Inhibition of the casein-kinase-1-ε/δ/ prevents relapse-like alcohol drinking.

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.

Response perseveration in stimulant dependence is associated with striatal dysfunction and can be ameliorated by a D(2/3) receptor agonist.

BACKGROUND: Compulsivity is a hallmark of drug addiction and in animal models is measured by consecutive incorrect responses to a previously rewarded stimulus during reversal learning. The aim of this study was to measure behavioral and neural markers of compulsivity in stimulant-dependent individuals and to test whether these markers could be modulated by treatment with drugs targeting the dopamine system. METHODS: In a randomized, double-blind, placebo-controlled, crossover design, stimulant-dependent individuals (SDIs; n = 18) and healthy volunteers (n = 18) received single doses of dopamine D(2/3) receptor antagonist (amisulpride, 400 mg) and agonist (pramipexole, 0.5 mg) drugs. To examine compulsivity and its dopaminergic modulation more generally, patients with obsessive-compulsive disorder (OCD; n = 18) were also included in the study. RESULTS: SDIs made significantly more perseverative responses to the previously correct stimulus immediately following reversal, compared with both healthy volunteers and patients with OCD. Across all participants, the number of perseverative errors was negatively correlated with functional activation in right fronto-striato-parietal networks-in particular, the right caudate nucleus. In SDIs, perseveration-related caudate activation was abnormally reduced in the placebo condition, but the dopamine D(2/3) agonist pramipexole normalized both perseverative responding and related activation of the right caudate. CONCLUSIONS: Perseveration during reversal learning was associated specifically with stimulant dependence rather than with compulsive behaviors more generally. The beneficial effects of a dopamine agonist drug challenge on both behavior and associated brain activation in SDIs may indicate new avenues for pharmacologic treatment in stimulant dependence.

Influence of compulsivity of drug abuse on dopaminergic modulation of attentional bias in stimulant dependence.

CONTEXT: There are no effective pharmacotherapies for stimulant dependence but there are many plausible targets for development of novel therapeutics. We hypothesized that dopamine-related targets are relevant for treatment of stimulant dependence, and there will likely be individual differences in response to dopaminergic challenges. OBJECTIVE: To measure behavioral and brain functional markers of drug-related attentional bias in stimulant-dependent individuals studied repeatedly after short-term dosing with dopamine D(2)/D(3) receptor antagonist and agonist challenges. DESIGN: Randomized, double-blind, placebo-controlled, parallel-groups, crossover design using pharmacological functional magnetic resonance imaging. SETTING: Clinical research unit (GlaxoSmithKline) and local community in Cambridge, England. PARTICIPANTS: Stimulant-dependent individuals (n = 18) and healthy volunteers (n = 18). INTERVENTIONS: Amisulpride (400 mg), pramipexole dihydrochloride (0.5 mg), or placebo were administered in counterbalanced order at each of 3 repeated testing sessions. MAIN OUTCOME MEASURES: Attentional bias for stimulant-related words was measured during functional magnetic resonance imaging by a drug-word Stroop paradigm; trait impulsivity and compulsivity of dependence were assessed at baseline by questionnaire. RESULTS: Drug users demonstrated significant attentional bias for drug-related words, which was correlated with greater activation of the left prefrontal and right cerebellar cortex. Attentional bias was greater in people with highly compulsive patterns of stimulant abuse; the effects of dopaminergic challenges on attentional interference and related frontocerebellar activation were different between high- and low-compulsivity subgroups. CONCLUSIONS: Greater attentional bias for and greater prefrontal activation by stimulant-related words constitute a candidate neurocognitive marker for dependence. Individual differences in compulsivity of stimulant dependence had significant effects on attentional bias, its brain functional representation, and its short-term modulation by dopaminergic challenges.

A stereotaxic MRI template set for the rat brain with tissue class distribution maps and co-registered anatomical atlas: application to pharmacological MRI.

We describe a stereotaxic rat brain MRI template set with a co-registered digital anatomical atlas and illustrate its application to the analysis of a pharmacological MRI (phMRI) study of apomorphine. The template set includes anatomical images and tissue class probability maps for brain parenchyma and cerebrospinal fluid (CSF). These facilitate the use of standard fMRI software for spatial normalisation and tissue segmentation of rat brain data. A volumetric reconstruction of the Paxinos and Watson rat brain atlas is also co-localised with the template, enabling the atlas structure and stereotaxic coordinates corresponding to a feature within a statistical map to be interactively reported, facilitating the localisation of functional effects. Moreover, voxels falling within selected brain structures can be combined to define anatomically based 3D volumes of interest (VOIs), free of operator bias. As many atlas structures are small relative to the typical resolution of phMRI studies, a mechanism for defining composite structures as agglomerations of individual atlas structures is also described. This provides a simple and robust means of interrogating structures that are otherwise difficult to delineate and an objective framework for comparing and classifying compounds based on an anatomical profile of their activity. These developments allow a closer alignment of pre-clinical and clinical analysis techniques.