title: The adrenergic α2 antagonist atipamezole alters the behavioural effects of pramipexole and increases pramipexole concentration in blood plasma.
abstract: Pramipexole is a dopaminergic agonist used in Parkinson's disease treatment. It is thought to exert its therapeutic and side effects through actions on dopamine D3 receptors. In a recent study, we found that at doses occupying D3 but not D2 receptors pramipexole reduced locomotion and operant responding for primary and conditioned reinforcement. These effects, however, were not blocked by a D3 receptor antagonist and were present in D3 knockout mice, suggesting non-D3 receptor mechanisms. Among the next highest affinity binding sites of pramipexole are adrenergic α2 receptors. Here we explored α2 receptor involvement in the behavioural effects of pramipexole. We found that the α2 antagonist atipamezole, which was itself behaviourally silent, counteracted pramipexole's reduction of locomotion, but not operant responding for water or a conditioned reinforcer. The resulting behavioural profile was similar to that of a higher dose of pramipexole, leading to the hypothesize that atipamezole mediates its behavioural effects by increasing pramipexole effective dose. In support of this hypothesis, we found that atipamezole increased pramipexole concentration in blood plasma. This is not likely due to an effect on drug metabolism since pramipexole is not known to undergo metabolic transformation. Future work should examine two alternative hypotheses; that pramipexole plasma concentration is elevated as the result of 1) competition with atipamezole for renal excretion, or 2) atipamezole blockade of peripheral α2 binding sites, thereby preventing pramipexole distribution to α2-rich tissues. The suggestion of adrenergic effects of pramipexole is important in light of recent interest in adrenergic pathophysiology in Parkinson's disease.
authors.affiliation: Centre for Addiction and Mental Health, Toronto, ON, Canada. Electronic address: p.mccormick@ucl.ac.uk.
authors.forename: P N
authors.initials: PN
authors.lastname: McCormick
authors.affiliation: Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychology, University of Toronto, Toronto, ON, Canada.
authors.forename: P J
authors.initials: PJ
authors.lastname: Fletcher
authors.affiliation: Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: V S
authors.initials: VS
authors.lastname: Wilson
authors.affiliation: Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: G J
authors.initials: GJ
authors.lastname: Remington
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D052160:Benzothiazoles / Q000037:antagonists & inhibitors / Q000097:blood* / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D018491:Dopamine Agonists / Q000097:blood / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D000077487:Pramipexole; D051381:Rats
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D052160:Benzothiazoles; D018491:Dopamine Agonists; D007093:Imidazoles; C050701:atipamezole; D000077487:Pramipexole
keywords: Atipamezole; Dopamine D2 receptor; Dopamine D3 receptor; Locomotion; Operant responding; Pramipexole; α2 adrenergic receptor