Pramipexole reverses Parkinson's disease-related motivational deficits in rats.

Recent evidence suggests that Parkinson's disease affects not only movement, but also cognitive and psychiatric functions. Among these nonmotor complications, apathy, which is defined as a lack of motivation and operationalized as a quantitative reduction in goal-directed behavior, may even precede motor impairments, disappearing with the introduction of dopaminergic (DA) therapies and possibly reappearing with its discontinuation, suggesting a causal role of DA. We recently developed a lesion-based model, with stereotaxic infusion of 6-hydroxydopamine (6-OHDA) into precise areas of the rat SNc or ventral tegmental area and showed, in several operant tasks, that a partial denervation of the nigrostriatal, but not of the mesocorticolimbic, DA system induced profound motivational deficits during instrumental action. We investigated the time course of the effects of nigrostriatal DA denervation on motivation in rats, by assessing the negative effect of SNc bilateral 6-OHDA infusion on preacquired operant behavior, and determining whether the induced deficits were sensitive to the introduction and withdrawal of a clinically relevant PD treatment, the DA D2/D3 receptor agonist, pramipexole (PRA). Partial nigrostriatal DA denervation was accompanied by a significant reduction in operant behavior. This deficit, indicative of a decrease in motivation, was fully reversed by PRA and reappeared after treatment withdrawal. This longitudinal preclinical study provides evidence for the implication of the DA nigrostriatal system in PD-associated apathy. Moreover, by showing a good isomorphy and predictive value, our model highlights the relevance of D2/D3 receptors as potential targets for alleviating apathy in PD.

Atomoxetine decreases vulnerability to develop compulsivity in high impulsive rats.

BACKGROUND: The factors contributing to the development and severity of obsessive-compulsive spectrum disorders such as obsessive-compulsive disorder, Tourette's syndrome, pathological gambling, and addictions remain poorly understood, limiting the development of therapeutic and preventive strategies. Recent evidence indicates that impulse-control deficits may contribute to the severity of compulsivity in several of these disorders. This suggests that impulsivity may be a transnosological endophenotype of vulnerability to compulsivity. However, the precise nature of the link between impulsivity and compulsivity in anxiety-related compulsive disorders remains unknown. METHODS: We investigated the relationship between impulsivity and the development of a compulsive behavior in rats, which captures the hallmarks of compulsivity as defined in the DSM-IV--namely, that it is maladaptive, excessive, repetitive, and anxiolytic. RESULTS: We demonstrate that a high-impulsivity trait, as measured in the five-choice serial reaction time task, predicts an increased propensity to develop compulsivity as measured in a schedule-induced polydipsia procedure. Trait impulsivity and compulsivity were nonlinearly related. This impulsivity-compulsivity relationship was lost after the development of compulsivity or under chronic treatment with atomoxetine, a noradrenergic reuptake inhibitor used to treat attention-deficit/hyperactivity disorder. Atomoxetine treatment both decreased impulsivity and prevented the development of compulsivity in high-impulsive animals. CONCLUSIONS: These observations provide insight into the reciprocal influence of impulsivity and compulsivity in compulsive disorders and suggest that atomoxetine may be a useful treatment for patients suffering from obsessive-compulsive spectrum disorders with high impulsivity.