Novelty, Dopamine and Response to Amphetamine

描述(由申请人提供)：已经相当重视旨在确定导致药物滥用易感性增加的表型表达的遗传因素的研究。确定决定脆弱性的多种遗传因素是至关重要的，目前利用现代分子技术是可行的。然而，还需要作出重大努力，以了解干预环境因素的影响，这些因素改变了个人遗传脆弱性的轨迹。在这项竞争性更新申请中，我们将调查开发期间环境丰富对成年后药物滥用脆弱性的影响。迄今为止的证据表明，在青春期前后反复接触新的刺激(即“丰富的”状态；EC)会产生深刻的变化，以应对新奇事物和对以后生活中滥用药物的反应。我们发现，与在“贫困”条件下长大的大鼠相比，EC大鼠表现出对蔗糖和视觉新颖性的动机较少，以及获得蔗糖奖励的冲动较少。与IC大鼠相比，EC大鼠在低单位剂量的测试中也显示出苯丙胺自我给药的减少。这些富集物诱导的行为变化伴随着内侧前额叶皮质(MPFC)突触前终末多巴胺(DA)摄取和代谢的减少，这是一个已知参与药物奖赏和行为抑制的大脑区域，可能是通过对伏隔核(NAcc)和其他相关兴奋回路组件中DA活动的调制影响而实现的。这项应用的总体工作假设是，在发育过程中暴露于新的环境刺激可以防止兴奋剂滥用，因为积极增强剂的激励价值降低，行为抑制随之增加，这些过程中的每个过程都与皮质边缘活动的变化有关。具体目的是确定环境丰富是否：1.防止长时间接触期间不断增加的兴奋剂摄入；2.改变兴奋剂暴露后的行为抑制；3.改变涉及奖赏和抑制的皮质边缘和纹状体区域的神经元活动模式；以及4.改变参与奖赏和抑制的皮质边缘和纹状体区域的单胺转运体功能。目前尚不清楚环境如何决定青少年滥用药物的轨迹。目前的基础研究将确定在不同环境中饲养青春期大鼠的行为和神经生物学后果。迄今取得的结果表明，环境浓缩可防止药物滥用的脆弱性。

DESCRIPTION (provided by applicant): There has been considerable emphasis on research aimed at determining the genetic factors responsible for phenotypic expression of increased drug abuse vulnerability. Identification of the multiple genetic factors that determine vulnerability is critically important and currently feasible with modern molecular technology. However, significant efforts also need to be directed at understanding the impact of intervening environmental factors that modify the trajectory of an individual's genetic vulnerability. In this competitive renewal application, we will investigate the effects of environmental enrichment during development on drug abuse vulnerability during adulthood. Evidence to date indicates that repeated exposure to novel stimuli (i.e., the "enriched" condition; EC) during the periadolescent period produces profound changes in response to novelty and response to drugs of abuse later in life. We have found that EC rats display less motivation for sucrose and for visual novelty, as well as less impulsivity for obtaining sucrose reward, compared to rats raised in an "impoverished" condition (IC). EC rats also show a reduction in amphetamine self-administration compared to IC rats when tested with low unit doses. These enrichment-induced behavioral changes are accompanied by a reduction in uptake and metabolism of dopamine (DA) in presynaptic terminals in medial prefrontal cortex (mPFC), a brain region known to be involved in both drug reward and behavioral inhibition, perhaps via a modulatory influence on DA activity in the nucleus accumbens (NAcc) and other related components of the motivational circuitry. The overall working hypothesis of this application is that exposure to novel environmental stimulation during development protects against stimulant abuse because there is a decrease in the incentive value of positive reinforcers and a concomitant increase in behavioral inhibition, with each of these processes being associated with changes in corticolimbic activity. The specific aims are to determine if environmental enrichment: 1. protects against escalating stimulant intake across long access sessions; 2. alters behavioral inhibition following stimulant exposure; 3. alters patterns of neuronal activity in corticolimbic and striatal regions involved in reward and inhibition; and 4. alters monoamine transporter function in corticolimbic and striatal regions involved in reward and inhibition. It is not clear how the environment determines the trajectory of drug abuse among adolescents. The current basic research will determine the behavioral and neurobiological consequences of raising adolescent rats in different environments. Results obtained thus far indicate that environmental enrichment protects against drug abuse vulnerability.