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Research ArticleBehavioral Pharmacology

Preclinical Efficacy of N-Substituted Benztropine Analogs as Antagonists of Methamphetamine Self-Administration in Rats

Takato Hiranita, Stephen J. Kohut, Paul L. Soto, Gianluigi Tanda, Theresa A. Kopajtic and Jonathan L. Katz
Journal of Pharmacology and Experimental Therapeutics January 2014, 348 (1) 174-191; DOI: https://doi.org/10.1124/jpet.113.208264
Takato Hiranita
Psychobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (T.H., S.J.K., G.T., T.A.K., J.L.K.); Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.L.S.)
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Stephen J. Kohut
Psychobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (T.H., S.J.K., G.T., T.A.K., J.L.K.); Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.L.S.)
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Paul L. Soto
Psychobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (T.H., S.J.K., G.T., T.A.K., J.L.K.); Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.L.S.)
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Gianluigi Tanda
Psychobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (T.H., S.J.K., G.T., T.A.K., J.L.K.); Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.L.S.)
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Theresa A. Kopajtic
Psychobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (T.H., S.J.K., G.T., T.A.K., J.L.K.); Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.L.S.)
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Jonathan L. Katz
Psychobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (T.H., S.J.K., G.T., T.A.K., J.L.K.); Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.L.S.)
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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.

Footnotes

    • Received July 23, 2013.
    • Accepted November 4, 2013.
  • ↵1 Current affiliation: Division of Neurotoxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas.

  • ↵2 Current affiliation: Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts.

  • ↵3 Current affiliation: College of Education, Texas Tech University, Lubbock, Texas.

  • This work was supported by the Intramural Research Program of the National Institutes of Health National Institute on Drug Abuse.

  • Portions of this work were presented as follows: Hiranita T, Soto PL, Tand G, and Katz JL (2013) Specificity of cocaine-induced dopamine-independent sigma agonist self-administration. Experimental Biology annual meeting; 2013 Apr 20–24; Boston, MA; and Hiranita T, Soto PL, Tanda G, Newman AH, and Katz JL (2013) Abuse liability assessment and preclinical indicators of N-substituted benztropine (BZT) analogs as medications for stimulant abuse; Katz JL, Zou MF, Kopajtic TA, Soto PL, Lupica CR, Newman AH, and Hiranita T (2013) Abuse liability and potential of 3-substituted phenyltropane dopamine uptake inhibitors as medications for cocaine abuse. Neuroscience Annual Meeting; 2013 Nov 9–13; San Diego, CA. Society for Neuroscience, Washington, D.C.

  • dx.doi.org/10.1124/jpet.113.208264.

  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 348 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 348, Issue 1
1 Jan 2014
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Research ArticleBehavioral Pharmacology

Benztropine Analogs as Methamphetamine Antagonists

Takato Hiranita, Stephen J. Kohut, Paul L. Soto, Gianluigi Tanda, Theresa A. Kopajtic and Jonathan L. Katz
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 174-191; DOI: https://doi.org/10.1124/jpet.113.208264

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Research ArticleBehavioral Pharmacology

Benztropine Analogs as Methamphetamine Antagonists

Takato Hiranita, Stephen J. Kohut, Paul L. Soto, Gianluigi Tanda, Theresa A. Kopajtic and Jonathan L. Katz
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 174-191; DOI: https://doi.org/10.1124/jpet.113.208264
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