C D Cook1, I F Carroll, P M Beardsley. 1. Department of Pharmacology & Toxicology, Virginia Commonwealth University, 410 North 12th Street, Smith Building, P.O. Box 980613, Richmond, VA 23298-0613, USA. ccook@hsc.vcu.edu
Abstract
RATIONALE: Cocaine dependence is a major health concern and there are no effective pharmacotherapies currently available. Although cocaine is an indirect DA agonist that binds to all three monoamine transporters, there is much evidence implicating a greater role for the dopamine (DAT) than norepinephrine (NET) and serotonin (SERT) transporters in the behavioral effects of cocaine. As such, several groups have developed compounds that exhibit high affinity and selectivity for the DAT. OBJECTIVE: The present investigation examined the cocaine-like discriminative stimulus effects in rats of novel cocaine analogs (RTI 12, 13, 15) and 3-phenyltropane analogs (RTI 111, 112, 113, 114, 117 120, 121, 123, 134 and 152) of which several exhibit high affinity (e.g., <7 nM) and selectivity for the DAT. RESULTS: During dose-effect testing all drugs produced 75-100% cocaine-lever responding. Analyses indicated that the potency of the compounds to produce cocaine-like discriminative stimulus effects was correlated with their affinity for the DAT and the NET but not SERT. Due to the extremely large concentrations (e.g., 10,000-31,024 nM) needed to occupy the NET in vitro, it is doubtful if the doses administered had meaningful NET activity. The selectivity at the DAT, relative to the other transporters, was not indicative of the potency with which these drugs substituted for cocaine. CONCLUSIONS: The cocaine-like discriminative stimulus of the RTI compounds tested appear to be mediated by the DAT, however the extent to which the NET is involved remains unclear. Additionally, several of the RTI compounds had properties consistent with those thought desirable in a pharmacotherapeutic for cocaine dependence.
RATIONALE: Cocaine dependence is a major health concern and there are no effective pharmacotherapies currently available. Although cocaine is an indirect DA agonist that binds to all three monoamine transporters, there is much evidence implicating a greater role for the dopamine (DAT) than norepinephrine (NET) and serotonin (SERT) transporters in the behavioral effects of cocaine. As such, several groups have developed compounds that exhibit high affinity and selectivity for the DAT. OBJECTIVE: The present investigation examined the cocaine-like discriminative stimulus effects in rats of novel cocaine analogs (RTI 12, 13, 15) and 3-phenyltropane analogs (RTI 111, 112, 113, 114, 117 120, 121, 123, 134 and 152) of which several exhibit high affinity (e.g., <7 nM) and selectivity for the DAT. RESULTS: During dose-effect testing all drugs produced 75-100% cocaine-lever responding. Analyses indicated that the potency of the compounds to produce cocaine-like discriminative stimulus effects was correlated with their affinity for the DAT and the NET but not SERT. Due to the extremely large concentrations (e.g., 10,000-31,024 nM) needed to occupy the NET in vitro, it is doubtful if the doses administered had meaningful NET activity. The selectivity at the DAT, relative to the other transporters, was not indicative of the potency with which these drugs substituted for cocaine. CONCLUSIONS: The cocaine-like discriminative stimulus of the RTI compounds tested appear to be mediated by the DAT, however the extent to which the NET is involved remains unclear. Additionally, several of the RTI compounds had properties consistent with those thought desirable in a pharmacotherapeutic for cocaine dependence.
Authors: Brenda M Gannon; Adrian Williamson; Masaki Suzuki; Kenner C Rice; William E Fantegrossi Journal: J Pharmacol Exp Ther Date: 2016-01-14 Impact factor: 4.030