title: Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys.
abstract: d-Amphetamine selectively promotes release of both dopamine (DA) and norepinephrine (NE) versus serotonin (5HT), and chronic d-amphetamine treatment decreases cocaine-taking behavior in rats, nonhuman primates, and humans. However, abuse liability limits the clinical utility of amphetamine maintenance for treating cocaine abuse. One strategy to improve safety and efficacy of monoamine releasers as candidate anticocaine medications has been to develop dual DA/5HT releasers like 1-napthyl-2-aminopropane (PAL-287), but the pharmacology of this class of compounds has not been extensively examined. In particular, PAL-287 has similar potencies to release DA, 5HT, and NE, and the role of manipulating NE release potency on abuse-related or anticocaine effects of dual DA/5HT releasers is not known. To address this issue, the present study compared effects of four novel DA/5HT releasers that varied >800-fold in their selectivities to release DA/5HT versus NE: [1-(5-chloro-1H-indol-3-yl)propan-2-amine (PAL-542), 1-(5-fluoro-1H-indol-3-yl)propan-2-amine (PAL-544), 1-(1H-indol-5-yl)propan-2-amine (PAL-571), and (R)-1-(1H-indol-1-yl)propain-2-amine (PAL-569). Abuse-related effects of all four compounds were evaluated in assays of intracranial self-stimulation (ICSS) in rats and cocaine discrimination in rats and monkeys, and none of the compounds reliably facilitated ICSS or substituted for cocaine. Anticocaine effects of the compound with highest selectivity to release DA/5HT versus NE (PAL-542) were tested in an assay of cocaine versus food choice in rhesus monkeys, and PAL-542 failed to reduce cocaine choice. These results suggests that potency to release NE has minimal influence on abuse liability of dual DA/5HT releasers, and reducing relative potency to release NE versus DA/5HT does not improve anticocaine efficacy.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA USA.|Institute for Drug and Alcohol Studies, Virginia Commonwealth University.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Banks
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA USA.
authors.forename: Clayton T
authors.initials: CT
authors.lastname: Bauer
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC USA.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
authors.affiliation: Medicinal Chemistry Section, Intramural Research Program, NIDA, Baltimore, MD USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.affiliation: Medicinal Chemistry Section, Intramural Research Program, NIDA, Baltimore, MD USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Partilla
authors.affiliation: Medicinal Chemistry Section, Intramural Research Program, NIDA, Baltimore, MD USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA USA.|Institute for Drug and Alcohol Studies, Virginia Commonwealth University.
authors.forename: S Stevens
authors.initials: SS
authors.lastname: Negus
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008253:Macaca mulatta; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D013045:Species Specificity; D019966:Substance-Related Disorders / Q000378:metabolism* / Q000523:psychology
chemical_list: D012701:Serotonin; D003042:Cocaine; D004298:Dopamine; D009638:Norepinephrine