The adrenergic α2 antagonist atipamezole alters the behavioural effects of pramipexole and increases pramipexole concentration in blood plasma.

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.

Low dose pramipexole causes D3 receptor-independent reduction of locomotion and responding for a conditioned reinforcer.

Pramipexole is a clinically important dopamine receptor agonist with reported selectivity for dopamine D3 receptors over other dopaminergic and non-dopaminergic sites. Many of its behavioural effects are therefore attributed to D3 receptor activity. Here we relate pramipexole's ex vivo D2 and D3 receptor binding (measured using [(3)H]-(+)-PHNO binding experiments) to its effects on locomotion and operant responding for primary and conditioned reinforcers. We show that pramipexole has inhibitory behavioural effects on all three behaviours at doses that occupy D3 but not D2 receptor. However, these effects are 1) not inhibited by a D3 selective dose of the antagonist SB-277011-A, and 2) present in D3 receptor knockout mice. These results suggest that a pharmacological mechanism other than D3 receptor activity must be responsible for these behavioural effects. Finally, our receptor binding results also suggest that these behavioural effects are independent of D2 receptor activity. However, firmer conclusions regarding D2 involvement would be aided by further pharmacological or receptor knock-out experiments. The implications of our findings for the understanding of pramipexole's behavioural and clinical effects are discussed.