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Preclinical efficacy of N-substituted benztropine analogs as antagonists of methamphetamine self-administration in rats.

Abstract
Atypical dopamine-uptake inhibitors have low abuse potential and may serve as leads for development of cocaine-abuse treatments. Among them, the benztropine (BZT) derivatives, N-butyl (JHW007), N-allyl (AHN2-005), and N-methyl (AHN1-055) analogs of 3α-[bis(4'-fluorophenyl)methoxy]-tropane dose-dependently decreased cocaine self-administration without effects on food-maintained responding. Our study examined selectivity by assessing their effects on self-administration of other drugs. As with cocaine, each BZT analog (1.0-10.0 mg/kg i.p.) dose-dependently decreased maximal self-administration of d-methamphetamine (0.01-0.32 mg/kg/infusion) but was inactive against heroin (1.0-32.0 µg/kg/infusion) and ketamine (0.032-1.0 mg/kg/infusion) self-administration. Further, standard dopamine indirect-agonists [WIN35,428 ((-)-3β-(4-fluorophenyl)-tropan-2-β-carboxylic acid methyl ester tartrate), d-amphetamine (0.1-1.0 mg/kg i.p., each)] dose-dependently left-shifted self-administration dose-effect curves for d-methamphetamine, heroin, and ketamine. Noncompetitive NMDA-glutamate receptor/channel antagonists [(+)-MK-801 (0.01-0.1 mg/kg i.p.), memantine (1.0-10.0 mg/kg i.p.)] also left-shifted dose-effect curves for d-methamphetamine and ketamine (but not heroin) self-administration. The µ-agonists [dl-methadone and morphine (1.0-10.0 mg/kg i.p., each)] dose-dependently decreased maximal self-administration of µ-agonists (heroin, remifentanil) but not d-methamphetamine or ketamine self-administration. The µ-agonist-induced decreases were similar to the effects of BZT analogs on stimulant self-administration and effects of food prefeeding on responding maintained by food reinforcement. Radioligand-binding and behavioral studies suggested that inhibition of dopamine transporters and σ receptors were critical for blocking stimulant self-administration by BZT-analogs. Thus, the present results suggest that the effects of BZT analogs on stimulant self-administration are similar to effects of µ-agonists on µ-agonist self-administration and food prefeeding on food-reinforced responding, which implicates behavioral mechanisms for these effects and further supports development of atypical dopamine uptake inhibitors as medications for stimulant abuse.
AuthorsTakato Hiranita, Stephen J Kohut, Paul L Soto, Gianluigi Tanda, Theresa A Kopajtic, Jonathan L Katz
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 348 Issue 1 Pg. 174-91 (Jan 2014) ISSN: 1521-0103 [Electronic] United States
PMID24194527 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
Chemical References
  • Benztropine
  • Methamphetamine
Topics
  • Animals
  • Behavior, Addictive (prevention & control, psychology)
  • Benztropine (analogs & derivatives, pharmacology, therapeutic use)
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical (methods)
  • Male
  • Methamphetamine (administration & dosage, antagonists & inhibitors)
  • Rats
  • Rats, Sprague-Dawley
  • Self Administration
  • Treatment Outcome

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