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？

• 批准号: 8732617
• 负责人: ALAN I GREEN
• 金额: $ 91.85万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732617
• 关键词: Adverse effects; Agonist; Alcohol or Other Drugs use; Antipsychotic Agents; Behavioral; Brain; Cannabinoids; Cannabis; Cigarette; Clozapine; Cognition; Cognitive deficits; Comorbidity; Data; Development; Disease; Dronabinol; Drug Formulations; Event; Functional Magnetic Resonance Imaging; Funding; General Population; Grant; Human; Image; Investigation; Laboratories; Lead; Link; Literature; Marijuana Smoking; Measures; Medical; Neurobiology; Patients; Pharmaceutical Preparations; Pharmacology; Physiological; Population; Prefrontal Cortex; Public Health; Research; Rest; Rewards; Schizophrenia; Self Medication; Smoke; Societies; Substance of Abuse; Symptoms; Testing; Therapeutic Agents; Time; Ventral Striatum; adverse outcome; atypical antipsychotic; base; behavior measurement; brain circuitry; craving; dopaminergic neuron; dual diagnosis; experience; improved; marijuana use; marijuana use disorder; mesolimbic system; negative mood; non-cannabinoid; pill; psychotic symptoms; public health relevance; relating to nervous system; response; reward circuitry; severe psychiatric disorder

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：大麻使用障碍（CUD）经常发生在精神分裂症（SCZ）患者中，并加剧这种严重精神疾病的病程。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）失调是他们使用大麻的基础，而大麻的使用可以改善这种失调的回路。我们和其他人研究了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，证明与正常受试者相比，SCZ 患者的 BRC 确实存在缺陷，并且奖励反应能力下降。此外，我们的 ARRA 资助的涉及静息状态功能连接 (RSC) 的试点数据表明，此类患者 BRC 内的内在区域间同步性也有所下降。最后，我们的试点成像数据进一步表明，根据与功能磁共振成像相关的货币探针和静息状态功能连接的评估，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。在本提案中，我们寻求确认并扩展 ARRA 资助的调查。第一个目的是评估 SCZ 和并发 CUD (SCZ-CUD) 患者以及 SCZ（无 CUD）和 CUD（无 SCZ）患者的 BRC 状态： (1a) 确认(i) 与金钱大脑奖励探针相关的任务相关功能磁共振成像活动； (ii) 区域间静止状态功能连通性； (iii) 与健康对照相比，SCZ-CUD 患者的奖赏反应行为测量将会降低； (1b) 在具有 SCZ（无 CUD）和具有 CUD（无 SCZ）的患者中探索这些措施。第二个目标将评估大麻和屈大麻酚对 SCZ-CUD 患者和 CUD（无 SCZ）患者 BRC 的影响：(2a) 确认功能失调 (i) 任务相关的 fMRI 活动是否与金钱大脑奖励相关探针，以及（ii）区域间静息状态功能连接将得到改善； (2b) 探索 SCZ-CUD 患者的奖赏反应行为测量是否会得到改善，(2c) 探索 CUD（无 SCZ）患者的这些测量方法，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 SCZ-CUD 患者的其他影响——对渴望、情绪、阴性症状、精神病症状和认知的影响。通过探讨 BRC 失调并测试吸食大麻对这种失调的影响，这项研究将有助于进一步阐明 BRC 缺陷的“自我药疗”是否可能是 SCZ 患者使用大麻的重要组成部分。此外，通过探讨屈大麻酚的生理和行为影响，这项研究可以促进治疗药物的开发，其中可能包括屈大麻酚、其他大麻素或非大麻素药物，它们可以改善 BRC 缺乏症，从而限制这些患者使用大麻。