Long-Term Consequences of Antidepressant Exposure During Adolescence in Male Rats

描述（由申请人提供）：直到几年前，儿童抑郁症几乎是不可想象的。现在我们不仅知道重度抑郁症（MDD）存在于儿童和青少年中，而且它也是一种常见的疾病。早年的重度抑郁症与反社会人格、双相情感障碍和自杀有关。据估计，患有抑郁症的青少年往往会出现行为障碍和焦虑症，其中20-25%会出现药物滥用障碍。因此，这导致给20岁以下青年开抗抑郁药的流行率不成比例地增加。尽管使用抗抑郁药的比例增加，但对成年前抗抑郁治疗导致的长期行为和神经适应知之甚少。为了在我们的基础知识中解决这一需求，本提案中描述的实验将检查“青春期”大鼠（出生后[PD] 35）对抗抑郁药物治疗的行为反应，并将进一步评估成年期青少年抗抑郁药物治疗的长期行为后果（PD90+）。这将在下列具体目标的框架内完成：[1]确定了幼年大鼠抗抑郁治疗的疗效，[2]评估了慢性青少年抗抑郁治疗对成年后奖励（自然、药物）和情绪相关（焦虑、压力）行为敏感性的长期影响，[3]评估了慢性青少年抗抑郁暴露后中脑边缘系统中奖励相关生物标志物[细胞外信号调节蛋白激酶（ERK）]的完整性。我们预计，青少年时期的抗抑郁药物暴露将导致与压力、焦虑、自然和药物奖励行为相关的长期改变。此外，我们预计特定部位的神经化学改变（腹侧被盖区的ERK波动）是介导这些情绪和奖励相关改变的一个因素，作为早期抗抑郁药物暴露的功能。

DESCRIPTION (provided by applicant): Childhood depression was almost unthinkable until several years ago. Now we not only know that major depressive disorder (MDD) exists in children and adolescents, but that it is also a common condition. Early-life MDD has been correlated with antisocial personality, bipolar disorder, and suicide. It is estimated that youngsters who suffer from depression often develop conduct and anxiety disorders, and that 20-25% develop substance abuse disorder. Consequently, this has resulted in a disproportionate increase in the prevalence of, antidepressants prescribed to youths below 20 years of age. Despite the heightened rates in antidepressant use, little is known about the long-term behavioral and neural adaptations resulting from antidepressant treatment during periods before adulthood. To address this need in our basic knowledge, the experiments described in this proposal will examine the behavioral responses to antidepressant treatment in "adolescent" rats (postnatal day [PD] 35), and will further assess the long-term behavioral consequences of adolescent antidepressant treatment in adulthood (PD90+). This will be accomplished within the framework of the following specific aims: [1] determine the efficacy of antidepressant treatment in juvenile rats, [2] assess long-term consequences of chronic adolescent antidepressant treatment on the sensitivity to reward- (natural, drug) and mood-related (anxiety, stress) behaviors in adulthood, and [3] evaluate the integrity of reward-related biological markers [extracellular signal regulated protein kinase (ERK)], within the mesolimbic system, following chronic adolescent antidepressant exposure. We expect that antidepressant exposure during adolescence will induce long-lived alterations associated with responses to stress, anxiety, natural- and drug-rewarded behaviors. Furthermore, we expect site-specific neurochemical alterations (ERK fluctuations within the ventral tegmental area) to be a factor mediating these mood- and reward-related alterations as a function of early-life antidepressant exposure.