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）：精神分裂症患者（SCZ）经常发生大麻使用障碍（CUD），并使这种严重的精神疾病的病程恶化。这些“双重诊断”患者可用的治疗不足。迫切需要新的治疗方法以限制精神分裂症患者的大麻使用。我们已经提出，SCZ患者使用大麻使用的患者中的中皮质胶体“脑奖励回路”（BRC），大麻使用可以缓解这种失调的电路。研究了与fMRI相关的货币探针的神经作用，以及奖励反应能力的行为度量，我们和其他人证明，与正常受试者相比，患有SCZ患者确实确实在BRC内确实有缺陷并降低了奖励反应能力。此外，我们从涉及静止状态功能连通性（RSC）的货币资助的赠款中的试点数据表明，此类患者在BRC内的内在区域间同步也降低了。最后，我们的试验成像数据进一步表明，大麻以及大麻素激动剂dronabinol都减少了功能障碍的BRC缺陷，这是通过与fMRI和息息息度相关的货币探针所评估的。在此提案中，我们寻求确认并扩大我们的ARRA资助调查。第一个目的是评估BRC在SCZ和COSCORRING CUD（SCZ-CUD）以及SCZ（无CUD）和CUD（无SCZ）的患者中的状态：（1A）确认（I）（I）与任务相关的FMRI活性与金钱奖励奖励相关的FMRI活动； （ii）区域间静止状态功能连接； （iii）与健康对照组相比，SCZ-CUD患者的奖励反应能力的行为度量将减少； （1B）在患有SCZ（无碳）和CUD（无SCZ）的人中探索这些措施。 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; （2B）探索SCZ-CUD患者的奖励反应能力的行为度量是否会提高，（2C）探索在患有CUD（没有SCZ）的患者中的这些措施，并将结果与​​（2A）的结果进行比较。第三个目标将评估dronabinol对SCZ-CUD患者的其他影响 - 渴望，情绪，阴性症状，精神病症状和认知。通过探测BRC失调并测试烟熏大麻对这种失调的影响，这项研究将有助于进一步阐明BRC赤字的“自我药物”是否可能是SCZ患者中大麻使用的重要组成部分。此外，通过探测dronabinol的生理和行为作用，这项研究可以导致治疗剂的发展，包括Dronabinol，其他大麻素或非核素剂，可能会改善BRC缺乏症并因此限制这些患者的大麻使用。