Khokhar Jibran Y, Chau David T, Dawson Ree, Green Alan I
Department of Psychiatry, Geisel School of Medicine at Dartmouth, Dartmouth College, Lebanon, NH, United States.
Frontier Science Research and Technology Foundation, Boston, MA, United States.
Drug Alcohol Depend. 2015 Jul 1;152:277-81. doi: 10.1016/j.drugalcdep.2015.04.003. Epub 2015 Apr 22.
Alcohol use disorder commonly occurs in patients with schizophrenia. Most antipsychotic drugs do not lessen alcohol use; although the atypical antipsychotic clozapine has been shown to reduce alcohol use in patients with schizophrenia, its toxicity severely limits its use in patients. With an eye toward creation of a safer clozapine-like drug, we have investigated the pharmacological basis of the clozapine's effects on alcohol drinking in the Syrian golden hamster. In this animal, as in patients with schizophrenia, clozapine reduces alcohol drinking while the typical antipsychotic haloperidol does not. We have suggested that clozapine decreases alcohol drinking due to its weak dopamine D2 receptor blockade, its potent norepinephrine α-2 receptor antagonism, as well as its ability to elevate plasma norepinephrine.
We recreated a clozapine-like drug to reduce alcohol drinking in the Syrian golden hamster by combining low dose haloperidol with a norepinephrine α-2 receptor antagonist, idazoxan, and a norepinephrine reuptake inhibitor, desipramine. Hamsters were given free access to water and alcohol (15% v/v) and were treated daily with each drug or with the three-drug combination for 23 days.
The drug combination reduced alcohol drinking and preference significantly as compared to vehicle or to haloperidol, idazoxan or desipramine, while not altering food-intake or body-weight.
These findings suggest that that haloperidol, which does not reduce alcohol drinking in patients with schizophrenia or the hamster, if combined with idazoxan and desipramine (producing a drug combination that mimics aspects of clozapine's pharmacology) is able to reduce alcohol drinking in the hamster.
酒精使用障碍在精神分裂症患者中普遍存在。大多数抗精神病药物并不能减少酒精使用；尽管非典型抗精神病药物氯氮平已被证明可减少精神分裂症患者的酒精使用，但其毒性严重限制了其在患者中的应用。为了研发一种更安全的类似氯氮平的药物，我们研究了氯氮平对叙利亚金仓鼠饮酒行为影响的药理学基础。在这种动物中，与精神分裂症患者一样，氯氮平可减少酒精摄入，而典型抗精神病药物氟哌啶醇则不能。我们认为氯氮平减少酒精摄入是由于其对多巴胺D2受体的弱阻断作用、对去甲肾上腺素α-2受体的强效拮抗作用以及升高血浆去甲肾上腺素的能力。
我们通过将低剂量氟哌啶醇与去甲肾上腺素α-2受体拮抗剂伊达唑胺和去甲肾上腺素再摄取抑制剂地昔帕明联合使用，创造了一种类似氯氮平的药物来减少叙利亚金仓鼠的酒精摄入。仓鼠可自由获取水和酒精（15% v/v），并每天接受每种药物或三种药物组合治疗，持续23天。
与溶剂对照组或氟哌啶醇、伊达唑胺或地昔帕明相比，药物组合显著降低了酒精摄入量和偏好，同时不改变食物摄入量或体重。
这些发现表明，在精神分裂症患者或仓鼠中不能减少酒精摄入的氟哌啶醇，若与伊达唑胺和地昔帕明联合使用（产生一种模拟氯氮平药理学某些方面的药物组合），能够减少仓鼠的酒精摄入。
