COCAINE ABUSE AND ALTERATIONS IN SEROTONERGIC FUNCTION

可卡因滥用和血清素功能的改变

• 批准号: 2122729
• 负责人: LAURE B BUYDENS-BRANCHEY
• 金额: $ 11.53万
• 依托单位: NARROWS INSTITUTE FOR BIOMEDICAL RES INC
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2122729
• 关键词: blood chemistry; cocaine; drug abuse chemotherapy; drug abuse therapy; drug addiction; drug interactions; drug withdrawal; fenfluramine; human subject; interview; medical records; neurochemistry; neuroendocrine system; neuropsychological tests; neurotransmitters; personality tests; physical chemical interaction; questionnaires; serotonin; serotonin inhibitor; statistics /biometry; substance abuse related disorder

Most of the information available at present about the biological underpinnings of cocaine effects derives from animal studies. These studies have shown that the dopaminergic system plays an important role in many of cocaine effects but that this role is not exclusive. Cocaine has a diversity of neurochemical actions involving the nonadrenergic and serotonergic systems as well as other neurotransmitter systems whose role still remains somewhat undetermined. The wealth of preclinical data on neurotransmitter alterations associated with cocaine administration is not matched by information derived from human studies. in man, much is known about the epidemiology of cocaine use, about its patterns of use and about the psychopathology associated with its consumption and discontinuation but our knowledge of neurochemical alterations underlying cocaine actions is still lagging. Information about neurochemical alterations preceding cocaine abuse is also extremely scarce. In order to gain information about the serotonergic function of individuals who engage in a lifestyle of cocaine abuse we studied their responsivity to challenges with a postsynaptic partial agonist, meta- chlorophenylpiperazine (mCPP) and compared it to the responsivity of healthy volunteers. Cocaine abusers differed significantly from control subjects. They displayed a psychological hyperresponsivity and a neuroendocrine hyporesponsivity to m-CPP. Associations were also found between personality characteristics indicating a poor impulse, mood and aggression control and psychological changes observed in response to m- CPP. These data could indicate that serotonin plays a role in the pathogenesis of cocaine addiction, at least in some individuals. The effects of cocaine itself could however not be assessed because our subjects were studied only once during the second week of an inpatient stay. The present proposal involves sequential assessments following cocaine discontinuation of the serotonergic function of individuals whose drug of choice has been cocaine for at least 3 years and who have used cocaine exclusively for a period of 6 months prior to the start of the study. The serotonergic function will be assessed through challenges with m-CPP and an indirect serotonin agonist, fenfluramine (FEN). Personality assessments will be done and psychological and neuroendocrine responses to m-CPP and FEN assessed first after admission to an inpatient rehabilitation unit and 4 days after cocaine discontinuation, and again prior to discharge, 3 weeks later. Patients will then be followed for a period of 6 months to see whether any of the assessments outlined above predicts clinical course and outcome. The study we propose to do will give us information about disturbances in a neurotransmitter system believed to play a significant role in cocaine actions, about the persistence of neurotransmitter alterations after a cocaine free period of 3 to 4 weeks, about the role played by premorbid characteristics in neurotransmitter function in cocaine addicts and about the predictive values of psychological and biological alterations on clinical course 6 months later. One can hypothesize that there is an interplay between predisposing neurochemical alterations and the superimposed effects of cocaine. Cocaine addicts could be biologically heterogeneous and treatment needs might be different in subgroups of patients with different psychopathological and biological profiles.

目前可用的大多数有关生物学的信息 可卡因效应的基础来自 动物研究。 这些研究表明多巴胺能系统 在许多可卡因作用中起着重要的作用，但这种作用是 不是排他性的。可卡因具有多种神经化学作用，涉及 非肾上腺素能和血清素能系统以及其他 作用的神经递质系统仍然不确定。 与神经递质改变有关的大量临床前数据相关 使用可卡因的给药不与来自 人类研究。在人中，对可卡因的流行病学知之甚少 关于其使用模式以及相关的心理病理学模式 随着它的消费和中断，我们对 可卡因作用的基础神经化学改变仍在落后。 滥用可卡因之前有关神经化学改变的信息是 也极为稀缺。 为了获得有关血清素能功能的信息 从事可卡因虐待生活方式的个人，我们研究了他们的 通过突触后部分激动剂对挑战的反应 氯苯基哌嗪（MCPP），并将其与 健康的志愿者。可卡因滥用者与对照明显不同 主题。 他们表现出心理过度反应性和 对M-CPP的神经内分泌低压。还发现了关联 在人格特征之间表明冲动不良，情绪和 侵略控制和心理变化是对M-的响应 CPP。这些数据可能表明5-羟色胺在 至少在某些个体中，可卡因成瘾的发病机理。这 但是，无法评估可卡因本身的影响，因为我们 在住院的第二周，仅研究一次受试者 停留。 本提案涉及可卡因后的顺序评估 中断的人的血清素能功能 选择已经是可卡因至少3年，并且使用了可卡因 在研究开始之前的6个月内，只有6个月。这 血清素能功能将通过M-CPP的挑战进行评估， 间接的5-羟色胺激动剂，芬氟拉明（FEN）。个性评估 将完成以及对M-CPP的心理和神经内分泌反应 进入住院康复单元后首先评估 可卡因停​​产后4天，然后在出院前再次，3 几周后。然后，将遵循患者6个月的时间 查看上面概述的任何评估是否预测临床课程 和结果。 我们建议做的研究将为我们提供有关干扰的信息 据信神经递质系统在可卡因中起重要作用 动作，关于神经递质改变后持续性的行为 可卡因的自由期为3至4周，关于Prembid扮演的角色 可卡因成瘾者的神经递质功能的特征以及大约 心理和生物学改变的预测值 临床课程6个月后。 可以假设有一个 易感神经化学改变与 可卡因的叠加作用。可卡因成瘾者可能是生物学上的 异质和治疗需求在亚组中可能有所不同 具有不同心理病理和生物学特征的患者。