title: Reinforcing strength of a novel dopamine transporter ligand: pharmacodynamic and pharmacokinetic mechanisms.
abstract: Drugs that block dopamine uptake often function as positive reinforcers but can differ along the dimension of strength or effectiveness as a positive reinforcer. The present study was designed to examine pharmacological mechanisms that might contribute to differences in reinforcing strength between the piperidine-based cocaine analog (+)-methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3-alpha-carboxylate [(+)-CPCA] and cocaine. Drugs were made available to rhesus monkeys (n = 5) for i.v. self-administration under a progressive ratio schedule. Both compounds maintained responding with sigmoidal or biphasic dose-response functions (0.1-1.0 mg/kg/injection). (+)-CPCA was one-fourth as potent as cocaine and maintained fewer injections per session, at maximum. For in vitro binding in monkey brain tissue, (+)-CPCA was about one-half as potent as cocaine at the dopamine transporter (DAT), and the two compounds had similar affinities at the norepinephrine transporter. (+)-CPCA was less than 1/10 as potent as cocaine at the serotonin transporter. In ex vivo binding in rat striatum, occupancy of the DAT increased directly with dose to a maximum of approximately 80% for both compounds, and (+)-CPCA was about one-fourth as potent as cocaine. Ex vivo DAT occupancy was significantly higher for cocaine than (+)-CPCA at 2 min after injection but similar at other times. Thus, the primary differences between these compounds were in serotonin transporter affinity and the kinetics of DAT binding. These results suggest that (+)-CPCA is a weaker positive reinforcer than cocaine because it has a slower onset of action over the first few minutes after i.v. injection.
authors.affiliation: Department of Psychiatry, University of Mississippi Medical Center, Jackson 39216, USA. wwoolverton@psychiatry.umsmed.edu
authors.forename: W L
authors.initials: WL
authors.lastname: Woolverton
authors.forename: R
authors.initials: R
authors.lastname: Ranaldi
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: G A
authors.initials: GA
authors.lastname: Ordway
authors.forename: I A
authors.initials: IA
authors.lastname: Paul
authors.forename: P
authors.initials: P
authors.lastname: Petukhov
authors.forename: A
authors.initials: A
authors.lastname: Kozikowski
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D015394:Molecular Structure; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010880:Piperidines / Q000493:pharmacokinetics*; D012646:Self Administration; D027981:Symporters / Q000187:drug effects / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010880:Piperidines; D027981:Symporters; C466798:methyl 4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate; D003042:Cocaine