Effects of dopaminergic D3-receptor-preferring ligands on the acquisition of place conditioning in rats

The involvement of a D3 receptor-mediated control of dopamine (DA) function in motivational processes was investigated in rats by examining the ability of two D3 receptor-preferring ligands (7-OH-DPAT and l-nafadotride) to establish incentive learning and/or to modulate the reinforcing properties of food. This was done using a place conditioning procedure which consisted of repeated pairings of a drug (or food + drug) with a single environmental cue, the door texture of an open field. (+/-)7-OH-DPAT, a partially selective D3 receptor agonist, produced a biphasic effect: the time spent on the drug-paired texture was reduced by 4 and 8 mu g/kg and lengthened by 4.0 mg/kg, suggesting intrinsic aversive and appetitive potentials, depending on the dose. The D3 receptor preferring antagonist, l-nafadotride, did not establish place conditioning and seemed therefore devoid of intrinsic reinforcing properties. However, when food was provided during the conditioning sessions preceded by drug administration, a low dose of l-nafadotride (0.12 mg/kg) but not higher doses, lengthened the time spent on the food-paired texture. Although the preferential affinity ratio of the two ligands in favour of the D3 vs. D2 subtype is low, these results suggest that DA function in the structures involved in incentive learning could be controlled through inhibitory D3 (or 'D2-like') receptor-mediated processes. Conditioned place aversion would indicate an impaired DA transmission due to a selective stimulation of these receptors, whereas their selective blockade would induce the inverse effect, providing that DA release was sufficient (as during eating) in the pathways involved in reward-related processes. The reversal of the effects of the two compounds at larger doses would likely result from an interaction with other subtypes of 'D2-like' receptors.