Scn4b regulates the hypnotic effects of ethanol and other sedative drugs.

The voltage-gated sodium channel subunit ß4 (SCN4B) regulates neuronal activity by modulating channel gating and has been implicated in ethanol consumption in rodent models and human alcoholics. However, the functional role for Scn4b in ethanol-mediated behaviors is unknown. We determined if genetic global knockout (KO) or targeted knockdown of Scn4b in the central nucleus of the amygdala (CeA) altered ethanol drinking or related behaviors. We used four different ethanol consumption procedures (continuous and intermittent two-bottle choice (2BC), drinking-in-the dark and chronic intermittent ethanol vapor) and found that male and female Scn4b KO mice did not differ from their wild-type (WT) littermates in ethanol consumption in any of the tests. Knockdown of Scn4b mRNA in the CeA also did not alter 2BC ethanol drinking. However, Scn4b KO mice showed longer duration of the loss of righting reflex induced by ethanol, gaboxadol, pentobarbital and ketamine. KO mice showed slower recovery to basal levels of handling-induced convulsions after ethanol injection, which is consistent with the increased sedative effects observed in these mice. However, Scn4b KO mice did not differ in the severity of acute ethanol withdrawal. Acoustic startle responses, ethanol-induced hypothermia and clearance of blood ethanol also did not differ between the genotypes. There were also no functional differences in the membrane properties or excitability of CeA neurons from Scn4b KO and WT mice. Although we found no evidence that Scn4b regulates ethanol consumption in mice, it was involved in the acute hypnotic effects of ethanol and other sedatives.

Apremilast Alters Behavioral Responses to Ethanol in Mice: II. Increased Sedation, Intoxication, and Reduced Acute Functional Tolerance.

BACKGROUND: In our companion paper, we reported that the phosphodiesterase type 4 inhibitor apremilast reduced ethanol (EtOH) intake and preference in different drinking models in male and female C57BL/6J mice. In this study, we measured the effects of apremilast on other behaviors that are correlated with EtOH consumption. METHODS: The effects of apremilast (20 mg/kg) on the following behaviors were studied in male and female C57BL/6J mice: locomotor response to a novel situation; EtOH- and lithium chloride (LiCl)-induced conditioned taste aversion (CTA) to saccharin; conditioned place preference (CPP) and conditioned place avoidance (CPA) to EtOH; severity of handling-induced convulsions after EtOH administration; EtOH-induced anxiolytic-like behavior in the elevated plus maze; duration of EtOH-induced loss of righting reflex (LORR); recovery from EtOH-induced motor impairment on the rotarod; and acute functional tolerance (AFT) to EtOH's ataxic effects. RESULTS: Apremilast did not change the acquisition of EtOH-induced CPP, severity of acute withdrawal from EtOH, or EtOH's anxiolytic-like effect. Apremilast did not alter the extinction of EtOH- or LiCl-induced CTA, but may interfere with acquisition of CTA to EtOH. Apremilast increased the acquisition of CPA to EtOH, reduced locomotor responses to a novel situation, and prolonged the duration of LORR and the recovery from acute motor incoordination induced by EtOH. The longer recovery from the ataxic effect may be attributed to reduced development of AFT to EtOH. CONCLUSIONS: Our results suggest that apremilast increases the duration of EtOH intoxication by reducing AFT. Apremilast also reduces some aspects of general reward and increases EtOH's aversive properties, which might also contribute to its ability to reduce EtOH drinking.

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

BACKGROUND: Phosphodiesterase 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. METHODS: We 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 2 hours after injection. RESULTS: In the continuous and intermittent drinking tests, apremilast (15 to 50 mg/kg, p.o.) dose dependently reduced EtOH intake and preference in male and female mice. Higher doses of apremilast (30 to 50 mg/kg) also reduced total fluid intake in these mice. Chronic administration of apremilast (20 mg/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 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 EtOH clearance. The highest levels of apremilast were found in liver followed by plasma and brain. CONCLUSIONS: Apremilast 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.