Novelty, Dopamine and Response to Amphetamine

描述（由申请人提供）：一直相当重视旨在确定导致药物滥用脆弱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至关重要，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，以了解改变个人遗传脆弱性轨迹的干预环境因素的影响。在这个竞争性的更新应用程序中，我们将调查环境丰富的发展过程中对药物滥用的脆弱性在成年期的影响。迄今为止的证据表明，重复暴露于新的刺激（即，“丰富”的条件; EC）在围青春期期间对新奇事物的反应和对以后生活中滥用药物的反应产生了深刻的变化。我们已经发现，EC大鼠表现出较少的动机，蔗糖和视觉新奇，以及较少的冲动获得蔗糖奖励，相比，大鼠提出了一个“贫困”的条件（IC）。当用低单位剂量测试时，与IC大鼠相比，EC大鼠还显示安非他明自我给药减少。这些富集诱导的行为变化伴随着内侧前额叶皮层（mPFC）突触前末梢中多巴胺（DA）的摄取和代谢减少，这是一个已知参与药物奖励和行为抑制的大脑区域，可能是通过调节多巴胺在延髓核（NAcc）和动机回路的其他相关成分中的活性。本申请的总体工作假设是，在发育期间暴露于新的环境刺激可以防止兴奋剂滥用，因为正性兴奋剂的激励值降低，行为抑制伴随增加，这些过程中的每一个都与皮质边缘活动的变化相关。具体目标是确定环境富集是否：1。防止在长时间访问会话中逐渐增加的兴奋剂摄入; 2.改变刺激暴露后的行为抑制; 3.改变涉及奖赏和抑制的皮质边缘和纹状体区域中的神经元活动模式;以及4.改变皮质边缘和纹状体区域中涉及奖赏和抑制的单胺转运体功能。环境如何决定青少年药物滥用的轨迹尚不清楚。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。迄今为止取得的结果表明，丰富的环境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.