Impaired cognitive and motor function are coincident with L-DOPA-induced dyskinesia in a model of Parkinson's disease.

Dopamine transmission has been implicated in motor and cognitive function. In Parkinson's disease (PD), dopamine replacement using the precursor drug L-DOPA is the predominant treatment approach, but long-term exposure leads to the onset of dyskinesias (LIDs). Chronic L-DOPA exposure has been associated with changes in gene expression and altered cortico-striatal plasticity. The aim of this research was to assess the functional consequence of long-term L-DOPA exposure on cognitive and motor function using a rodent model of PD. Across two independent experiments, we assessed the impact of chronic L-DOPA exposure, or a control D2R agonist, on motor and cognitive function in intact and in hemi parkinsonian rats, in the absence of drug. Abnormal involuntary movements associated with LID were measured and brain tissues were subsequently harvested for immunohistochemical analysis. Exposure to chronic L-DOPA, but not the D2R agonist, impaired motor and cognitive function, when animals were tested in the absence of drug. A meta-analysis of the two experiments allowed further dissociation of L-DOPA -treated rats into those that developed LIDs (dyskinetic) and those that did not develop LIDs (non-dyskinetic). This analysis revealed impaired cognitive and motor performance were evident only in dyskinetic, but not in non-dyskinetic, rats. These data reveal a functional consequence of the altered plasticity associated with LID onset and have implications for understanding symptom progression in the clinic.

Long-term restorative effects of bromocriptine on operant responding in the 6-hydroxydopamine-lesioned rat.

Despite recent recognition of the complexity of the motor and nonmotor dysfunctions that manifest in Parkinson's disease, the propensity of drugs to alleviate the dopamine-dependent symptoms in the 6-hydroxydopamine rat model is still typically being assessed using relatively simple measures of motor function. We investigated the ability of the D2 agonist, bromocriptine, to ameliorate impairments in a more complex operant task, which simultaneously assessed both motor and nonmotor deficits. Rats were trained on a lateralized choice reaction time task that has previously been found to be sensitive to dopamine depletion. One subgroup of rats was then given unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. Once they exhibited stable postlesion deficits, the rats in the lesion group were administered bromocriptine (1.25 mg/kg) 120 min before testing. Bromocriptine induced a transient improvement in motor function but most notably produced a persistent improvement in the accuracy of performance in the task. The improvement in response initiation and selection persisted on testing in the absence of bromocriptine and was not reversed by the D2 antagonist, raclopride (0.2 mg/kg). These results may reflect a conditioning effect of bromocriptine on operant behaviour.

Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones.

Maintenance of a reduced body weight is associated with decreased 24-hour energy expenditure, and decreased circulating concentrations of leptin and thyroid hormones. To determine whether these adaptive metabolic and endocrine changes are partly leptin-mediated, we measured body composition, aspects of energy expenditure, and circulating concentrations of leptin and thyroid hormones in 4 subjects at 3 time points: 1.) Usual body weight; 2.) While stable at 10% reduced body weight; and 3.) During a 5-week period at 10% reduced body weight while receiving twice per day leptin injections that restored 8 AM circulating leptin concentrations to those seen at usual body weight. During maintenance of a 10% reduced body weight, circulating T3, T4, and leptin concentrations were decreased. All of these endocrine changes were reversed by administration of "replacement" doses of leptin (r-metHuLeptin). Indirect calorimetry, and subtle changes in body composition associated with leptin administration, were used to calculate the net change in stored calories and in 24-hour energy expenditure. Total energy expenditure increased in all subjects during r-metHuLeptin administration. These data indicate that decrease leptin concentrations resulting from loss of fat mass account for some aspects of the endocrine/metabolic phenotype associated with the weight-reduced state.