Heterogeneity of behavioural profile between three new putative selective D3 dopamine receptor antagonists using an ethologically based approach

Abstract

The effects on behaviour of the putative selective D₃ dopamine receptor antagonists GR 103691, nafadotride and U 99194A were compared with those of the generic D₂-like antagonist haloperidol, using an ethologically based approach. Neither GR 103691 (0.008–1.0 mg/kg) nor nafadotride (0.025–1.6 mg/kg) influenced any element of behaviour. Conversely, U99194A (1.67–45 mg/kg) effected a dose-dependent stimulation of episodes of non-stereotyped sniffing, locomotion, chewing and eating, with some stimulation of rearing, and reduced baseline levels of grooming; thereafter, as sniffing and locomotion declined, stimulation of episodes of grooming emerged. Haloperidol (0.0008–0.1 mg/kg) failed to promote any element of behaviour and reduced baseline levels of grooming; responsivity to U99194A was antagonised by pretreatment with haloperidol. The lack of effect of GR 103691 (>100-fold D₃/D₂ selectivity) and nafadotride (10-fold D₃/D₂ preference), in contrast to the characteristic ‘‘ethogram’’ for U99194A (25-fold D₃/D₂ selectivity), indicated a fundamental difference in their mechanisms of action. This topography of responsivity to U99194A overlapped somewhat with the profiles of both D₂-like and D₁-like agonists, and its sensitivity to antagonism by haloperidol also indicated a dopaminergic basis thereto. However, differences among GR 103691, nafadotride and U99194A bore no relation to their relative selectivities for the D₃ receptor, and the basis thereof remains unclear. Theorising as to the behavioural role of the D₃ receptor may need to be tempered pending the identification of a range of chemically distinct D₃ antagonists of higher selectivity.