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，并影响这种严重精神疾病的病程。对这些“双重诊断”患者的治疗是不够的。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“大脑奖励回路”（BRC）失调支持他们使用大麻，而大麻的使用改善了这种失调的回路。通过研究与功能磁共振成像相关的金钱探针的神经效应，以及奖励反应的行为测量，我们和其他人已经证明，与正常受试者相比，SCZ患者的BRC确实存在缺陷，并且奖励反应性降低。此外，我们的ARRA资助的涉及静息状态功能连接（RSC）的试验数据表明，这些患者在BRC内的内在区域间同步性也有所降低。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，减少功能失调的BRC赤字，如通过与fMRI相关的货币探针和静息状态功能连接所评估的。在这项提案中，我们寻求确认和扩大我们的ARRA资助的调查。第一个目的是评估SCZ和合并CUD（SCZ-CUD）患者以及SCZ患者的BRC状态（不含CUD）和CUD（无SCZ）：（1a）确认（i）与货币大脑奖励探针相关的任务相关fMRI活动;（ii）区域间静息状态功能连接;和（iii）奖赏反应的行为测量，与健康对照组相比，SCZ-CUD患者中将降低;和（1b）在SCZ（无CUD）和CUD（无SCZ）患者中探索这些测量。第二个目标是评估大麻和屈大麻酚对SCZ-CUD患者和CUD患者BRC的影响（无SCZ）：（2a）确认功能障碍（i）与货币脑奖励探针相关的任务相关fMRI活动，以及（ii）区域间静息状态功能连接是否会得到改善;（2b）探索SCZ-CUD患者的奖励反应行为测量是否会得到改善，（2c）探索CUD患者（无SCZ）的这些测量，并将结果与（2a）的结果进行比较。第三个目标是评估屈大麻酚对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。通过探测BRC失调和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“自我药物治疗”是否可能是SCZ患者使用大麻的重要组成部分。此外，通过探索屈大麻酚的生理和行为影响，这项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，这些药物可以改善BRC缺乏症，从而限制大麻在这些患者中的使用。