The apremilast effect on motor activity was also evaluated by comparing the areas under the motor activity curves, which showed a reduction of motor activity in female (p 0
The apremilast effect on motor activity was also evaluated by comparing the areas under the motor activity curves, which showed a reduction of motor activity in female (p 0.01) but not in male PF-04217903 methanesulfonate mice (Fig. and brain were measured one or two hours after injection. Results In the continuous and intermittent drinking tests, apremilast (15-50 mg/kg, p.o.) dose dependently reduced ethanol intake and preference in male and female mice. Higher doses of apremilast (30-50 mg/kg) also reduced total fluid intake in these mice. Chronic administration of apremilast (20 mg/kg) produced a stable reduction of ethanol 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 2-4 days. Six daily apremilast injections did not alter preference for saccharin or sucrose in male or female mice. Apremilast (20 mg/kg) transiently decreased spontaneous locomotor activity and did not alter blood ethanol clearance. The highest levels of apremilast were found in liver followed by plasma and brain. Conclusions Apremilast produces stable reductions in voluntary ethanol consumption and is rapidly distributed to plasma and tissues (including the brain), suggesting that it may be an improved PDE4 PF-04217903 methanesulfonate inhibitor for medication development and repurposing efforts to treat alcohol abuse. tests, and Student’s analyses showed significant decreases in all drinking parameters at doses of 30-50 mg/kg, while 15 mg/kg of apremilast reduced the amount of ethanol consumed without changing total fluid intake. There was a trend for 15 mg/kg to reduce preference for ethanol, but this did not reach statistical significance. In female mice, apremilast also dose dependently reduced ethanol intake (F4,27 = 15.8, p 0.001), preference for ethanol (F4,27 = 9.4, p 0.001), and total fluid intake (F4,27 = 15.5, p 0.001; Fig. 1D-F). The raw drinking data in female mice are shown in Supplemental Fig. 1D-F. analyses showed that 15-50 mg/kg apremilast significantly decreased the amount of ethanol consumed and preference for ethanol, and 30-50 mg/kg apremilast also reduced total fluid intake. The lowest dose of apremilast tested (5 mg/kg) did not significantly alter ethanol consumption in male or female mice. Based on the dose-response effects, a 20 mg/kg dose was chosen for chronic drug treatment experiments. Open in a separate window Figure 1 Apremilast dose dependently decreases 15% ethanol intake in the continuous 2BC testEffects of apremilast (5-50 mg/kg) on ethanol (EtOH) intake (A), preference for EtOH (B), and total fluid intake (C) in male C57BL/6J mice; n= 7-8 per group. Effects of apremilast (5-50 mg/kg) on EtOH intake (D), preference for EtOH (E), and total fluid intake (F) in female C57BL/6J mice; n= 6-7 per group. Data are offered as the variations between two-day drinking averages Nedd4l after drug injection (days 3, 4 after apremilast) and the 1st two days of saline (control) injections (days 1, 2). Data were analyzed by one-way ANOVA with Bonferroni checks (*p 0.05, **p 0.01, ***p 0.001 compared with control). Six daily injections of apremilast (20 mg/kg) significantly reduced ethanol usage (F1,14 = 12.8, p 0.001, effect of treatment; F2,28 = 3.8, p 0.05, effect of time) and preference for ethanol (F1,14 = 9.9, p 0.001, effect of treatment) but did not alter total fluid consumption in male mice (Fig. 2A-C). During the washout phase when injection of apremilast was replaced with saline, mice previously treated with apremilast showed no variations in ethanol usage or preference compared with control mice. Similar to male mice, 6 daily injections of apremilast (20 mg/kg) in female mice reduced ethanol usage (F1,16 = 16.4, p PF-04217903 methanesulfonate 0.001,.