Irreversible suppression of alcohol drinking in cyanamide-treated rats after sustained delivery of the 5-HT2 antagonist amperozide |
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| Affiliation: | 1. Departments of Pharmacology and Psychiatric Medicine, School of Medicine East Carolina University, Greenville, NC 27858 USA;2. Business Unit CNS, Kabi Pharmacia A.B., Malmö, Sweden;1. Technical University of Denmark, Department of Wind Energy, Risø Campus, DK-4000 Roskilde, Denmark;2. Aalborg University, Department of Civil Engineering, Sohngårdsholmsvej 57, DK-9000 Aalborg, Denmark;1. Key Laboratory of Disaster Prevention and Structural Safety of Ministry of Education, Guangxi University, China;2. College of Civil Engineering and Architecture, Guangxi University, Nanning 530004, China;3. Department of Structural Engineering, College of Civil Engineering, Tongji University, Shanghai 200092, China;4. Guangxi Key Laboratory of Disaster Prevention and Engineering Safety, Guangxi University, China;1. University of Zurich, Department of Business Administration, Affolternstrasse 56, 8050 Zurich, Switzerland;2. Glemco GmbH, Kammergasse 9a, 85354 Freising, Germany;1. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing 210023, China;2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Rd, Shanghai 201203, China;3. Zhongshan Institute for Drug Discovery, SIMM, CAS, Zhongshan 528437, China;4. Center of Clinical Pharmacology, The Second Affiliated Hospital Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou 310009, China;5. Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Rd, Shanghai 201203, China;6. Artemisinin Research Center, Guangzhou University of Chinese Medicine, 12 Jichang Rd, Guangzhou 510405, China;7. Department of Cardiology, Ningbo First Hospital, 59 Liuting Street, Ningbo 315010, China;8. NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, Shanghai 201203, China |
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| Abstract: | The purpose of this study was to evaluate the long-term effect of sustained treatment with amperozide, which has been shown to attenuate the volitional drinking of ethyl alcohol in the rat without side effects. Preference for alcohol first was induced pharmacologically in Sprague-Dawley rats by the inhibitor of aldehyde dehydrogenase, cyanamide, administered in a dose of 10 mg/kg twice daily for 3 days. Then following a standard preference test, each rat was offered water and its maximally preferred concentration of alcohol which ranged from 7% to 15%. Following a 4-day pre-drug test, saline control vehicle or amperozide was administered for 7 days by an osmotic minipump implanted in the intrascapular space. A single dose of 208 μg/kg/h (i.e., 5.0 mg/kg/day) was selected on the basis of a prior dose response study of amperozide. During the interval of sustained release of amperozide, the consumption of alcohol declined significantly in terms of both absolute g/kg intake and proportion of alcohol to water. When the preference of the rats was retested at 4, 30, 70, 110, and 140 day intervals after the pump had exhausted amperozide, the absolute g/kg consumption of alcohol continued to decline significantly. Unlike other drugs, amperozide did not produce any side effects, particularly on the intake of food or water or on body weight, which suggests a pharmacological specificity of its action. Because amperozide acts centrally on 5-HT2 receptors as well as on dopaminergic synapses in the limbic system, it is envisaged that the drug exerts a unique effect on reward systems in the brain by affecting their receptor reuptake mechanisms, release of the respective transmitters, or other processes potentially involved in the abnormal imbibition of alcohol. Finally, because the effect of amperozide on alcohol drinking is progressive and irreversible, it thus may serve as a pharmacological adjunct to current therapy used in the clinical treatment of the disease of alcoholism. |
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