Preclinical studies suggest that
dopamine D3 receptor (D3R) antagonists are promising for the treatment of
drug abuse and addiction. However, few D3R antagonists have potential to be tested in humans due to short half-life, toxicity or limited preclinical research into pharmacotherapeutic efficacy. Here, we report on a novel D3R antagonist
YQA14, which has improved half-life and pharmacokinetic profile and which displays potent pharmacotherapeutic efficacy in attenuating
cocaine reward and relapse to drug-seeking behavior. Electrical brain-stimulation reward (BSR) in laboratory animals is a highly sensitive experimental approach to evaluate a
drug's rewarding effects. We found that
cocaine (2 mg/kg) significantly enhanced electrical BSR in rats (i.e., decreased stimulation threshold for BSR), while
YQA14 alone had no effect on BSR. Pretreatment with
YQA14 significantly and dose-dependently attenuated
cocaine-enhanced BSR.
YQA14 also facilitated extinction from drug-seeking behavior in rats during early behavioral extinction, and attenuated
cocaine- or contextual cue-induced relapse to drug-seeking behavior.
YQA14 alone did not maintain
self-administration in either naïve rats or in rats experienced at
cocaine self-administration.
YQA14 also inhibited expression of repeated
cocaine-induced behavioral sensitization. These findings suggest that
YQA14 may have pharmacotherapeutic potential in attenuating
cocaine-taking and
cocaine-seeking behavior. Thus,
YQA14 deserves further investigation as a promising agent for treatment of
cocaine addiction.