Inhibition of the Casein-Kinase-1-Epsilon/Delta Prevents Relapse-Like Alcohol Drinking

Abstract

During the past decade, it has been shown that circadian clock genes have more than a simple circadian time-keeping role. Clock genes also modulate motivational processes and have been implicated in the development of psychiatric disorders such as drug addiction. Recent studies indicate that casein-kinase 1ε/δ (CK1ε/δ)--one of the components of the circadian molecular clockwork-might be involved in the etiology of addictive behavior. The present study was initiated to study the specific role of CK1ε/δ in alcohol relapse-like drinking using the 'Alcohol Deprivation Effect' model. The effect of CK1ε/δ inhibition was tested on alcohol consumption in long-term alcohol-drinking rats upon re-exposure to alcohol after deprivation using a four-bottle free-choice paradigm with water, 5%, 10%, and 20% ethanol solutions, as well as on saccharin preference in alcohol-naive rats. The inhibition of CK1ε/δ with systemic PF-670462 (0, 10, and 30 mg/kg) injections dose-dependently decreased, and at a higher dosage prevented the alcohol deprivation effect, as compared with vehicle-treated rats. The impact of the treatment was further characterized using nonlinear regression analyses on the daily profiles of drinking and locomotor activity. We reveal that CK1ε/δ inhibition blunted the high daytime alcohol intake typically observed upon alcohol re-exposure, and induced a phase shift of locomotor activity toward daytime. Only the highest dose of PF-670462 shifted the saccharin intake daily rhythm toward daytime during treatment, and decreased saccharin preference after treatment. Our data suggest that CK1 inhibitors may be candidates for drug treatment development for alcoholism.

A role for the circadian clock protein Per1 in the regulation of aldosterone levels and renal Na+ retention

“…To further confirm the regulation of 3␤-HSD by Per1, WT mice were either given vehicle or PF-670462 as previously published and described by others (27). Adrenal glands were harvested, and 3␤-HSD mRNA levels were assessed by quantitative PCR.…”

“…PF-670462 has been previously shown to have an IC 50 for CK1-␦ of 15 nM and 7.7 nM for CK1-ε (5). To provide further confirmation of the regulation of 3␤-HSD, NCI-H295R cells were treated with PF-670462, and 3␤-HSD Weight-matched male WT 129/sv mice were given either vehicle (20% hydroxypropyl-␤-cyclodextrin) or 30 mg/kg PF-670462 subcutaneously every 12 h for 2.5 days starting at noon and euthanized at midnight 12 h after the last injection, as previously published and described (27). Adrenal glands were harvested, and 3␤-HSD (A) and CYPB11 (B) mRNA expression was measured by quantitative PCR.…”

“…3, C and D). 5 days starting at noon and euthanized at midnight 12 h after the last injection as previously described (27). Adrenal glands were harvested, and Cry2 expression was measured by quantitative PCR.…”

Circadian Clock and Stress Interactions in the Molecular Biology of Psychiatric Disorders

“…Bright light therapy and sleep manipulation, especially in combination, are effective in mood disorders [90], and novel pharmacological approaches may hold promise for the treatment of a wide variety of psychiatric disorders that currently lack adequate drug therapies. Indeed, it has been suggested that the mood stabilizer lithium may have a circadian mechanism of action [97], and casein kinase 1δ/ε inhibitors have shown promise in pre-clinical animal models of AUD [121] and BD [122]. Additional compounds have been developed to target the ROR/REV-ERB nuclear receptors [123], CRYs [124], melanopsin-containing photoreceptors [125] and other complex mechanisms [123] that strongly affect circadian rhythms, but remain poorly characterized with respect to brain effects and potential as treatments for psychiatric conditions.…”

Adenosinergic Regulation of Striatal Clock Gene Expression and Ethanol Intake During Constant Light

“…A central role for the circadian system in AUD is underscored by evidence linking most clock genes with AUD (Albrecht et al, 2001;Franken et al, 2000;Gamsby et al, 2013;Kovanen et al, 2010;Le-Niculescu et al, 2008;Lopez-Molina et al, 1997;Melendez et al, 2011;Perreau-Lenz et al, 2012;Spanagel et al, 2005;Steinlechner et al, 2002;Wang et al, 2012;Yang et al, 2012). In addition to ethanol (Melendez et al, 2011), morphine (Hood et al, 2011) and amphetamine (Wongchitrat et al, 2013) alter circadian variation in clock gene expression in the mesolimbic reward system during chronic use and/or withdrawal, which may contribute to addictive behavior and/or circadian misalignment.…”