(±)VK4-40, a novel dopamine D3 receptor partial agonist, attenuates cocaine reward and relapse in rodents

Background and Purpose Despite widespread abuse of cocaine, there are no approved treatments for cocaine use disorder. Chronic cocaine use is associated with up-regulated dopamine D(3)receptor expression in the brain. Therefore, most D-3-based medication development has focused on D(3)antagonists. However, D(3)antagonists do not attenuate cocaine intake under easy self-administration conditions, when response requirements are low. We evaluated a novel, highly selective and metabolically stable D(3)partial agonist, (+/-)VK4-40, for its efficacy in reducing cocaine intake and relapse to drug seeking. Experimental Approach The impact of (+/-)VK4-40 on cocaine intake and relapse was evaluated using intravenous self-administration procedures under a fixed-ratio 2 reinforcement schedule and cocaine-primed reinstatement conditions in rats. Optogenetic brain-stimulation reward procedures were used to evaluate the interaction of (+/-)VK4-40 and cocaine in the mesolimbic dopamine system in mice. Sucrose self-administration in rats and a conditioned place preference paradigm in mice were used to evaluate the abuse potential of (+/-)VK4-40 alone and other unwanted effects. Key Results (+/-)VK4-40 dose-dependently reduced cocaine self-administration and cocaine-primed reinstatement of drug-seeking behaviour. (+/-)VK4-40 also inhibited cocaine-enhanced brain-stimulation reward caused by optogenetic stimulation of dopamine neurons in the ventral tegmental area. (+/-)VK4-40 alone decreased brain-stimulation reward but produced neither conditioned place preference nor place aversion. This new D(3)partial agonist also failed to alter oral sucrose self-administration. Conclusion and Implications The novel D(3)partial agonist, (+/-)VK4-40 attenuates cocaine reward and relapse in rodents, without significant unwanted effects. These findings support further investigation of D(3)partial agonists as putative treatments for cocaine use disorder.