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 [3H]-(+)-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. •Pramipexole's dopamine receptor binding and behavioural effects were measure in rat.•At low doses pramipexole bound to dopamine D3 but not D2 receptors.•At these doses pramipexole decreased operant responding and locomotion.•These behavioural effects were insensitive to D3 receptor knockout or blockade.•We conclude that pramipexole has D3 receptor-independent effects at low doses.