Developmental Psychopharmacology of Antipsychotics

抗精神病药的发展精神药理学

• 批准号: 6679438
• 负责人: JENNY L. WILEY
• 金额: $ 25.5万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6679438
• 关键词: age difference; antipsychotic agents; autoradiography; behavior test; behavioral /social science research tag; catalepsy; chordate locomotion; clozapine; cognition; developmental neurobiology; dopamine agonists; dopamine antagonists; dopamine receptor; dosage; drug hypersensitivity; drug screening /evaluation; haloperidol; laboratory rat; mental disorder chemotherapy; protein localization; psychomotor function; psychopharmacology; receptor binding; receptor expression; sensorimotor system

DESCRIPTION (provided by applicant): Antipsychotics are administered to children and adolescents for a number of disorders with chronic use often continuing into adulthood. Yet, little is known about short- and long-term effects of these agents on the developing brain and behavior. Research on the effects of atypical antipsychotics (e.g., clozapine) that do not produce extrapyramidal motor effects is particularly lacking. The major hypotheses of this grant proposal are that (1) developing animals are more sensitive to the effects of dopamine antagonists, including antipsychotics, on motor processes than are adult animals and (2) chronic dosing with antipsychotics during development produces long-term changes in response to challenges with dopaminergic agents in later life such that animals are more sensitive to the effects of dopamine agonists and less sensitive to those of dopamine antagonists. In order to test the first hypothesis, rats of different ages (postnatal day 22 to adult) will be administered acute doses of selected antipsychotics; subsequently, they will be evaluated in behavioral procedures designed to measure motor activity (locomotion and catalepsy). In order to test the second hypothesis, rats will be chronically injected with selected antipsychotics during development. After reaching adulthood, these rats will be evaluated in behavioral procedures to evaluate motor activity (locomotion and catalepsy), cognition (sensorimotor gating, acquisition of a response, short-term memory), and the reinforcing efficacy of food. In addition to baseline activity in these procedures, the effects of challenges with antipsychotics and dopamine agonists will also be assessed in these rats. In order to determine possible underlying changes in dopamine receptor binding and distribution, autoradiography of the brains of rats that received identical chronic injection regimens will be performed using radioligands selective for dopamine D1 and D2 receptors. The proposed studies will provide empirical information on acute and long-term effects of traditional and atypical antipsychotics on the developing brain and behavior. This information will help to provide a more rational basis for making treatment decisions concerning children and adolescents who may benefit from treatment with an antipsychotic.

描述（由申请人提供）：抗精神病药是针对多种长期使用疾病的儿童和青少年经常持续成年的。然而，对于这些药物对发展中的大脑和行为的短期和长期影响知之甚少。关于不产生腹膜外运动作用的非典型抗精神病药（例如氯氮平）的影响的研究尤其缺乏。该赠款提案的主要假设是（1）与成年动物相比，发展动物对多巴胺拮抗剂（包括抗精神病药物）的影响更敏感，包括抗精神病药，以及（2）在发育过程中使用抗精神病药的慢性剂量会产生长期变化。对以后的多巴胺能剂对挑战的反应使动物对多巴胺激动剂的影响更敏感，对多巴胺拮抗剂的影响较少。为了检验第一个假设，将服用不同年龄的大鼠（成年后第22天）的大鼠。随后，将在旨在测量运动活动（运动和蠕虫病）的行为程序中评估它们。为了检验第二个假设，在发育过程中将长期注射大鼠选择的抗精神病药。成年后，这些大鼠将在评估运动活动（运动和细胞危机），认知（感觉运动门控，响应，短期记忆的获得，短期记忆）和增强食品效力的行为过程中进行评估。除了这些程序中的基线活性外，还将在这些大鼠中评估抗精神病药和多巴胺激动剂的挑战的影响。为了确定多巴胺受体结合和分布的潜在变化，将使用对多巴胺D1和D2受体选择性进行选择的大鼠大脑的放射自显影。拟议的研究将提供有关传统和非典型抗精神病药对发展中的大脑和行为的急性和长期影响的经验信息。这些信息将有助于为做出有关抗精神病药治疗的儿童和青少年做出治疗决策提供更合理的基础。