Kuzmin A, Semenova S, Zvartau E, De Vry J
Pavlov Medical University, St. Petersburg, Russia.
Eur Neuropsychopharmacol. 1999 Mar;9(3):197-203. doi: 10.1016/s0924-977x(98)00025-x.
In the present study the involvement of voltage-operated calcium channels (VOCCs) in the acquisition and maintenance of operant i.v. ethanol (EtOH) self-administration was investigated in rats. Rats readily learned to self-administer EtOH (unit dose range: 0.5-4% v/v) within five daily 2-h sessions, when infusions were made contingent upon nose-poking in a hole containing infrared sensors. Response rate was related to the EtOH concentration in an inverted U-shaped manner, the maximal rate and intake being observed at a unit dose of 1% v/v (0.27 mg EtOH/infusion). Self-administration of EtOH appeared to be behaviorally specific, as responding in the reinforced hole did not coincide with increased responding in a nonreinforced hole. Daily treatment with the dihydropyridine VOCC blocker nimodipine (2.5-20 mg/kg, i.p., t-15 min) dose-dependently attenuated acquisition of EtOH self-administration; the 5 mg/kg dose resulting in a partial, and the 10 and 20 mg/kg doses in a complete prevention of i.v. self-administration behavior. The effects of nimodipine (2.5-5.0 mg/kg) were considered to be relatively specific, as an inhibition of the reinforced responding could be demonstrated in the absence of a significant effect on nonreinforced responding. When tested in rats showing stable self-administration behavior (unit dose: 1% v/v EtOH), nimodipine showed biphasic dose-response effects; with 2.5 and 5 mg/kg resulting in a mild increase, and 10 and 20 mg/kg resulting in a decrease of self-administration behavior, respectively. The present study suggests that blockade of VOCCs attenuates the reinforcing stimulus effects of EtOH; and, as such, the data may offer an explanation for the previously reported EtOH intake-reducing effects of dihydropyridine calcium channel ligands obtained in two-bottle choice paradigms. Dihydropyridine derivatives, such as nimodipine, may therefore offer an interesting approach to the pharmacotherapy of alcoholism.
在本研究中，研究了电压门控钙通道（VOCCs）在大鼠静脉注射乙醇（EtOH）自我给药的获得和维持过程中的作用。大鼠在每天5次、每次2小时的实验中，当静脉注射取决于在装有红外传感器的孔中戳鼻时，很容易学会自我给药EtOH（单位剂量范围：0.5 - 4% v/v）。反应率与EtOH浓度呈倒U形关系，在单位剂量为1% v/v（0.27 mg EtOH/次注射）时观察到最大反应率和摄入量。EtOH的自我给药似乎具有行为特异性，因为在强化孔中的反应与在非强化孔中增加的反应不一致。用二氢吡啶VOCC阻滞剂尼莫地平（2.5 - 20 mg/kg，腹腔注射，提前15分钟）每日治疗剂量依赖性地减弱EtOH自我给药的获得；5 mg/kg剂量导致部分减弱，10和20 mg/kg剂量完全阻止静脉自我给药行为。尼莫地平（2.5 - 5.0 mg/kg）的作用被认为相对具有特异性，因为在对非强化反应无显著影响的情况下，可以证明对强化反应有抑制作用。当在表现出稳定自我给药行为（单位剂量：1% v/v EtOH）的大鼠中进行测试时，尼莫地平显示出双相剂量反应效应；2.5和5 mg/kg导致自我给药行为轻度增加，10和20 mg/kg分别导致自我给药行为减少。本研究表明，VOCCs的阻断减弱了EtOH的强化刺激作用；因此，这些数据可能为先前报道的二氢吡啶钙通道配体在双瓶选择范式中获得的减少EtOH摄入量的作用提供解释。因此，二氢吡啶衍生物，如尼莫地平，可能为酒精中毒的药物治疗提供一种有趣的方法。
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