COCAINE ABUSE AND ALTERATIONS IN SEROTONERGIC FUNCTION

目前可获得的关于生物的大部分信息 可卡因效应的基础来自于 动物研究。这些研究表明，多巴胺能系统 在许多可卡因效应中起着重要作用，但这种作用是 不是排他性的。可卡因有多种神经化学作用，包括 非肾上腺素能和5-羟色胺能系统以及其他 神经递质系统的作用仍在某种程度上尚不确定。 与神经递质改变相关的大量临床前数据 与可卡因注射的信息不匹配 人体研究。在人类身上，可卡因的流行病学是众所周知的。 使用，关于它的使用模式和与之相关的精神病理学 它的消耗和停止，但我们知道 可卡因作用背后的神经化学变化仍然滞后。 关于可卡因滥用前的神经化学改变的信息是 也极其稀少。 为了获得有关5-羟色胺能功能的信息 我们研究了那些滥用可卡因的生活方式的人 突触后部分激动剂Meta-1对挑战的反应性 氯苯哌嗪(MCPP)，并将其与 健康的志愿者。可卡因滥用者与对照组有显著不同 研究对象。他们表现出一种心理上的高反应性和 神经内分泌对m-CPP的低反应性。还发现了一些关联 表明不良冲动、情绪和情绪的人格特征 攻击控制与m-反应心理变化的观察 CPP。这些数据可能表明5-羟色胺在 可卡因成瘾的发病机制，至少在某些人中是这样。这个 然而，可卡因本身的影响无法评估，因为我们的 受试者在住院的第二周只进行了一次研究。 留下来。 目前的提议涉及可卡因之后的顺序评估 5-羟色胺能功能的中断 选择吸食可卡因至少3年，并使用过可卡因的人 在研究开始前仅为期6个月。这个 5-羟色胺能功能将通过m-CPP和 一种间接的5-羟色胺激动剂芬氟拉明(Fen)。个性评估 对m-CPP的心理和神经内分泌反应以及 在住院康复单元入院后首先进行FEN评估 在可卡因停药后4天，以及在出院前，3 几周后。然后对患者进行为期6个月的跟踪调查 看看上面概述的评估中是否有任何一项可以预测临床过程 和结果。 我们计划进行的研究将为我们提供有关 一种被认为在可卡因中起重要作用的神经递质系统 行动，关于神经递质变化的持久性 戒毒期为3至4周，约为发病前所起的作用 可卡因成瘾者神经递质功能特点及相关因素分析 心理和生物变化对脑出血的预测价值 6个月后开始临床疗程。人们可以假设有一个 易感性神经化学改变与 可卡因的叠加效应。可卡因成瘾者可能是生物学上的 异质性和治疗需求在不同的亚组中可能不同 有不同精神病理和生物学特征的患者。

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.