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

描述(申请人提供)：直到几年前，儿童抑郁症几乎是不可想象的。现在我们不仅知道严重抑郁障碍(MDD)存在于儿童和青少年中，而且它也是一种常见的疾病。早期MDD与反社会人格、双相情感障碍和自杀相关。据估计，患有抑郁症的青少年往往会发展为品行障碍和焦虑症，20%-25%的人会发展成药物滥用障碍。因此，这导致为20岁以下的年轻人开的抗抑郁药的流行率不成比例地增加。尽管抗抑郁药物的使用率增加，但人们对成年前抗抑郁药物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满足这一需要，本提案中描述的实验将检查“青少年”大鼠对抗抑郁药物治疗的行为反应(出生后35天[PD]35)，并将进一步评估成年后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]确定抗抑郁药物治疗对幼年大鼠的疗效，[2]评估长期青少年抗抑郁药物治疗对成年后对奖赏相关(自然、药物)和情绪相关(焦虑、应激)行为的敏感性的长期后果，以及[3]评估慢性青少年抗抑郁药物暴露后，与奖赏相关的生物标记物[细胞外信号调节蛋白激酶(ERK)]在中脑边缘系统中的完整性。我们预计，青春期接触抗抑郁药物将导致与对压力、焦虑、自然和药物奖励行为的反应相关的长期变化。此外，我们预计特定部位的神经化学改变(腹侧被盖区内ERK的波动)将是作为早期抗抑郁药物暴露的功能而调节这些情绪和奖赏相关改变的因素。

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.