Abstract
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.