Developmental Psychopharmacology of Antipsychotics

抗精神病药的发展精神药理学

• 批准号: 6748096
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6748096
• 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）：抗精神病药用于儿童和青少年，用于治疗许多长期使用的疾病，这些疾病通常持续到成年。然而，人们对这些药物对发育中的大脑和行为的短期和长期影响知之甚少。对于不产生锥体外系运动效应的非典型抗精神病药（例如氯氮平）的作用的研究尤其缺乏。该拨款提案的主要假设是（1）发育中的动物比成年动物对多巴胺拮抗剂（包括抗精神病药物）对运动过程的影响更敏感，（2）在发育过程中长期服用抗精神病药物会产生长期的变化动物在以后的生活中对多巴胺能药物的挑战做出反应，使得动物对多巴胺激动剂的作用更敏感，而对多巴胺拮抗剂的作用不太敏感。为了检验第一个假设，不同年龄（出生后第22天至成年）的大鼠将被给予急性剂量的选定的抗精神病药物；随后，将在旨在测量运动活动（运动和僵直）的行为程序中对它们进行评估。为了检验第二个假设，大鼠将在发育过程中长期注射选定的抗精神病药物。成年后，这些大鼠将接受行为程序评估，以评估运动活动（运动和僵直）、认知（感觉运动门控、反应获得、短期记忆）和食物的强化功效。除了这些程序中的基线活动外，还将在这些大鼠中评估抗精神病药物和多巴胺激动剂挑战的影响。为了确定多巴胺受体结合和分布可能发生的潜在变化，将使用对多巴胺 D1 和 D2 受体选择性的放射性配体对接受相同慢性注射方案的大鼠的大脑进行放射自显影。拟议的研究将提供传统和非典型抗精神病药物对发育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可能受益于抗精神病药物治疗的儿童和青少年的治疗决策提供更合理的基础。