Apremilast Alters Behavioral Responses to Ethanol in Mice: I. Reduced Consumption and Preference

作者：Blednov Yuri A; Da Costa Adriana J; Tarbox Tamara; Ponomareva Olga; Messing Robert O; Harris R Adron^*

来源：Alcoholism: Clinical and Experimental Research , 2018, 42(5): 926-938.

DOI：10.1111/acer.13616

• PDE4 Inhibitor
• Two-Bottle Choice Ethanol Drinking
• Locomotor Activity
• Apremilast Biodistribution
• C57BL/6J Mice

BackgroundPhosphodiesterase type 4 (PDE4) inhibitors produce widespread anti-inflammatory effects and reduce ethanol (EtOH) consumption in several rodent models. These drugs are potential treatments for several diseases, including central nervous system disorders, but clinical use is limited by their emetic activity. Apremilast is a selective PDE4 inhibitor with fewer gastrointestinal side effects that is FDA-approved for the treatment of psoriasis.
MethodsWe measured the acute and chronic effects of apremilast on EtOH consumption in male and female C57BL/6J mice using the continuous and intermittent 24-hour 2-bottle choice drinking models. We also studied the effects of apremilast on preference for sucrose or saccharin, spontaneous locomotor activity, and blood EtOH clearance. Finally, apremilast levels in plasma, liver, and brain were measured 1 or 2hours after injection.
ResultsIn the continuous and intermittent drinking tests, apremilast (15 to 50mg/kg, p.o.) dose dependently reduced EtOH intake and preference in male and female mice. Higher doses of apremilast (30 to 50mg/kg) also reduced total fluid intake in these mice. Chronic administration of apremilast (20mg/kg) produced a stable reduction in EtOH consumption in both drinking tests with no effect on total fluid intake. The drinking effects were reversible after drug treatment was replaced with vehicle administration (saline) for 2 to 4days. Six daily apremilast injections did not alter preference for saccharin or sucrose in male or female mice. Apremilast (20mg/kg) transiently decreased spontaneous locomotor activity and did not alter blood EtOH clearance. The highest levels of apremilast were found in liver followed by plasma and brain.
ConclusionsApremilast produced stable reductions in voluntary EtOH consumption and was rapidly distributed to plasma and tissues (including the brain), suggesting that it may be an improved PDE4 inhibitor for medication development and repurposing efforts to treat alcohol abuse.

• 出版日期2018-5