Serotonergic Contribution to Adolescent Risk Taking

描述（由申请人提供）：冒险行为在青春期达到顶峰，并可能导致不良行为，如吸毒和不安全性行为。控制动机行为的神经回路不成熟可能导致青少年冒险行为。5 -羟色胺调节这种神经回路，可能对青少年的冒险行为很重要，因为它已被证明可以促进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行为中的作用。在初步研究中，我们测试了血清素能药物对67-73日龄成年雄性大鼠（PN67-73）和青春期早期雄性大鼠（PN28-34）的行为影响。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）对成年大鼠有抗焦虑作用，但对青春期大鼠的焦虑无影响。在光/暗（LD）试验中，青春期大鼠对5 -羟色胺释放剂芬氟拉明（2 mg/kg）和5 -羟色胺再摄取抑制剂氟西汀（10 mg/kg）的焦虑效应也不敏感。前额叶皮层初步微透析显示，青春期大鼠对芬氟拉明（1、2.5和10 mg/kg）的血清素能反应低于成年大鼠。我们假设青少年有未成熟的5 -羟色胺能神经支配前脑，导致去抑制行为。我们将用PN28-32和PN67-73雄性大鼠来研究这一假设，并有三个特定的目的。在目标一中，我们将通过评估芬氟拉明（1,2.5和10mg /kg），氟西汀（5,10和20mg /kg）和PCPA（2剂150mg /kg）在升高+迷宫（EPM）中的作用来测试血清素张力和储存的影响。目标二将使用微透析来研究内侧前额皮质中血清素能功能的年龄差异，这是一个血清素调节焦虑样行为和冲动的区域。我们将使用零净通量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，并使用去极化钾来评估释放血清素的能力。然后，我们将测量对氟西汀剂量范围（5、10和20 mg/kg）的反应，并用生理盐水或0.3 mg/kg WAY-100635对实验用动物进行预处理，比较5- ht1a对氟西汀反应的调节。目标三将确定在焦虑测试中，血清素在大脑的哪个部位发挥年龄特异性作用。我们将比较NIH测试后的神经元激活，使用即刻早期基因c-Fos的表达，成年和青少年大鼠接受PCPA或载体治疗。这一建议与NIMH战略目标1.1相关，因为它的目标是研究青春期血清素系统的发展如何改变血清素对行为的调节。该提案还涉及NIMH战略目标2.1，因为血清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障碍的药物的效果。

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.