Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction.
Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction.
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DOI：
10.1523/jneurosci.4256-09.2010
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发表时间：
2010-01-06
期刊：
影响因子：
--
通讯作者：
Eisch AJ
中科院分区：
文献类型：
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作者：
Noonan MA;Bulin SE;Fuller DC;Eisch AJ
滥用药物动态调节成人神经发生，这对某些类型的学习和记忆很重要。有趣的是，成年神经发生的一个主要部位--海马体--在成瘾动物模型中，在药物-环境关联的形成以及药物服用和药物寻求行为的介导中非常重要。相关证据表明，海马神经发生与吸毒或寻药行为之间存在负相关关系，但由于缺乏因果联系，成人产生的神经元与成瘾之间的关系尚不清楚。我们在啮齿类动物中使用大鼠静脉注射可卡因自我给药，这是一种临床相关的成瘾动物模型，以检验抑制成年海马神经发生增强成瘾和复发的脆弱性的假设。抑制成人海马神经发生通过颅照射前服药显着增加可卡因自我管理的固定比例和渐进比例的时间表，以及诱导剂量-反应曲线的垂直移动。这不是学习、动机或运动的普遍增强，因为蔗糖自我给药和运动活动在辐照大鼠中没有变化。抑制成年海马神经发生后，吸毒显着增强抵抗灭绝的药物寻求行为。这些研究在可卡因成瘾的动物模型中将成年海马神经发生减少确定为成瘾相关行为的新风险因素。此外，他们认为，专门增加或稳定成人海马神经发生的治疗方法可以帮助预防初始成瘾以及未来复发。
Drugs of abuse dynamically regulate adult neurogenesis, which appears important for some types of learning and memory. Interestingly, a major site of adult neurogenesis - the hippocampus - is important in the formation of drug-context associations and in the mediation of drug-taking and drug-seeking behaviors in animal models of addiction. Correlative evidence suggests an inverse relationship between hippocampal neurogenesis and drug-taking or drug-seeking behaviors, but the lack of a causative link has made the relationship between adult-generated neurons and addiction unclear. We used rat i.v. cocaine self-administration in rodents, a clinicall-relevant animal model of addiction, to test the hypothesis that suppression of adult hippocampal neurogenesis enhances vulnerability to addiction and relapse. Suppression of adult hippocampal neurogenesis via cranial irradiation before drug-taking significantly increased cocaine self-administration on both fixed-ratio and progressive-ratio schedules, as well as induced a vertical shift in the dose-response curve. This was not a general enhancement of learning, motivation or locomotion, as sucrose self-administration and locomotor activity were unchanged in irradiated rats. Suppression of adult hippocampal neurogenesis after drug-taking significantly enhanced resistance to extinction of drug-seeking behavior. These studies identify reduced adult hippocampal neurogenesis as a novel risk factor for addiction-related behaviors in an animal model of cocaine addiction. Further, they suggest that therapeutics to specifically increase or stabilize adult hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.