Adolescent Antidepressant Treatment and Drug Reward

直到最近，考虑儿童抑郁症几乎是不可能的。现在我们不仅知道重度抑郁症存在于儿童和青少年中，而且它也是一种常见的疾病。据估计，患有抑郁症的青少年经常发展为行为和焦虑障碍，20-25%发展为药物滥用障碍，5-10%的青少年可能在首次严重抑郁症发作后的15年内完成自杀。这导致20岁以下青少年使用抗抑郁药物的比例不成比例地增加。尽管抗抑郁药的使用增加，但对青少年时期抗抑郁药治疗引起的短期和长期行为和神经适应知之甚少。因此，本研究的主要目的是研究大鼠青春期抗抑郁治疗的行为反应，并评估这种早期抗抑郁治疗在成年后的长期行为后果。首先，将通过设计用于评价选择性5-羟色胺抑制剂（SSRI）在青少年和成年大鼠中的有效性的实验（使用强迫游泳试验范例）来实现该目标。其次，一旦确定了有效剂量，将进行评估SSRIs治疗对奖励依赖行为的长期行为后果的实验。这将通过使用条件性位置偏好范例评估动物对a）自然奖励（蔗糖和新奇诱导的）和B）对滥用药物（例如可卡因）的敏感性的实验来完成。因此，拟议研究的近期总体目标是开始“缩小差距”，我们对早期抗抑郁药治疗的长期行为影响的基本知识，以及它们与调节晚年奖励依赖行为的大脑回路的相互作用。长期目标是为后续实验奠定基础，这些实验将进一步检查早期生命中长期精神治疗的行为后果，并在治疗后使用基本蛋白质生物化学分析评估奖励途径的生物化学完整性。从这些实验中获得的数据将提高我们对精神药物如何影响发育中的大脑的理解，从而导致神经适应影响以后的生活行为，特别是对滥用药物的脆弱性。

Until relatively recently, to think about childhood depression was almost impossible. Now we not only know that major depressive disorder exists in children and adolescents, but that it is also a common condition. It is estimated that youngsters who suffer from depression often develop conduct and anxiety disorders, 20-25% develop substance abuse disorder, and that 5-10% are likely to complete suicide within 15 years of their initial episode of major depression. This has resulted in disproportionate increases in the prevalence of antidepressant drugs prescribed to youths under 20 years of age. Despite increases in antidepressant use, little is known about the short- and long-term behavioral and neuronal adaptations resulting from antidepressant treatment during the juvenile period. Thus, the major objective of this research proposal is to study the behavioral responses to antidepressant treatment during the adolescent period in rats, and to assess the long-term behavioral consequences of this early antidepressant treatment later in adulthood. First, this objective(s) will be accomplished with experiments designed to evaluate the effectiveness of selective serotonin inhibitors (SSRI), using the Forced Swim Test paradigm, in adolescent and adult rats. Second, once effective doses are determined, experiments assessing the long-term behavioral consequences of SSRIs treatment on reward-dependent behaviors will follow. This will be done with experiments assessing animals' sensitivity to a) natural rewards (sucrose and novelty-induced), and b) sensitivity to drugs of abuse (e.g. cocaine) using the Conditioned Place Preference paradigm. Thus, the immediate overall goal of the proposed studies is to begin "closing the gap" in our basic knowledge of the long-term behavioral effects of early life antidepressant treatment, and their interaction with brain circuits that modulate reward-dependent behaviors later in life. The long-term goal is to setup the stage for follow up experiments that will further examine the behavioral consequences of long-term psychotropic treatments during early life, and to assess the biochemical integrity of reward pathways, using basic protein biochemistry analysis, after such treatments. Data obtained from these experiments will improve our understanding of how psychotropics drugs affect developing brain resulting in neural adaptations to influence behavior later in life, especially vulnerability to drugs of abuse.