of Michigan, Ann Arbor, MI, USA; Department of Psychology, University of Michigan, Ann Arbor, MI, USA.
Neuropharmacology. 2014 Jan;76 Pt B(0 0):425-36. doi: 10.1016/j.neuropharm.2013.04.033. Epub 2013 Apr 29.
Human genetic and epidemiological studies provide evidence that only a subset of individuals who experiment with potentially addictive drugs become addicts. What renders some individuals susceptible to addiction remains to be determined, but most would agree that there is no single trait underlying the disorder. However, there is evidence in humans that addiction liability has a genetic component, and that certain personality characteristics related to temperament (e.g. the sensation-seeking trait) are associated with individual differences in addiction liability. Consequently, we have used a selective breeding strategy based on locomotor response to a novel environment to generate two lines of rats with distinct behavioral characteristics. We have found that the resulting phenotypes differ on a number of neurobehavioral dimensions relevant to addiction. Relative to bred low-responder (bLR) rats, bred high-responder (bHR) rats exhibit increased exploratory behavior, are more impulsive, more aggressive, seek stimuli associated with rewards, and show a greater tendency to relapse. We therefore utilize this unique animal model to parse the genetic, neural and environmental factors that contribute to addiction liability. Our work shows that the glucocorticoid receptor (GR), dopaminergic molecules, and members of the fibroblast growth factor family are among the neurotransmitters and neuromodulators that play a role in both the initial susceptibility to addiction as well as the altered neural responses that follow chronic drug exposure. Moreover, our findings suggest that the hippocampus plays a major role in mediating vulnerability to addiction. It is hoped that this work will emphasize the importance of personalized treatment strategies and identify novel therapeutic targets for humans suffering from addictive disorders. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
人类遗传学和流行病学研究提供的证据表明，只有一小部分尝试潜在成瘾药物的个体成为成瘾者。是什么使一些个体易患成瘾仍有待确定，但大多数人都认为这种疾病没有单一的特征。然而，人类有证据表明成瘾倾向具有遗传成分，某些与气质相关的个性特征（例如寻求刺激的特质）与成瘾倾向的个体差异有关。因此，我们使用基于对新环境的运动反应的选择性繁殖策略来产生具有不同行为特征的两种大鼠品系。我们发现，由此产生的表型在与成瘾相关的许多神经行为维度上存在差异。与繁殖低反应（bLR）大鼠相比，繁殖高反应（bHR）大鼠表现出增加的探索行为、更冲动、更具攻击性、寻求与奖励相关的刺激，并且更倾向于复发。因此，我们利用这种独特的动物模型来解析导致成瘾倾向的遗传、神经和环境因素。我们的工作表明，糖皮质激素受体（GR）、多巴胺能分子和成纤维细胞生长因子家族成员是在最初易患成瘾以及慢性药物暴露后神经反应改变中起作用的神经递质和神经调质之一。此外，我们的研究结果表明，海马在介导成瘾易感性方面起着主要作用。希望这项工作将强调个性化治疗策略的重要性，并为患有成瘾障碍的人类确定新的治疗靶点。本文是题为“NIDA 40 周年特刊”的特刊的一部分。
