In vivo effects of pardoprunox (SLV308), a partial D₂/D₃ receptor and 5-HT1A receptor agonist, on rat dopamine and serotonin neuronal activity

The nonergot ligand pardoprunox (SLV308) is a dopamine (DA) D₂/D₃ and serotonin (5-HT)(1A) receptor agonist and a new candidate for the treatment of Parkinson's disease. We used in vivo electrophysiological paradigm in the rat to assess the effects of pardoprunox on DA neuronal activity in ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) as well as on 5-HT neuronal activity in dorsal raphe nucleus (DRN). In the VTA, pardoprunox (2-20 μg kg⁻¹, i.v.) decreased partially the firing activity of DA neurons. Interestingly, the bursting activity of VTA DA neurons was completely suppressed. This compound both reversed and prevented the inhibition of firing rate induced by the full D₂-like receptor agonist apomorphine, confirming its partial D₂-like receptor agonistic property. Surprisingly in the SNc, pardoprunox (10 μg kg⁻¹, i.v.) either partially or fully suppressed the firing activity in two separate populations of DA neurons. Finally, in the DRN, pardoprunox (5-40 μg kg⁻¹, i.v.) completely suppressed the firing activity of 5-HT neurons. Moreover, the selective 5-HT(1A) receptor antagonist WAY-100,635 prevented and reversed the effects of pardoprunox. The present study shows that pardoprunox acts in the VTA as a potent partial D₂-like receptor agonist reducing preferentially the burst activity linked to the phasic activity of DA neurons. Unexpectedly in the SNc, pardoprunox behaves either as apartial or a full D₂-like receptor agonist. Finally in the DRN, pardoprunox is a potent full 5-HT(1A) receptor agonist. Hence, this in vivo study suggests that pardoprunox represents a promising approach for the treatment of Parkinson's disease.