Novelty, Dopamine and Response to Amphetamine

描述（由申请人提供）：有相当多的研究旨在确定负责增加药物滥用易感性表型表达的遗传因素。确定决定易感性的多种遗传因素是至关重要的，并且在现代分子技术下是可行的。然而，还需要作出重大努力，以了解改变个体遗传易感性轨迹的干预环境因素的影响。在这个竞争性更新应用中，我们将研究发育期间环境富集对成年期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奇刺激（即“丰富”条件；EC）会在以后的生活中对新奇事物的反应和对滥用药物的反应产生深刻的变化。我们发现，与在“贫困”条件下（IC）饲养的大鼠相比，EC大鼠对蔗糖和视觉新鲜感的动机较低，对获得蔗糖奖励的冲动也较低。在低单位剂量的测试中，EC大鼠与IC大鼠相比，自我服用安非他明的量也有所减少。这些富集诱导的行为改变伴随着内侧前额叶皮层（mPFC）突触前末端多巴胺（DA）摄取和代谢的减少，这一大脑区域已知参与药物奖励和行为抑制，可能是通过对伏隔核（NAcc） DA活性和动机回路其他相关成分的调节影响。该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，因为正强化物的激励价值降低，行为抑制随之增加，这些过程中的每一个都与皮质边缘活性的变化有关。具体目的是确定环境富集是否：防止在长时间访问期间不断升级的兴奋剂摄入；2. 改变兴奋剂暴露后的行为抑制；3. 改变参与奖励和抑制的皮质边缘和纹状体区域的神经元活动模式；和4。改变参与奖励和抑制的皮质边缘和纹状体区域单胺转运蛋白功能。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。迄今为止获得的结果表明，环境富集可以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.