title: Blockade of D3 receptors by YQA14 inhibits cocaine's rewarding effects and relapse to drug-seeking behavior in rats.
abstract: 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.
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA; Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Song
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA.
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Bi
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA.
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Zhang
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Ri-Fang
authors.initials: RF
authors.lastname: Yang
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA.
authors.forename: Eliot L
authors.initials: EL
authors.lastname: Gardner
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: jinli9802@163.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA. Electronic address: zxi@intra.nida.nih.gov.
authors.forename: Zheng-Xiong
authors.initials: ZX
authors.lastname: Xi
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy; D001522:Behavior, Animal / Q000187:drug effects; D001583:Benzoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D018492:Dopamine Antagonists / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D004558:Electric Stimulation; D008297:Male; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D020318:Rats, Long-Evans; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*; D012008:Recurrence; D012201:Reward
chemical_list: D001583:Benzoxazoles; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; D050637:Receptors, Dopamine D3; C571881:YQA14; D003042:Cocaine
keywords: Cocaine; D3 receptors; Dopamine; Reinstatement; Reward; YQA14