title: Effects of phendimetrazine treatment on cocaine vs food choice and extended-access cocaine consumption in rhesus monkeys.
abstract: There is currently no Food and Drug Administration-approved pharmacotherapy for cocaine addiction. Monoamine releasers such as d-amphetamine constitute one class of candidate medications, but clinical use and acceptance are hindered by their own high-abuse liability. Phendimetrazine (PDM) is a schedule III anorectic agent that functions as both a low-potency monoamine-uptake inhibitor and as a prodrug for the monoamine-releaser phenmetrazine (PM), and it may serve as a clinically available, effective, and safer alternative to d-amphetamine. This study determined efficacy of chronic PDM to reduce cocaine self-administration by rhesus monkeys (N=4) using a novel procedure that featured both daily assessments of cocaine vs food choice (to assess medication efficacy to reallocate behavior away from cocaine choice and toward choice of an alternative reinforcer) and 20 h/day cocaine access (to allow high-cocaine intake). Continuous 21-day treatment with ramping PDM doses (days 1-7: 0.32 mg/kg/h; days 8-21: 1.0 mg/kg/h) reduced cocaine choices, increased food choices, and nearly eliminated extended-access cocaine self-administration without affecting body weight. There was a trend for plasma PDM and PM levels to correlate with efficacy to decrease cocaine choice such that the monkey with the highest plasma PDM and PM levels also demonstrated the greatest reductions in cocaine choice. These results support further consideration of PDM as a candidate anti-cocaine addiction pharmacotherapy. Moreover, PDM may represent a novel pharmacotherapeutic approach for cocaine addiction because it may simultaneously function as both a monoamine-uptake inhibitor (via the parent drug PDM) and as a monoamine releaser (via the active metabolite PM).
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA. mbanks7.vcu.edu|Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Matthew L
authors.identifier: 0000-0003-4949-5246
authors.initials: ML
authors.lastname: Banks
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute International, Research Triangle Park, NC, USA
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
authors.affiliation: Department of Pharmacology and Toxicology, Research Triangle Institute International, Research Triangle Park, NC, USA
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Fennell
authors.affiliation: Department of Pharmacology and Toxicology, Research Triangle Institute International, Research Triangle Park, NC, USA
authors.forename: Rodney W
authors.initials: RW
authors.lastname: Snyder
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.|Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA
authors.forename: S Stevens
authors.initials: SS
authors.lastname: Negus
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000697:Central Nervous System Stimulants / Q000097:blood / Q000494:pharmacology*; D002755:Choice Behavior / Q000187:drug effects*; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005502:Food; D008253:Macaca mulatta; D008297:Male; D009025:Morpholines / Q000097:blood / Q000494:pharmacology*; D012054:Reinforcement, Psychology; D012646:Self Administration; D013997:Time Factors
chemical_list: D000697:Central Nervous System Stimulants; D018765:Dopamine Uptake Inhibitors; D009025:Morpholines; C100294:phendimetrazine; D003042:Cocaine
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