Jing Shi1, Huaxia Liu2, Jianchun Pan3, Jie Chen3, Nianping Zhang4, Kaiping Liu3, Ning Fei3, James M O'Donnell5, Han-Ting Zhang6,7, Ying Xu8. 1. School of Pharmacy, Hangzhou Medical College, Hangzhou, 310053, Zhejiang Province, China. 2. School of Nursing, Taishan Medical University, Tai'an, 271016, Shandong Province, China. 3. Brain Institute, Wenzhou Medical University School of Pharmacy, Wenzhou, 325021, Zhejiang Province, China. 4. Datong University Medical College, Datong, 037009, Shanxi Province, China. 5. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, the State University of New York, Buffalo, NY, 14214, USA. 6. Departments of Behavioral Medicine & Psychiatry and Physiology, Pharmacology & Neuroscience, Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, 26506, USA. hzhang@hsc.wvu.edu. 7. Institute of Pharmacology, Taishan Medical University, Tai'an, 271016, Shandong, China. hzhang@hsc.wvu.edu. 8. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, the State University of New York, Buffalo, NY, 14214, USA. yxu9@buffalo.edu.
Abstract
RATIONALE: Alcohol use disorder (AUD) is a chronically relapsing condition, which affects nearly 11% of population worldwide. Currently, there are only three FDA-approved medications for treatment of AUD, and normally, satisfactory effects are hard to be achieved. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling has been implicated in regulation of ethanol intake. Phosphodiesterase 2 (PDE), a dual substrate PDE that hydrolyzes both cAMP and cGMP, may play a crucial role in regulating ethanol consumption. METHODS: The present study determined whether PDE2 was involved in the regulation of ethanol intake and preference. The two-bottle choice procedure was used to examine the effects of the selective PDE2 inhibitor Bay 60-7550 on ethanol intake. The sucrose and quinine intake (taste preference) and locomotor activity (sedative effects) were also measured to exclude the false positive effects of Bay 60-7550. RESULTS: Treatment with Bay 60-7550 (1 and 3 mg/kg, i.p.) decreased ethanol intake and preference, without changing total fluid intake. In addition, Bay 60-7550 at doses that reduced ethanol intake did not affect sucrose and quinine intake and preference, which excluded the potential influence of taste preference and sedative effects on ethanol drinking behavior. Moreover, Bay 60-7550 at 3 mg/kg did not alter locomotor activity or ethanol metabolism, further supporting the specific effect of Bay 60-7550 on ethanol drinking behavior. CONCLUSIONS: The results suggest that PDE2 plays a role in the regulation of ethanol consumption and that PDE2 inhibitors may be a novel class of drugs for treatment of alcoholism.
RATIONALE: Alcohol use disorder (AUD) is a chronically relapsing condition, which affects nearly 11% of population worldwide. Currently, there are only three FDA-approved medications for treatment of AUD, and normally, satisfactory effects are hard to be achieved. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling has been implicated in regulation of ethanol intake. Phosphodiesterase 2 (PDE), a dual substrate PDE that hydrolyzes both cAMP and cGMP, may play a crucial role in regulating ethanol consumption. METHODS: The present study determined whether PDE2 was involved in the regulation of ethanol intake and preference. The two-bottle choice procedure was used to examine the effects of the selective PDE2 inhibitor Bay 60-7550 on ethanol intake. The sucrose and quinine intake (taste preference) and locomotor activity (sedative effects) were also measured to exclude the false positive effects of Bay 60-7550. RESULTS: Treatment with Bay 60-7550 (1 and 3 mg/kg, i.p.) decreased ethanol intake and preference, without changing total fluid intake. In addition, Bay 60-7550 at doses that reduced ethanol intake did not affect sucrose and quinine intake and preference, which excluded the potential influence of taste preference and sedative effects on ethanol drinking behavior. Moreover, Bay 60-7550 at 3 mg/kg did not alter locomotor activity or ethanol metabolism, further supporting the specific effect of Bay 60-7550 on ethanol drinking behavior. CONCLUSIONS: The results suggest that PDE2 plays a role in the regulation of ethanol consumption and that PDE2 inhibitors may be a novel class of drugs for treatment of alcoholism.
Entities:
Keywords:
Bay 60-7550; Ethanol intake; PDE2; Two-bottle choice; cAMP/cGMP
Authors: Wilma C G Van Staveren; Harry W M Steinbusch; Marjanne Markerink-Van Ittersum; David R Repaske; Michael F Goy; Jun Kotera; Kenji Omori; Joseph A Beavo; Jan De Vente Journal: J Comp Neurol Date: 2003-12-22 Impact factor: 3.215
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