Corticotropin-Releasing Factor in Prepulse Inhibition

描述(由申请人提供)：精神分裂症患者的声学惊吓反应的脉冲前抑制(PPI)不足。在大鼠身上，PPI已被用于研究改变脑多巴胺(DA)和5-羟色胺(5-HT)神经传递的药物的效果，因为这些系统与精神分裂症有关。促肾上腺皮质激素释放因子(CRF)改变脑细胞外多巴胺、5-羟色胺和去甲肾上腺素(NE)的浓度，中枢应用CRF有许多行为效应。初步数据显示，侧脑室(IV)注射CRF降低了基础PPI较低的棕色挪威(BN)大鼠和基础PPI相对较高的Wistar-京都(WKY)大鼠的PPI。本实验旨在进一步研究CRF在BN和WKY大鼠PPI中的作用，并探讨CRF引起的PPI降低是否依赖于单胺类神经递质。具体目的1是检查不同剂量的CRF(Icv)对PPI和惊厥幅度的影响，以及外周给药激活垂体/肾上腺轴是否足以降低PPI。具体目的2是研究给予CRF拮抗剂(Icv)是否改善BN大鼠的PPI，以及在CRF给药之前或之后给予该拮抗剂是否减弱CRF对PPI的影响。具体目的3是检查选择性地耗竭单胺(DA、5-HT或NE)，或使用DA、5-HT或NE受体拮抗剂是否能减弱CRF所产生的PPI的下降。具体目的4是评估重复CRF(Icv)是否导致CRF引起的PPI下降的敏化或脱敏，或者是多巴胺激动剂、苯丙胺和阿朴吗啡的应用引起的PPI下降。除了检查每种处理对WKY和BN大鼠PPI的影响外，还将评估每种处理和大鼠品系对惊厥幅度和CRF诱导的梳理的影响。在单胺耗竭研究中，将用高效液相色谱法评估额叶皮质、海马体、伏隔核和下丘脑中DA、5-HT和NE的水平。

DESCRIPTION (provided by applicant): Prepulse inhibition (PPI) of the acoustic startle response is deficient in patients with schizophrenia. In rats, PPI has been used to study the effects of drugs that alter brain dopamine (DA) and serotonin (5-HT) neurotransmission, since these systems are implicated in schizophrenia. Corticotropin-releasing factor (CRF) alters brain extracellular concentrations of DA, 5-HT, and norepinepherine (NE), and central administration of CRF has numerous behavioral effects. Preliminary data show that intracerebroventricular (IV) administration of CRF decreases PPI in both Brown Norway (BN) rats, a strain with low basal PPI, and in Wistar-Kyoto (WKY) rats, a strain with relatively high basal PPI. Experiments are designed to futher study the role of CRF in PPI in BN and WKY rats, and to examine whether the decrease in PPI caused by CRF is dependent on monoamine neurotransmission. Specific Aim 1 is to examine the effects of a range of doses of CRF (ICV) on PPI and startle amplitude, and to examine whether peripheral administration of CRF, which activated the pituitary/adrenal axis, is sufficient to decrese PPI. Specific Aim 2 is to examine whether administraion of a CRF antagonist (ICV) improves PPI in BN rats, and to examine whether administration of the antagonist, either prior to or following CRF administration, attenuates the effect of CRF on PPI. Specific Aim 3 is to examine whether selective depletion of the monoamines (DA, 5-HT, or NE), or adminstration of drugs that are antagonists at DA, 5-HT or NE receptors attenuates the decrease in PPI produced by CRF. Specific Aim 4 is to assess whether repeated CRF (ICV) results in sensitization or desensitization of the CRF-induced decrease in PPI or of the decrese in PPI caused by adminstration of the dopamine agonists, amphetamine and apomorphine. In addition to examining the effects of each treatment on PPI in both WKY and BN rats, effects of each treatment and of rat strain on startle amplitude and CRF-induced grooming willl be assessed. In the monoamine depletion studies, levels of DA, 5-HT, and NE in frontal cortex, hippocampus, nucleus accumbens and hypothalamus will be assessed by HPLC.