title: Decreases in cocaine self-administration with dual inhibition of the dopamine transporter and σ receptors.
abstract: Sigma receptor (σR) antagonists attenuate many behavioral effects of cocaine but typically not its reinforcing effects in self-administration procedures. However, the σR antagonist rimcazole and its N-propylphenyl analogs, [3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]diphenylamine hydrochloride (SH 3-24) and 9-[3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]carbazole hydrobromide (SH 3-28), dose-dependently decreased the maximal rates of cocaine self-administration without affecting comparable responding maintained by food reinforcement. In contrast, a variety of σR antagonists [N-phenethylpiperidine oxalate (AC927), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide (BD 1008), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine dihydrobromide (BD 1047), N-[2-(3,4-dichlorophenyl) ethyl]-4-methylpiperazine dihydrochloride (BD 1063), and N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100)] had no effect on cocaine self-administration across the range of doses that decreased rates of food-maintained responding. Rimcazole analogs differed from selective σR antagonists in their dual affinities for σRs and the dopamine transporter (DAT) assessed with radioligand binding. Selective DAT inhibitors and σR antagonists were studied alone and in combination on cocaine self-administration to determine whether actions at both σRs and the DAT were sufficient to reproduce the effects of rimcazole analogs. Typical DAT inhibitors [2β-carbomethoxy-3β-(4-fluorophenyl)tropane (WIN 35,428), methylphenidate, and nomifensine] dose-dependently shifted the cocaine dose-effect curve leftward. Combinations of DAT inhibitor and σR antagonist doses that were behaviorally inactive alone decreased cocaine self-administration without effects on food-maintained responding. In addition, whereas the DAT inhibitors were self-administered at rates similar to those of cocaine, neither rimcazole analogs nor typical σR antagonists (NE-100 and AC927) maintained responding above control levels across a wide range of doses. These findings suggest that the unique effects of rimcazole analogs are due to dual actions at the DAT and σRs and that a combined target approach may have utility in development of medical treatments for cocaine abuse.
authors.affiliation: Psychobiology Section, Medications Discovery Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 251 Bayview Blvd., Suite 200, Baltimore, MD 21224, USA.
authors.forename: Takato
authors.initials: T
authors.lastname: Hiranita
authors.forename: Paul L
authors.initials: PL
authors.lastname: Soto
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kohut
authors.forename: Theresa
authors.initials: T
authors.lastname: Kopajtic
authors.forename: Jianjing
authors.initials: J
authors.lastname: Cao
authors.forename: Amy H
authors.initials: AH
authors.lastname: Newman
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Tanda
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Katz
mesh_terms: D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D003042:Cocaine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D003216:Conditioning, Operant / Q000187:drug effects; D050483:Dopamine Plasma Membrane Transport Proteins / Q000032:analysis / Q000037:antagonists & inhibitors*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D058990:Molecular Targeted Therapy; D010070:Oxalates / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011437:Propylamines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000032:analysis / Q000037:antagonists & inhibitors*; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: D000840:Anisoles; D014150:Antipsychotic Agents; D002227:Carbazoles; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; C470324:N-phenethylpiperidine oxalate; D010070:Oxalates; D010880:Piperidines; D011437:Propylamines; D017480:Receptors, sigma; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; C034931:rimcazole; D003042:Cocaine