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

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，并使这种严重精神障碍的病程恶化。可用于这些“双重诊断”患者的治疗方法不足。迫切需要新的治疗方法来限制精神分裂症患者使用大麻。我们提出SCZ患者中皮质边缘“大脑奖励回路”（BRC）失调是他们使用大麻的基础，而大麻的使用改善了这种失调的回路。通过研究与fMRI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，与正常受试者相比，SCZ患者的BRC确实存在缺陷，奖励反应也有所下降。此外，我们ARRA资助的涉及静息状态功能连接（RSC）的试点数据表明，这些患者BRC内的内在区域间同步也有所减少。最后，我们的试点成像数据进一步表明，通过与fMRI相关的货币探针和静息状态功能连通性评估，大麻和大麻素激动剂dronabinol都可以减少功能失调的BRC赤字。在本提案中，我们试图确认并扩大我们由arra资助的调查。第一个目的是评估SCZ合并合并CUD （SCZ-CUD）患者以及SCZ（不合并CUD）和CUD（不合并SCZ）患者BRC的状态：（1a）确认(i)任务相关的fMRI活动与金钱脑奖励探针相关；（ii）区域间静息状态功能连接；（iii）与健康对照组相比，SCZ-CUD患者的奖励反应性行为测量将降低；（1b）探讨SCZ（无CUD）和CUD（无SCZ）患者的这些指标。第二个目的是评估大麻和大麻酚对SCZ- CUD患者和CUD（无SCZ）患者BRC的影响：（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改善；（2b）探讨SCZ-CUD患者是否会改善奖励反应的行为测量，（2c）探讨CUD（无SCZ）患者的这些测量，并将结果与（2a）的结果进行比较。第三个目的是评估曲大麻酚对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。通过探索BRC失调并测试吸食大麻对这种失调的影响，本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，通过探索大麻酚的生理和行为影响，本研究可以促进治疗药物的开发，可能包括大麻酚、其他大麻素或非大麻素药物，这些药物可以改善BRC缺乏症，从而限制这些患者使用大麻。

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.