Abstract
The effects of the monoamine uptake inhibitor Lu 19-005 ((±)-trans-3-(3,4-dichlorophenyl)-N-methyl-1-indanamine) and its (+) and (−) enantiomers, Lu 20-042 and Lu 20-043, were compared with those of cocaine and the selective dopamine uptake inhibitor GBR 12909 (1-{2-[bis-(4-fluorophenyl)methoxyl]ethyl}-4-(3-phenylpropyl)piperazin e) in behavioral and radioligand binding experiments. Behavioral experiments were conducted in groups of squirrel monkeys trained under fixed-interval schedules of reinforcement in which responding was maintained either by presentation of food or by termination of a visual stimulus associated with mild electric shock. Radioligand binding studies were conducted using [3H]CFT and [3H]GBR 12935 to label elements of the dopamine uptake system in caudate-putamen membranes of cynomolgus monkeys. All drugs produced dose-related increases in response rate under the fixed-interval schedules. Lu 19-005, Lu 20-042, and Lu 20-043 had relatively slow onsets (approximately 2 h) and relatively long durations of action, with effects persisting for two or more days following administration. Stereoselectivity was evident in the behavioral effects of the enantiomers of Lu 19-005, with Lu 20-042 being approximately 14 times more potent than Lu 20-043. In radioligand binding experiments, Lu 19-005 and its enantiomers were potent inhibitors of specifically bound [3H]CFT and [3H]GBR 12935. As in behavioral experiments, Lu 20-042 was more potent than Lu 20-043. The degree of stereoselectivity, however, varied with the temperature of the assay medium. At 37° C, Lu 20-043 was approximately 36 times more potent than Lu 20-043 in inhibiting the binding of [3H]CFT, whereas at 0–4° C, the difference in potency was only about 2-fold. The increased stereoselectivity at 37° C was due to a reduced potency for Lu 20-043. The results support the view that the behavioral effects of Lu 19-005 and its enantiomers are mediated at cocaine recognition sites associated with the dopamine uptake system. The results also show that incubation temperature can be a relevant factor in determining the relative potencies of drugs at [3H]CFT binding sites in vitro.
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Animals used in this study were maintained in accordance with the guidelines of the Committee on Animals of the Harvard Medical School and of the “Guide for Care and Use of Laboratory Animals” of the Institute of Laboratory Animal Resources, National Research Council, Department of Health, Education and Welfare, Publication No. (NIH)85-23, revised 1985. This research was supported by USPHS grants DA03774, DA06303, DA00499, and by Research Scientist Development Award DA00088 to RDS. Facilities and services were provided by the New England Regional Primate Research Center (USPHS Division of Research Resources Grant RR00168).
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Rosenzweig-Lipson, S., Bergman, J., Spealman, R.D. et al. Stereoselective behavioral effects of Lu 19-005 in monkeys: relation to binding at cocaine recognition sites. Psychopharmacology 107, 186–194 (1992). https://doi.org/10.1007/BF02245136
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DOI: https://doi.org/10.1007/BF02245136