Dopamine D3 receptor antagonists for treating drug addiction: Preclinical models

National Institute On Drug Abuse

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Linked publications & trials

Abstract

During the present reporting period, modest laboratory work was conducted on this project. In addition, a backlog of laboratory findings on this project were brought forward to the publication stage during this reporting period. First, using a new additional animal behavioral model, we reported that our lead proof-of-concept dopamine D3 receptor antagonist compound SB277011A decreases binge-like consumption of ethanol in C57BL/J6 mice. Second, we reported that SB277011A attenuates drug- or food-deprivation stress-induced reactivation of the expression of cocaine-induced conditioned place preference in laboratory rats. Third, we reported that SB277011A significantly accelerates extinction to environmental cues associated with cocaine-induced place preference in laboratory rats. Fourth, we reported that SB277011A does not alter Pavlovian conditioned approach behaviors in rats (sign-tracking versus goal-tracking). Fifth, we reported on a new and novel series of 4-phenylpiperazines with exceptionally high dopamine D3 receptor affinities and/or selectivities. Compound 19 of this new chemical series inhibited oxycodone-induced hyperlocomotion in mice, and inhibited oxycodone-induced locomotor sensitization. In addition, pretreatment with compound 19 dose-dependently inhibited the acquisition of oxycodone-induced conditioned place preference in laboratory rats. Sixth, we reported that a combination of levo-tetrahydropalmatine and low dose naltrexone constitutes a promising new therapy for prevention of relapse to cocaine-seeking behavior.