Departments of Physiology and Pharmacology (W.S.J., S.H.N., M.A.N.), Anesthesiology (T.J.M.), and Radiology (K.K.S.S., H.D.G., A.M., M.A.N.), Wake Forest School of Medicine, Winston-Salem, North Carolina.
Departments of Physiology and Pharmacology (W.S.J., S.H.N., M.A.N.), Anesthesiology (T.J.M.), and Radiology (K.K.S.S., H.D.G., A.M., M.A.N.), Wake Forest School of Medicine, Winston-Salem, North Carolina
J Pharmacol Exp Ther. 2018 Feb;364(2):300-310. doi: 10.1124/jpet.117.244194. Epub 2017 Dec 4.
Cannabis-related impairments to cognitive function may represent novel therapeutic targets for cannabis-use disorder, although the nature, persistence, and reversibility of such deficits remain unclear. Adult male rhesus monkeys ( = 6) responded in the morning on tasks designed to assess different cognitive domains using the Cambridge Neuropsychological Test Automated Battery (CANTAB) touchscreens followed by responding maintained under a fixed-ratio (FR) 10 schedule of food presentation in different operant chambers. First, the acute effects of Δ-tetrahydrocannabinol (THC; 0.01-0.56 mg/kg, i.v.) on cognitive performance, FR responding, and body temperature were determined. Next, THC (1.0-2.0 mg/kg, s.c.) was administered daily after FR 10 sessions for 12 weeks, during which the residual effects of THC (i.e., 22 hours after administration) on cognition were examined and the acute effects of THC were redetermined. In a subgroup of monkeys, dopamine D2/D3 receptor availability was assessed after 4 weeks of chronic THC exposure and compared with drug-naive controls using positron emission tomography and [C]-raclopride ( = 4/group). Acute THC pretreatments dose-dependently decreased FR responding and body temperature, and impairment to cognitive performance was task specific. During chronic treatment, THC produced persistent residual impairment only to working memory; tolerance differentially developed to acute cognitive impairments. There was recovery from residual cognitive impairments to working memory within 2 weeks of abstinence. Compared with controls, D2/D3 receptor availability was not altered during chronic THC treatment. In conclusion, THC-induced disruptions in cognition were task-specific, as was tolerance development, and not related to changes in D2/D3 receptor availability. Intervention strategies for cannabis-use disorder that enhance working memory performance may facilitate positive treatment outcomes.
大麻相关认知功能损害可能代表大麻使用障碍的新治疗靶点，尽管这些缺陷的性质、持续时间和可逆性仍不清楚。雄性恒河猴（n=6）在上午进行测试，使用剑桥神经心理学测试自动化电池（CANTAB）触摸屏评估不同认知领域的认知功能，然后在不同操作室中根据固定比率（FR）10 方案进行食物呈现的反应。首先，确定了 Δ-四氢大麻酚（THC；0.01-0.56mg/kg，静脉注射）对认知表现、FR 反应和体温的急性影响。接下来，在 FR10 个疗程后每天给予 THC（1.0-2.0mg/kg，皮下注射）12 周，在此期间检查了 THC（即给药后 22 小时）对认知的残留影响，并重新确定了 THC 的急性影响。在一组猴子中，在慢性 THC 暴露 4 周后使用正电子发射断层扫描和 [C]-raclopride（n=4/组）评估多巴胺 D2/D3 受体可用性，并与未用药对照进行比较。急性 THC 预处理剂量依赖性地降低了 FR 反应和体温，并且认知表现受损具有任务特异性。在慢性治疗期间，THC 仅对工作记忆产生持续的残留损害；急性认知损伤的耐受性不同。在戒断后 2 周内，工作记忆的残留认知损伤有恢复。与对照组相比，在慢性 THC 治疗期间 D2/D3 受体可用性没有改变。总之，THC 引起的认知障碍具有任务特异性，耐受性的发展也是如此，与 D2/D3 受体可用性的变化无关。增强工作记忆表现的大麻使用障碍干预策略可能有助于积极的治疗结果。
