Psychobiology Section, Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
Psychopharmacology (Berl). 2019 Dec;236(12):3601-3612. doi: 10.1007/s00213-019-05332-x. Epub 2019 Aug 9.
Rimcazole, a σ-receptor antagonist with affinity for the dopamine transporter (DAT), decreases rates of cocaine self-administration at doses lower than those that affect food-reinforced responding. As response rates are multiply determined, behavioral-economic analyses were used to provide measures of the reinforcing effectiveness of cocaine and food after rimcazole treatment. Further, effects of combinations of the DAT inhibitor, methylphenidate, and σ-receptor antagonists (BD1008, BD1063) were compared to those of rimcazole to assess mechanism of rimcazole effects.
Male Sprague-Dawley rats were trained to lever press with food reinforcement (one or three 20-mg sucrose pellets) or cocaine injection (0.1 or 0.32 mg/kg) under fixed-ratio (FR) 5-response schedules. Drugs or vehicle were administered (i.p.) 5-min before sessions in which FR value was increased from 5 to 80. Economic demand functions were generated from effects of FR value (price) on intake (consumption), with the parameters of demand, consumption at no cost (Q) and sensitivity to price (essential value, EV), derived.
Rimcazole dose-dependently decreased Q and EV at both cocaine doses/injection. In contrast, rimcazole had no effect on these parameters at either food amount. Combinations of methylphenidate and the σ-receptor antagonists decreased Q at the lower cocaine dose/injection but had no effect on EV; these treatments were ineffective on both economic parameters at the higher cocaine dose/injection and at either food amount.
Though the drug combinations only replicated rimcazole's effects incompletely, the present results suggest a specific decrease in the reinforcing effects of cocaine due to dual DAT σ-receptor blockade.
Rimcazole 是一种 σ 受体拮抗剂，对多巴胺转运体（DAT）具有亲和力，可降低可卡因自我给药的速度，其剂量低于影响食物强化反应的剂量。由于反应率是多重决定的，因此使用行为经济学分析来提供 rimcazole 治疗后可卡因和食物的强化效力的测量。此外，还比较了 DAT 抑制剂（哌醋甲酯）和 σ 受体拮抗剂（BD1008、BD1063）与 rimcazole 的组合的效果，以评估 rimcazole 作用的机制。
雄性 Sprague-Dawley 大鼠接受训练，用食物强化（一个或三个 20 毫克蔗糖丸）或可卡因注射（0.1 或 0.32 毫克/千克）进行杠杆按压，反应比率（FR）为 5 次。药物或载体在 FR 值从 5 增加到 80 的会话前 5 分钟（i.p.）给药。从 FR 值（价格）对摄入（消耗）的影响生成经济需求函数，从需求参数、无成本消耗（Q）和对价格的敏感性（基本值，EV）中得出。
Rimcazole 剂量依赖性地降低了可卡因的两种剂量/注射的 Q 和 EV。相比之下，rimcazole 对这两个参数在任何食物量上都没有影响。哌醋甲酯和 σ 受体拮抗剂的组合降低了较低剂量的可卡因的 Q，但对 EV 没有影响；这些治疗方法在较高剂量的可卡因和任何食物量上对这两个经济参数都没有影响。
尽管药物组合仅不完全复制了 rimcazole 的作用，但目前的结果表明，由于 DAT-σ 受体双重阻断，可卡因的强化作用特异性降低。
