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

摘要 大麻使用障碍（CUD）常发生于精神分裂症（SCZ）患者， 这种严重的精神疾病对这些“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患者中皮质边缘“脑奖励回路”（BRC）失调， 支持他们的大麻使用，大麻使用改善了这种失调的电路。研究 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， 与正常受试者相比，奖励反应降低。此外，我们的ARRA- 涉及静息状态功能连接（RSC）的资助基金表明，这些患者也有 布拉迪斯拉发区域中心内部内在的区域间同步性下降。最后，我们的飞行员成像数据进一步表明， 大麻和大麻素激动剂屈大麻酚都能减少功能失调的BRC缺陷， 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。第一个目标是 评估SCZ和合并CUD（SCZ-CUD）患者以及 SCZ（无CUD）和CUD（无SCZ）患者：（1a）确认（i）任务相关的fMRI活动 连接到货币大脑奖励探针;（ii）区域间静息状态功能连接;和（iii） 奖励反应的行为测量，将减少与SCZ-CUD患者相比， 健康对照组;（1b）在SCZ（无CUD）和CUD（无 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CUD患者（无SCZ）：（2a）确认功能障碍是否（i）任务相关fMRI 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 改善;及（2b）探讨奖赏反应的行为量度是否会改善 在SCZ-CUD患者中，和（2c）在CUD患者（无SCZ）中探索这些措施，并 将结果与（2a）中的结果进行比较。第三个目标是评估屈大麻酚对患者的其他影响 与SCZ-CUD -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”是否可能是大麻的重要组成部分 用于SCZ患者。此外，通过探测屈大麻酚的生理和行为效应， 研究可以导致治疗剂的开发，可能包括屈大麻酚，其他大麻素或 可以改善BRC缺乏症并因此限制这些患者使用大麻的非大麻素药物。

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.