Background and Purpose: Preclinical studies suggest that highly selective dopamine D3 receptor (D3R) antagonists or partial agonists hold promise for treating substance use disorders (SUD). However, their limited effectiveness in reducing cocaine self-administration is a major drawback. This study investigated whether cariprazine (a D3R-preferring partial agonist) and its analogs ESG-1-60 and ESG-1-61 have enhanced efficacy in reducing cocaine-taking and -seeking behavior. Experimental Approach: In vitro BRET experiments were used to characterize the functional efficacies of cariprazine and its analogs. Intravenous cocaine self-administration and reinstatement models were used to evaluate efficacy in reducing cocaine-taking and -seeking behavior. Optical intracranial self-stimulation (oICSS) procedures assessed effects on DA-dependent behavior. Open-field locomotion, oral sucrose self-administration, and conditioned place-preference were used to evaluate potential unwanted side effects. Key Results: BRET functional assays indicated that cariprazine and ESG-1-60 are D3R-preferring partial agonists, while ESG-1-61 is a D3R-preferring antagonist/inverse agonist. All three compounds inhibited cocaine self-administration under both fixed-ratio and progressive-ratio reinforcement schedules and reduced cocaine-induced reinstatement of drug-seeking behavior in both male and female rats. The compounds did not alter locomotor behavior but suppressed sucrose intake and DA-dependent oICSS. Cariprazine and ESG-1-61 produced significant place aversion, while ESG-1-60 did not. Chronic administration of ESG-1-60 inhibited cocaine self-administration. Conclusions and Implications: Novel D3R-preferring compounds ESG-1-60 and ESG-1-61 are highly effective in reducing cocaine taking and seeking under various reinforcement conditions. ESG-1-60 warrants further investigation as a new pharmacotherapy for treating cocaine use disorder due to its effectiveness in these models and lack of unwanted behavioral effects.

Background and Purpose. Despite widespread abuse of cocaine, there are no approved treatments for cocaine use disorder. Chronic cocaine use is associated with upregulated dopamine D3 receptor (D3R) expression in the brain, and therefore, most D3R-based medication development has focused on D3R antagonists. However, D3R antagonists do not attenuate cocaine intake under “easy” self-administration conditions when response requirements are low. Here we evaluated a novel, highly selective and metabolically stable D3R 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 were 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. Sucrose self-administration and a conditioned place preference paradigm was 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 behavior. In addition, VK4-40 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, and produced neither conditioned place preference nor place aversion. This new D3R partial agonist also failed to alter oral sucrose self-administration. Conclusions and Implications. The novel D3R partial agonist, VK4-40, attenuates cocaine reward and relapse in rodents, without significant unwanted effects. These findings support further investigation of D3R partial agonists as putative treatments for cocaine use disorder.