guanosine-5--o-(3-thiotriphosphate) and Dyskinesia--Drug-Induced

Aripiprazole is a novel antipsychotic drug, which displays partial agonist activity at the dopamine D(2) receptor. Aripiprazole has been extensively studied pre-clinically, both in vitro and in vivo, and these results have been correlated with clinical findings. However, aripiprazole is metabolised differently in rats and man and these metabolites may contribute to the profile of aripiprazole observed in vivo. We have therefore studied the interaction of aripiprazole and its principal rat and human metabolites in both in vitro models of dopamine hD(2) receptor function and affinity, and of in vivo models of dopamine rat D(2) receptor function. The human metabolite displayed similar levels of partial agonist activity to aripiprazole at the dopamine hD(2) receptor and displayed similar behavioural profile to aripiprazole in vivo, suggesting that in man the metabolite may maintain the effects of aripiprazole. In contrast, the rat metabolite displayed antagonist activity both in vitro and in vivo. Thus care must be taken in ascribing effects seen in vivo with aripiprazole in rats to dopamine D(2) receptor partial agonist activity in man, and that care must also be taken in extrapolating effects seen in rats to man, particularly from long-term studies.

Topics: Amphetamine; Animals; Antipsychotic Agents; Aripiprazole; Behavior, Animal; Binding, Competitive; Biotransformation; Catalepsy; CHO Cells; Cricetinae; Cricetulus; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Guanosine 5'-O-(3-Thiotriphosphate); HeLa Cells; Humans; Male; Motor Activity; Oxidopamine; Piperazines; Quinolones; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Species Specificity; Transfection

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa therapy for Parkinson's disease. Although changes affecting D(1) and D(2) dopamine receptors have been studied in association with this condition, no causal relationship has yet been established. Taking advantage of a monkey brain bank constituted to study levodopa-induced dyskinesia, we report changes affecting D(1) and D(2) dopamine receptors within the striatum of normal, parkinsonian, nondyskinetic levodopa-treated parkinsonian, and dyskinetic levodopa-treated parkinsonian animals. Whereas D(1) receptor expression itself is not related to dyskinesia, D(1) sensitivity per D(1) receptor measured by D(1) agonist-induced [(35)S]GTPgammaS binding is linearly related to dyskinesia. Moreover, the striata of dyskinetic animals show higher levels of cyclin-dependent kinase 5 (Cdk5) and of the dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32). Our data suggest that levodopa-induced dyskinesia results from increased dopamine D(1) receptor-mediated transmission at the level of the direct pathway.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Analysis of Variance; Animals; Antiparkinson Agents; Autoradiography; Behavior, Animal; Blotting, Western; Cyclin-Dependent Kinase 5; Cyclin-Dependent Kinases; Disease Models, Animal; Dopamine and cAMP-Regulated Phosphoprotein 32; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Drug Interactions; Dyskinesia, Drug-Induced; Female; Guanosine 5'-O-(3-Thiotriphosphate); Immunohistochemistry; In Situ Hybridization; Isotopes; Levodopa; Macaca fascicularis; Membrane Glycoproteins; Membrane Transport Proteins; Motor Activity; Nerve Tissue Proteins; Nortropanes; Parkinsonian Disorders; Phosphoproteins; Radioligand Assay; Receptors, Dopamine D1; Receptors, Dopamine D2; Signal Transduction; Substantia Nigra; Time Factors; Tyrosine 3-Monooxygenase