Novelty, Dopamine and Response to Amphetamine

描述（由申请人提供）：证据表明，生命早期反复暴露于丰富的环境会导致对新奇事物的反应和对以后滥用药物的反应发生变化。这项建议的总体工作假设是，暴露于新的环境刺激在发展过程中减少响应非药物和药物的成瘾者在成年期，这种行为的变化是由于，至少部分，以增强基础DA活性中皮质边缘奖励系统。实验的具体目的是确定环境富集是否改变：（1）寻找苯丙胺行为的消失或恢复;（2）非药物成瘾者减少苯丙胺自我给药的能力;（3）对非药物成瘾者反应的中脑核（Nacc）和内侧前额叶皮层（mPFC）的神经元加工;（4）多巴胺转运体（DAT）和囊泡单胺转运体（VMAT 2）的活性。 在拟定的实验中，大鼠将从21日龄起在富集条件（EC）、社会条件（SC）或改良条件（IC）下饲养。在50日龄时，将训练来自每种条件的大鼠以各种剂量之一自我施用安非他明。将在EC、SC和IC大鼠中检查安非他明应答的消退和恢复，并检查同时替代非药物替代剂（甜味溶液或视觉新颖性）减少安非他明自我给药的能力。为了确定这些富集诱导的行为变化背后的关键神经机制，将检查EC和IC大鼠的单独组在mPFC、Nacc核心和Nacc壳中的单单位神经元活性，同时获得甜味溶液或新颖性。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大鼠中DAT或VMAT 2的潜在变化。 在某种程度上，新奇事物和滥用药物都会激活相同的中皮质边缘DA回路，这表明新奇刺激可能会取代药物奖励。新颖性引起的安非他明自我给药减少将为研究在有滥用药物倾向的人中进行药物滥用预防干预时提供丰富刺激的有效性提供动力。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，可以在对照人体研究中进行评估。

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.