Cannabis, Schizophrenia and Reward: Self-Medication and Agonist Treatment?

大麻、精神分裂症和奖励：自我药疗和激动剂治疗？

基本信息

批准号：
8632172
负责人：
ALAN I GREEN
金额：
$ 83.49万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8632172
关键词：
Adverse effects Agonist Alcohol or Other Drugs use Antipsychotic Agents Behavioral Brain Cannabinoids Cannabis Cannabis Smoking Cigarette Clozapine Cognition Cognitive deficits Comorbidity Data Development Disease Drug Formulations Event Functional Magnetic Resonance Imaging Funding General Population Grant Human Image Investigation Laboratories Lead Link Literature Measures Medical Mental disorders Neurobiology Patients Pharmaceutical Preparations Pharmacology Physiological Population Prefrontal Cortex Public Health Research Rest Rewards Schizophrenia Self Medication Smoke Societies Substance of Abuse Symptoms Testing Tetrahydrocannabinol Therapeutic Agents Time Ventral Striatum adverse outcome atypical antipsychotic base behavior measurement craving dopaminergic neuron dual diagnosis experience improved mesolimbic system negative mood pill public health relevance relating to nervous system response reward circuitry

项目摘要

ABSTRACT Cannabis use disorder (CUD) occurs frequently in patients with schizophrenia (SCZ) and worsens the course of this severe psychiatric disorder. Treatments available for these "dual diagnosis" patients are inadequate. New treatments to limit cannabis use in patients with schizophrenia are sorely needed. We have proposed that a dysregulated mesocorticolimbic "brain reward circuit" (BRC) in patients with SCZ underpins their cannabis use, and that cannabis use ameliorates this dysregulated circuitry. Studying the neural effects of a monetary probe linked to fMRI, as well as a behavioral measure of reward responsiveness, we and others have demonstrated that patients with SCZ do indeed have a deficit within their BRC and decreased reward responsiveness, as compared to normal subjects. Moreover, pilot data from our ARRA- funded grant involving resting state functional connectivity (RSC) suggest that such patients also have decreased intrinsic inter-regional synchronization within the BRC. Lastly, our pilot imaging data further indicate that both cannabis, as well as the cannabinoid agonist dronabinol, decrease the dysfunctional BRC deficit, as assessed by a monetary probe linked to fMRI and by resting state functional connectivity. In this proposal, we seek to confirm and expand upon our ARRA-funded investigation. The first aim is to assess the status of the BRC in patients with SCZ and co-occurring CUD (SCZ-CUD), as well as in those with SCZ (without CUD) and CUD (without SCZ): (1a) To confirm that (i) task-related fMRI activity linked to a monetary brain reward probe; (ii) inter-regional resting state functional connectivity; and (iii) a behavioral measure of reward responsiveness, will be decreased in patients with SCZ-CUD as compared to healthy controls; and (1b) to explore these measures in those with SCZ (without CUD) and with CUD (without SCZ). The second aim will assess the effect of cannabis and dronabinol on BRC in patients with SCZ- CUD and in those with CUD (without SCZ): (2a) To confirm whether dysfunctional (i) task-related fMRI activity linked to a monetary brain reward probe, and (ii) inter-regional resting state functional connectivity will be ameliorated; and (2b) to explore whether a behavioral measure of reward responsiveness will be improved in patients with SCZ-CUD, and (2c) to explore these measures in those with CUD (without SCZ), and to compare the results to those from (2a). The third aim will assess other effects of dronabinol in patients with SCZ-CUD -- on craving, mood, negative symptoms, psychotic symptoms and cognition. By probing BRC dysregulation and testing the effects of smoked cannabis on this dysregulation, this study will help further elucidate whether "self-medication" of a BRC deficit may be an important component of cannabis use in patients with SCZ. Moreover, by probing the physiological and behavioral effects of dronabinol, this research can lead to development of therapeutic agents, potentially including dronabinol, other cannabinoids or non-cannabinoid agents that may ameliorate a BRC deficiency and thus limit cannabis use in these patients.

抽象的大麻使用障碍 (CUD) 经常发生在精神分裂症 (SCZ) 患者中，并使病程恶化这种严重的精神疾病。对于这些“双重诊断”患者可用的治疗是不够的。迫切需要限制精神分裂症患者使用大麻的新疗法。我们提出 SCZ 患者的中皮质边缘“大脑奖赏回路”（BRC）失调支撑他们使用大麻，而大麻的使用改善了这种失调的电路。正在学习与功能磁共振成像相关的货币探针的神经效应，以及奖励反应的行为测量，我们和其他人已经证明，SCZ 患者的 BRC 确实存在缺陷，并且与正常受试者相比，奖励反应能力降低。此外，来自我们 ARRA 的试点数据涉及静息状态功能连接（RSC）的资助表明，此类患者也有 BRC 内固有的区域间同步性降低。最后，我们的试点成像数据进一步表明大麻以及大麻素激动剂屈大麻酚都能减少功能失调的 BRC 赤字，因为通过与功能磁共振成像相关的货币探针和静息状态功能连接进行评估。在本提案中，我们寻求确认并扩展 ARRA 资助的调查。第一个目标是评估 SCZ 和并发 CUD (SCZ-CUD) 患者以及具有 SCZ（无 CUD）和 CUD（无 SCZ）的患者：(1a) 确认 (i) 任务相关的 fMRI 活动与金钱大脑奖励探针相关； (ii) 区域间静止状态功能连通性； (iii) 一个与其他患者相比，SCZ-CUD 患者的奖赏反应行为测量值会降低健康控制； (1b) 在患有 SCZ（无 CUD）和患有 CUD（无 CUD）的患者中探索这些措施 SCZ）。第二个目标是评估大麻和屈大麻酚对 SCZ 患者 BRC 的影响 CUD 和患有 CUD 的患者（无 SCZ）：(2a) 确认 (i) 任务相关功能磁共振成像 (fMRI) 是否功能失调与货币大脑奖励探针相关的活动，以及（ii）区域间静息状态功能连接将得到改善； (2b) 探索奖励反应的行为测量是否会得到改善 (2c) 在患有 CUD（无 SCZ）的患者中探索这些措施，并将结果与 (2a) 的结果进行比较。第三个目标将评估屈大麻酚对患者的其他影响 SCZ-CUD——关于渴望、情绪、负面症状、精神病症状和认知。通过探究 BRC 失调并测试吸食大麻对这种失调的影响，本研究将帮助进一步阐明 BRC 缺陷的“自我药疗”是否可能是大麻的重要组成部分用于 SCZ 患者。此外，通过探讨屈大麻酚的生理和行为影响，这研究可以导致治疗药物的开发，可能包括屈大麻酚、其他大麻素或非大麻素药物可以改善 BRC 缺乏症，从而限制这些患者使用大麻。