, Volume 10, Issue 3, pp 255–284 | Cite as

Classical conditioning of a morphine abstinence phenomenon, reinforcement of opioid-drinking behavior and “relapse” in morphine-addicted rats

  • Abraham Wikler
  • Frank T. Pescor
Original Investigations


  1. 1.

    For 6-week periods in two studies, rats made tolerant to and maintained on intraperitoneal injection of morphine (200 mg/kg) once daily in the morning resided on alternate nights in one end of a 3-compartment linear maze with water for drinking and on the intervening nights in the other end-compartment with etonitazene (10 meg/ml) for drinking. On this schedule, temporal contiguity was provided between the unrelieved nocturnal “primary” morphine abstinence syndrome (including elevated frequency of “wet dog” shakes) and the specific environment of the water-end of the linear maze, while in the other end, opportunity was provided for reinforcement of etonitazene-drinking through reduction of the nocturnal “primary” morphine abstinence syndrome. Saline-injected normal rats were trained identically except that the concentration of etonitazene was 5 meg/ml. In one study, the etonitazene solution was tagged with anise-flavor while in the other study, tactile-visual cues were used. Also, other morphine-tolerant and normal rats were maintained on intraperitoneal injections of morphine (200mg/ kg) or saline respectively once each morning for 6 weeks in home cages without any training.

  2. 2.

    At the end of the 6-week periods, all injections were terminated and all rats in linear mazes were transferred to home cages. On test days at intervals of one or more weeks thereafter, the previously morphine-injected rats exhibited higher “wet dog” shake frequencies in their former “abstinence places” (linear maze or home cage) over periods of 155 and 44 days after termination of injections in the two studies, while conditions of previous housing were not systematically related to “wet dog” shake frequencies in the previously saline-injected normal rats.

  3. 3.

    In “free choice” tests (etonitazene, 5 meg/kg, versus water) conducted on the nights of the same test days, the previously morphine-injected rats (both studies) drank more of the etonitazene solution than the previously saline-injected normal rats up to 58 days after termination of injections in one study and 44 days in the other, but “trained” and “untrained” previously morphine-injected rats did not differ significantly from each other in this regard.

  4. 4.

    It is concluded that although classical conditioning of morphine-abstinence phenomena (and by inference, “craving” for the drug) is demonstrable, the pre-potent factor in disposing to relapse, at least in the rat under the experimental conditions described, is the long-term persistence of unconditioned disturbances in homeostasis following with-drawal of morphine which can provide a source of reinforcement for operant conditioning of opioid-seeking behavior during “relapse-testing” sessions even without benefit of previous “training”.



Morphine Intraperitoneal Injection Home Cage Classical Conditioning Operant Conditioning 
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  1. Davis, W. M., and J. R. Nichols: Physical dependence and sustained opiate-directed behavior in the rat. Psychopharmacologia (Berl.) 3, 139–145 (1962).Google Scholar
  2. Edwards, A. L.: Chapter 15 (288–296) in Experimental Design in Psychological Research. New York: Rinehardt and Co. 1957.Google Scholar
  3. Himmelsbach, C. K.: Clinical studies on drug addiction. Physical dependence, withdrawal and recovery. Arch. intern. Med. 69, 766–772 (1942).Google Scholar
  4. Martin, W. R., A. Wikler, C. G. Eades, and F. T. Pescor: Tolerance to and physical dependence on morphine in rats. Psychopharmacologia (Berl.) 4, 247–260 (1963).Google Scholar
  5. Mowrer, O. H.: Chapters 9 (222–274) and 10 (257–317) in Learning Theory and Personality Dynamics. New York: Ronald Press Co. 1950.Google Scholar
  6. Nichols, J. R., C. P. Headlee, and H. W. Coppock: Drug addiction. I. Addiction by escape training. J. Amer. pharm. Ass., sci. Ed. 45, 788–791 (1956).Google Scholar
  7. Siegel, S.: Non-parametric Statistics for the Behavioral Sciences. New York: McGraw-Hill 1956.Google Scholar
  8. Weeks, J. R.: Experimental morphine addiction: Method for automatic intravenous injections in unrestrained rats. Science 138, 143 (1962).PubMedGoogle Scholar
  9. Wilker, A.: Recent progress in research on the neurophysiologic basis of morphine addiction. Amer. J. Psychiat. 105, 329–338 (1948).Google Scholar
  10. —: Psychodynamic study of a patient during experimental self-regulated readdiction to morphine. Psychiat. Quart. 26, 270–293 (1952).PubMedGoogle Scholar
  11. —: Opiate Addiction. Psychological and Neurophysiological Aspects in Relation to clinical problems. Springfield, Ill.: Ch. C. Thomas 1953.Google Scholar
  12. —: Rationale of the diagnosis and treatment of addictions. Conn. med. J. 19, 560–569 (1955).Google Scholar
  13. —: Mechanisms of Action of Opiates and Opiate Antagonists. Pub. Hlth Mgr. No. 52. Washington: U. S. Government Printing Office 1958.Google Scholar
  14. —: On the nature of addiction and habituation. Brit. J. Addict. 57, 73–79 (1961).Google Scholar
  15. —: Conditioning factors in opiate addiction and relapse. Chapter 6 in Narcotics (D. M. Wilner and G. G. Kassebaum, eds.) New York: McGraw-Hill 1965.Google Scholar
  16. —, C. P. Green, H. D. Smith, and F. T. Pescor: Use of a dilute solution (5 meg/ml) of a benzimidazole derivative with potent morphine-like actions orally as a presumptive reinforcing agent in conditioning of drug-seeking behavior in rats. Fed. Proc. 19, 22 (1960).Google Scholar
  17. —, W. R. Martin, F. T. Pescor, and C. G. Eades: Factors regulating oral consumption of an opioid (etonitazene) by morphine-addicted rats. Psychopharmacologia (Berl.) 5, 55–76 (1963).Google Scholar

Copyright information

© Springer-Verlag 1967

Authors and Affiliations

  • Abraham Wikler
    • 1
    • 2
  • Frank T. Pescor
    • 1
    • 2
  1. 1.Department of PsychiatryUniversity of Kentucky Medical CenterLexingtonUSA
  2. 2.NIMH Addiction Research CenterLexingtonUSA

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