Novelty, Dopamine and Response to Amphetamine

描述(由申请者提供)：证据表明，早期反复暴露在丰富的环境中会产生变化，以应对新奇事物和后来生活中滥用药物的反应。这一建议的总体工作假设是，在发育过程中暴露于新的环境刺激会降低对成年期非药物和药物增强剂的反应，这种行为变化至少部分是由于中皮质边缘奖赏系统中基础DA活性的增强。拟议实验的具体目的是确定环境丰富是否改变：(1)苯丙胺寻找行为的消失或恢复；(2)非药物增强剂减少苯丙胺自我给药的能力；(3)伏隔核(NACC)和内侧前额叶皮质(MPFC)对非药物增强剂反应的神经元加工；以及(4)mPFC中DA转运体(DAT)和囊泡单胺转运体(VMAT2)的活动。 在拟议的实验中，大鼠将从21日龄起在丰富条件(EC)、社会条件(SC)和改善条件(IC)中饲养。在50天龄时，每种情况下的大鼠将被训练以不同剂量的苯丙胺自我给药。将检查对苯丙胺反应的消退和恢复，并将检查EC、SC和IC大鼠同时使用替代非药物增强剂(甜味剂或视觉新颖性)减少苯丙胺自我给药的能力。为了确定这些富集物诱导的行为变化背后的关键神经机制，将对不同组的EC和IC大鼠进行检查，以确定mPFC、NACC核心和NACC外壳中的单位神经元活动，同时获得甜味溶液或新奇事物。其他实验将使用体内伏安法或体外结合/摄取来评估EC和IC大鼠DAT或VMAT2的电位变化。 在某种程度上，新鲜感和滥用药物都激活了相同的中皮质边缘DA回路，这表明新的刺激可能会取代药物奖励。新颖性诱导的苯丙胺自我给药减少将为研究在有药物滥用倾向的人中提供丰富刺激预防药物滥用干预措施的有效性提供动力。我们工作的长期目标是设计生物相关的行为治疗和预防策略，这些策略可以在受控的人类研究中进行评估。

DESCRIPTION (provided by applicant): Evidence indicates that repeated early life exposure to an enriched environment produces changes in response to novelty and response to drugs of abuse later in life. The overall working hypothesis of this proposal is that exposure to novel environmental stimulation during development decreases responding for nondrug and drug reinforcers during adulthood and that this behavioral change is due, at least in part, to enhanced basal DA activity in the mesocorticolimbic reward system. The specific aims of the proposed experiments are to determine if environmental enrichment alters: (1) extinction or reinstatement of amphetamine seeking behavior; (2) the ability of nondrug reinforcers to decrease amphetamine self-administration; (3) neuronal processing in the nucleus accumbens (Nacc) and medial prefrontal cortex (mPFC) in response to nondrug reinforcers; and (4) activity of the DA transporter (DAT) and vesicular monoamine transporter (VMAT2) in mPFC. In the proposed experiments, rats will be raised from 21 days of age in either an enriched condition (EC), social condition (SC) or imporverished condition (IC). At 50 days of age, rats from each condition will be trained to self-administer amphetamine at one of various doses. Extinction and reinstatement of responding for amphetamine will be examined, and the ability of a concurrent alternative nondrug reinforcer (sweet solution or visual novelty) to reduce amphetamine self-administration will be examined in EC, SC and IC rats. To identify the critical neural mechanisms that underlie these enrichment-induced behavioral changes, separate groups of EC and IC rats will be examined for single-unit neuronal activity in the mPFC, Nacc core and Nacc shell while having access to sweet solution or novelty. Other experiments will use in vivo voltammetry or in vitro binding/uptake to access potential changes in DAT or VMAT2 in EC and IC rats. To the extent that both novelty and drugs of abuse activate the same mesocorticolimbic DA circuitry, this would suggest that novel stimulation might substitute for drug reward. Novelty-induced reductions in amphetamine self-administration would provide the impetus for examining the effectiveness of presenting enriching stimulation in drug abuse prevention interventions in humans prone to abuse drugs. The long-term objective of our work is to design biologically relevant, behavioral treatment and prevention strategies that can be evaluated in a controlled human study.