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Research ArticleArticle

Chronic l-Alpha Acetylmethadol in Rhesus Monkeys: Discriminative Stimulus and Other Behavioral Measures of Dependence and Withdrawal

Michael R. Brandt and Charles P. France
Journal of Pharmacology and Experimental Therapeutics December 1998, 287 (3) 1029-1037;
Michael R. Brandt
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Charles P. France
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Abstract

This study characterized discriminative stimulus and other effects of naltrexone in rhesus monkeys treated daily with the long-acting opioidl-alpha acetylmethadol (LAAM). An initial dose-finding study assessed the rate-decreasing effects of naltrexone in three monkeys receiving LAAM daily (0.32–1.78 mg/kg); subsequently, these monkeys and a fourth received 1.0 mg/kg/12 hr of LAAM although discriminating between naltrexone and saline. Responding occurred on the saline lever after the administration of LAAM, whereas >90% drug-lever responding occurred after the administration of 0.1 mg/kg of naltrexone that also elicited signs of withdrawal. Naloxone and quadazocine, but not morphine, nalbuphine or ketamine, substituted for naltrexone. Morphine and nalbuphine shifted the naltrexone dose-effect curve to the right. Compared to precipitated withdrawal, deprivation-induced withdrawal occasioned less naltrexone-lever responding and fewer observable signs of withdrawal. Maximal naltrexone-level responding occurred 24 to 48 hr after the discontinuation of LAAM treatment; the frequency of other withdrawal signs also peaked 24 to 48 hr after the discontinuation of LAAM. Partial naltrexone-lever responding occurred for up to 10 days after discontinuation of LAAM treatment; 4 and 8 days after the discontinuation of LAAM treatment, 0.1 mg/kg of naltrexone did no further increase naltrexone-lever responding or withdrawal signs suggesting that less-then-maximal naltrexone-lever responding was not due to long-lasting effects of LAAM or its metabolites. The discriminative stimuli that are associated with LAAM deprivation might be different from the stimuli associated with either training condition. This study is the first antagonist discrimination in non-humans primates treated chronically with LAAM and the results indicate that the naltrexone stimulus is related to opioid withdrawal.

Footnotes

  • Send reprint requests to: Charles P. France, Department of Pharmacology and Experimental Therapeutics, Louisiana State University Medical Center, 1901 Perdido Street, New Orleans, LA 70112-1393.

  • ↵1 This work was supported by United States Public Health Service Grant DA05018. C.P.F. is the recipient of a Research Scientist Development Award (DA00211). Animals used in these studies were maintained in accordance with the Institutional Animal Care and Use Committee, Louisiana State University Medical Center, and guidelines of the Committee on Care and Use of Laboratory Animal Resources, National Research Council (Department of Health, Education and Welfare, Publication No. (NIH) 85-23, revised 1983).

  • Abbreviations:
    % DR
    percent drug responding
    FR
    fixed ratio
    LAAM
    l-alpha acetylmethadol
    nor-LAAM
    l-alpha acetylnormethadol
    dinor-LAAM
    l-alphaacetyldinormethadol
    • Received January 14, 1998.
    • Accepted July 13, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 3
1 Dec 1998
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Research ArticleArticle

Chronic l-Alpha Acetylmethadol in Rhesus Monkeys: Discriminative Stimulus and Other Behavioral Measures of Dependence and Withdrawal

Michael R. Brandt and Charles P. France
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 1029-1037;

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Research ArticleArticle

Chronic l-Alpha Acetylmethadol in Rhesus Monkeys: Discriminative Stimulus and Other Behavioral Measures of Dependence and Withdrawal

Michael R. Brandt and Charles P. France
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 1029-1037;
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