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

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 D₃ receptor expression in the brain. Therefore, most D₃ -based medication development has focused on D₃ antagonists. However, D₃ 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 D₃ 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 D₃ partial agonist also failed to alter oral sucrose self-administration.

Conclusion and implications

The novel D₃ partial agonist, (±)VK4-40 attenuates cocaine reward and relapse in rodents, without significant unwanted effects. These findings support further investigation of D₃ partial agonists as putative treatments for cocaine use disorder.

SUBMITTER: Jordan CJ 

PROVIDER: S-EPMC7520435 | biostudies-literature |

REPOSITORIES: biostudies-literature