Serotonergic Contribution to Adolescent Risk Taking

描述（由申请人提供）：冒险行为在青春期达到高峰，可能导致不受欢迎的行为，如吸毒和不安全的性活动。控制动机行为的神经回路不成熟可能会导致青少年冒险。5-羟色胺调节这种神经回路，可能对青少年冒险很重要，因为它已被证明有助于对厌恶结果的行为抑制。然而，很少有研究调查血清素在青少年冒险中的作用。在初步研究中，我们测试了67-73日龄成年雄性（PN 67 -73）和青春期早期雄性（PN 28 -34）大鼠中多巴胺能药物的行为效应。我们使用啮齿动物焦虑测试，因为这些测试中的行为可能反映行为抑制和冒险以及焦虑。色氨酸羟化酶抑制剂对氯苯丙氨酸（PCPA）消耗5-羟色胺在新奇诱导的食欲减退（NIH）试验中对成年大鼠具有抗焦虑作用，但对青少年大鼠的焦虑没有影响。在光/暗（LD）测试中，青春期大鼠对5-羟色胺抑制剂芬氟拉明（2 mg/kg）和5-羟色胺再摄取抑制剂氟西汀（10 mg/kg）的致焦虑作用的敏感性也低于成年大鼠。前额叶皮层的初步微透析显示，青春期大鼠对芬氟拉明（1、2.5和10 mg/kg）的多巴胺能反应低于成年大鼠。我们假设青少年前脑有不成熟的多巴胺能神经支配，导致了去抑制行为。我们将使用PN 28 -32和PN 67 -73雄性大鼠研究这一假设，具体目标有三个。在目标一中，我们将通过评估芬氟拉明（1、2.5和10 mg/kg）、氟西汀（5、10和20 mg/kg）和PCPA（2个剂量150 mg/kg）在高架十字迷宫（高架十字迷宫）中的作用来测试5-羟色胺张力和储存的影响。目的二将使用微透析来研究内侧前额叶皮层中羟色胺能功能的年龄差异，在该区域中，5-羟色胺调节焦虑样行为和冲动。我们将使用零净通量方法来比较成年和青春期大鼠的基线血清素水平。我们将完成芬氟拉明的初步研究，并使用钾去极化来评估释放5-羟色胺的能力。然后，我们将测量对一系列剂量的氟西汀（5、10和20 mg/kg）的反应，并用生理盐水或0.3 mg/kg WAY-100635预处理本实验中使用的动物，以比较5-HT 1A对氟西汀反应的调节。目标三将确定在焦虑测试中，大脑中5-羟色胺在哪里发挥年龄特异性作用。我们将比较使用PCPA或溶剂处理的成年和青少年大鼠中即刻早期基因c-Fos表达进行NIH试验后的神经元激活。该提案与NIMH战略目标1.1相关，因为其目标是研究青春期血清素系统的发展如何改变行为的多巴胺能调节。该提案还涉及NIMH战略目标2.1，因为肾上腺素能系统的发育变化可能影响情绪障碍的出现，并调节用于治疗青少年这些疾病的药物的作用。 公共卫生相关性：该提案调查了青少年和成年期之间冒险行为的肾上腺素能调节可能如何变化。在啮齿类动物中5-羟色胺如何调节行为的发育差异的发现将增加我们对青少年为什么会从事消极冒险行为的理解，也可能对青少年期情绪障碍的出现和治疗产生影响。

DESCRIPTION (provided by applicant): Risk taking behavior peaks during adolescence and can lead to undesired behaviors such as drug use and unsafe sexual activity. Immaturity of the neural circuitry that controls motivated behavior may contribute to adolescent risk taking. Serotonin modulates this neural circuit and may be important for adolescent risk taking because it has been shown to facilitate behavioral inhibition in response to aversive outcomes. However, few studies have investigated the role of serotonin in adolescent risk taking. In preliminary studies we tested the behavioral effects of serotonergic drugs in adult male 67-73 day old (PN67-73) and early adolescent male (PN28-34) rats. We used rodent anxiety tests because behavior in these tests may reflect behavioral inhibition and risk taking as well as anxiety. Depletion of serotonin with the tryptophan hydroxylase inhibitor p- chlorophenylalanine (PCPA) was anxiolytic in adult rats in the novelty induced hypophagia (NIH) test, but had no effect on anxiety in adolescent rats. Adolescent rats were also less sensitive than adults to the anxiogenic effects of the serotonin releaser fenfluramine (2 mg/kg) and the serotonin reuptake inhibitor fluoxetine (10 mg/kg) in the light/dark (LD) test. Preliminary microdialysis in the prefrontal cortex showed that adolescent rats have a lower serotonergic response to fenfluramine (1, 2.5, and 10 mg/kg) than adults. We hypothesize that adolescents have immature serotonergic innervation to the forebrain that results in disinhibited behavior. We will investigate this hypothesis with three specific aims using PN28-32 and PN67-73 male rats. In aim one we will test the impact of serotonin tone and stores by evaluating the effects of fenfluramine (1, 2.5, and 10 mg/kg), fluoxetine (5, 10, and 20 mg/kg), and PCPA (2 doses of 150 mg/kg) in the elevated plus maze (EPM). Aim two will use microdialysis to investigate age differences in serotonergic function in the medial prefrontal cortex, a region in which serotonin modulates anxiety-like behavior and impulsivity. We will use the zero net flux method to compare baseline serotonin levels in adult and adolescent rats. We will complete our preliminary fenfluramine study and use potassium depolarization to assess the capacity to release serotonin. We will then measure the response to a range of doses of fluoxetine (5, 10, and 20 mg/kg) and pretreat animals used in this experiment with saline or 0.3 mg/kg WAY-100635 to compare 5-HT1A regulation of the fluoxetine response. Aim three will determine where in the brain serotonin exerts age-specific effects during performance of an anxiety test. We will compare neuronal activation after performance of the NIH test using expression of the immediate early gene c-Fos in adult and adolescent rats treated with PCPA or vehicle. This proposal is relevant to NIMH strategic objective 1.1 because its goal is to investigate how development of the serotonin system across adolescence changes serotonergic modulation of behavior. This proposal also addresses NIMH strategic objective 2.1 as developmental changes in the serotonergic system could affect the emergence of mood disorders and modulate the effects of drugs used to treat these disorders in adolescents. PUBLIC HEALTH RELEVANCE: This proposal investigates how serotonergic modulation of risk taking behavior may change between adolescence and adulthood. Findings of developmental differences in how serotonin modulates behavior in rodents will increase our understanding of why adolescents engage in negative risk taking behaviors and may also have implications for the emergence and treatment of mood disorders during adolescence.