Role of the dopamine D3 receptor in reactivity to cocaine-associated cues in mice

Environmental stimuli previously associated with drug effects can acquire secondary reinforcing properties, able to maintain drug-seeking behaviour or induce relapse. We have used a classical Pavlovian conditioning procedure to assess the role of the dopamine D-3 receptor (D-3 R) in the expression of drug-conditioned responses. Mice repeatedly receiving cocaine in a particular environment distinct from home-cages displayed hyperlocomotion after subsequent exposure to the drug-paired environment. Cocaine-conditioned hyperactivity was inhibited by BP 897 or SB-277011-A, D3R-selective partial agonist and antagonist, respectively. D3R gene-targeted mice showed a trend towards an increase in cocaine cue-conditioned hyperactivity. BP 897 had no effect on reactivity to neutral or aversive cues. Cocaine-conditioned mice had increased levels of D-3 R mRNA and binding in the nucleus accumbens (NAc), and transcripts of brain-derived neurotrophic factor (BDNF), a factor controlling D-3 R expression, in the ventral tegmental area (VTA). Cocaine had no effects on D-3 R or BDNF genes when administered in home-cages. Cocaine cue-conditioned c-fos expression was found in cortical areas, notably in the somatosensory cortex, where it was inhibited by BP 897, and in several regions belonging or linked to the limbic system. In conditioned mice, BP 897 inhibited c-fos expression in VTA and activated it in amygdala. These results demonstrate a modulation of reactivity to cocaine cues by the D-3 R, the expression of which is elevated in the NAc by the repeated association of drug effects with a particular context, through a BDNF-dependent mechanism. D-3 R-selective partial agonist or antagonist inhibit cocaine cue-conditioned activity possibly by normalizing exacerbated D-3 R function in the NAc, but our results also point to a possible participation of a pathway involving the VTA, amygdala and somatosensory cortex.