RATIONALE: A novel scheme for the synthesis of cocaine analogs from vinylcarbenoid precursors has made available compounds that have a diverse range of affinities for the DA and 5-HT transporters. These compounds were used to explore the relationship between their biochemical properties and their reinforcing effects. OBJECTIVES: The objective was to assess the reinforcing efficacy of selected cocaine analogs and compare the results with their selectivity in binding to DA and 5-HT transporters. METHODS: Rats were prepared with chronically indwelling intravenous cannulae and trained to self-administer cocaine on a progressive ratio (PR) schedule. A range of doses of seven cocaine analogs were substituted for cocaine in separate groups of animals. RESULTS: The results demonstrate a wide range of reinforcing efficacies and potencies among the seven selected drugs. Four tropane analogs (WF-11, WF-23, WF-24, WF-55) were found to support self-administration behavior on a PR schedule while three did not (WF-31, WF-54 and WF-60). The DA/5-HT selectivity ratio was found to be a better predictor of self-administration behavior than affinity at the DA transporter alone. CONCLUSION: These data suggest that drugs with a higher affinity for the DA versus the 5-HT transporter are more likely to be self-administered.
RATIONALE: A novel scheme for the synthesis of cocaine analogs from vinylcarbenoid precursors has made available compounds that have a diverse range of affinities for the DA and 5-HT transporters. These compounds were used to explore the relationship between their biochemical properties and their reinforcing effects. OBJECTIVES: The objective was to assess the reinforcing efficacy of selected cocaine analogs and compare the results with their selectivity in binding to DA and 5-HT transporters. METHODS:Rats were prepared with chronically indwelling intravenous cannulae and trained to self-administer cocaine on a progressive ratio (PR) schedule. A range of doses of seven cocaine analogs were substituted for cocaine in separate groups of animals. RESULTS: The results demonstrate a wide range of reinforcing efficacies and potencies among the seven selected drugs. Four tropane analogs (WF-11, WF-23, WF-24, WF-55) were found to support self-administration behavior on a PR schedule while three did not (WF-31, WF-54 and WF-60). The DA/5-HT selectivity ratio was found to be a better predictor of self-administration behavior than affinity at the DA transporter alone. CONCLUSION: These data suggest that drugs with a higher affinity for the DA versus the 5-HT transporter are more likely to be self-administered.
Authors: I Sora; F S Hall; A M Andrews; M Itokawa; X F Li; H B Wei; C Wichems; K P Lesch; D L Murphy; G R Uhl Journal: Proc Natl Acad Sci U S A Date: 2001-04-24 Impact factor: 11.205
Authors: Jermaine D Jones; F Scott Hall; George R Uhl; Kenner Rice; Anthony L Riley Journal: Pharmacol Biochem Behav Date: 2009-04-17 Impact factor: 3.533
Authors: Michael A Nader; Paul W Czoty; Robert W Gould; Natallia V Riddick Journal: Philos Trans R Soc Lond B Biol Sci Date: 2008-10-12 Impact factor: 6.237