The adrenergic alpha2 antagonist atipamezole alters the behavioural effects of pramipexole and increases pramipexole concentration in blood plasma.

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McCormick PN, Fletcher PJ, Wilson VS, Remington GJ

The adrenergic alpha2 antagonist atipamezole alters the behavioural effects of pramipexole and increases pramipexole concentration in blood plasma.

Life Sci. 2016 Apr 15;151:300-304. doi: 10.1016/j.lfs.2016.03.017. Epub 2016 Mar 11.

PubMed ID

26976325 [ View in PubMed

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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 alpha2 receptors. Here we explored alpha2 receptor involvement in the behavioural effects of pramipexole. We found that the alpha2 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 alpha2 binding sites, thereby preventing pramipexole distribution to alpha2-rich tissues. The suggestion of adrenergic effects of pramipexole is important in light of recent interest in adrenergic pathophysiology in Parkinson's disease.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Pramipexole	Alpha-2A adrenergic receptor	Protein	Humans	Unknown	Agonist	Details