title: Relations between stimulation of mesolimbic dopamine and place conditioning in rats produced by cocaine or drugs that are tolerant to dopamine transporter conformational change.
abstract: BACKGROUND
  Dopamine transporter (DAT) conformation plays a role in the effectiveness of cocaine-like and other DAT inhibitors. Cocaine-like stimulants are intolerant to DAT conformation changes having decreased potency in cells transfected with DAT constructs that face the cytosol compared to wild-type DAT. In contrast, analogs of benztropine (BZT) are among compounds that are less affected by DAT conformational change.
  
  
  METHODS
  We compared the displacement of radioligand binding to various mammalian CNS sites, acute stimulation of accumbens shell dopamine levels, and place conditioning in rats among cocaine and four BZT analogs with Cl substitutions on the diphenyl-ether system including two with carboalkoxy substitutions at the 2-position of the tropane ring.
  
  
  RESULTS
  Binding assays confirmed high-affinity and selectivity for the DAT with the BZT analogs which also produced significant stimulation of mesolimbic dopamine efflux. Because BZT analogs produced temporal patterns of extracellular dopamine levels different from those by cocaine (3-10 mg/kg, i.p.), the place conditioning produced by BZT analogs and cocaine was compared at doses and times at which both the increase in dopamine levels and rates of increase were similar to those produced by an effective dose of cocaine. Despite this equilibration, none of the BZT analogs tested produced significant place conditioning.
  
  
  CONCLUSIONS
  The present results extend previous findings suggesting that cocaine-like actions are dependent on a binding equilibrium that favors the outward conformational state of the DAT. In contrast, BZT analogs with reduced dependence on DAT conformation have reduced cocaine-like behavioral effects and may prove useful in development of medications for stimulant abuse.
authors.affiliation: Psychobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 251 Bayview Blvd., NIDA suite 200, Baltimore, MD 21224, USA.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Tanda
authors.forename: Su Min
authors.initials: SM
authors.lastname: Li
authors.forename: Maddalena
authors.initials: M
authors.lastname: Mereu
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Thomas
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Ebbs
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Chun
authors.forename: Valeria
authors.initials: V
authors.lastname: Tronci
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Green
authors.forename: Mu-Fa
authors.initials: MF
authors.lastname: Zou
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Kopajtic
authors.forename: Amy Hauck
authors.initials: AH
authors.lastname: Newman
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Katz
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001590:Benztropine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D001590:Benztropine; D003042:Cocaine; D004298:Dopamine