Dopamine Function During Adolescence

描述(申请人提供)：大多数人第一次接触成瘾药物发生在青春期，成瘾可能在青春期比晚年发展得更快。目前的建议检验了这样的假设，即突触前多巴胺机制中的成熟事件有助于青少年对行为和药物刺激的生物反应改变。它是基于初步数据显示，与年轻成年(60天大鼠)相比，青春期(第28天)大鼠的基线多巴胺摄取量更高，对可卡因的多巴胺反应增强，对可卡因的行为反应增强。我们将通过评估多巴胺末端功能以及青春期期间对行为刺激和药物的多巴胺反应来检验这一假设。我们将使用快速扫描循环伏安法(FSCV)评估雄性和雌性大鼠青春期对多巴胺的摄取和释放，包括清醒、行为动物和使用体外制剂。首先，我们将确定突触体和囊泡摄取对体内观察到的增强摄取的贡献。其次，我们将用FSCV测定28、42、60和90日龄正常雌雄大鼠在基础状态、可卡因和L-多巴作用后的多巴胺摄取和释放动力学。第三，我们将使用FSCV在清醒行为的动物身上确定多巴胺对环境刺激(自愿暴露在新环境中)的反应。这些研究应该为影响青春期吸毒开始的潜在生物机制提供洞察力。

DESCRIPTION (provided by applicant): The first experience most people have with addictive drugs occurs during adolescence and addiction may develop more quickly during adolescence than later in life. The present proposal tests the hypothesis that maturational events in presynaptic dopamine mechanisms contribute to the altered biologic reactivity of adolescents to behavioral and pharmacological stimuli. It is based on preliminary data showing greater baseline dopamine uptake, enhanced dopamine responses to cocaine and enhanced behavioral responses to cocaine in adolescent (day 28) compared to young adult (60 day old) rats. We will test this hypothesis by evaluating dopamine terminal function and dopamine responses to behavioral stimuli and drugs through adolescence. We will evaluate dopamine uptake and release through adolescence in male and female rats using both fast scan cyclic voltammetry (FSCV) in awake, behaving animals, and using in vitro preparations. First, we will determine the contribution of synaptosomal and vesicular uptake to the enhanced uptake observed in vivo. Second, we will determine the kinetics of dopamine uptake and release at baseline and after cocaine and L-Dopa using FSCV in 28, 42, 60 and 90 day old intact behaving male and female rats. Third, we will determine dopamine responses to an environmental stimulus (voluntary exposure to a novel environment) using FSCV in awake behaving animals. These studies should provide insight into potential biologic mechanisms that influence the onset of drug taking during adolescence.