Abstract
Experimental evaluation of Wikler’s interoceptive conditioning hypothesis of relapse to opioid use in ex-addicts requires a preliminary study of the degree of physical dependence produced by two methods of drug administration. Wistar rats were made physically dependent on morphine by single daily intravenous injections or by a continuous i.v. infusion. Rats received the same total daily dose regardless of administration schedule. The initial daily morphine dose was 20 mg/kg, and was increased every fourth day by 20 mg/kg, until a dose of 200 mg/kg per day was reached. The rats were maintained at the highest dose level for 18 days, at which time morphine was discontinued. Body weight and water intake were the primary variables measured during addiction, maintenance, and abstinence phases of the study. Equivalent and parallel changes in mean weight and water intake in injection and infusion rats indicate equivalent degrees of physical dependence were developed. This finding allows separation of the contribution of conditioning factors and of protracted abstinence in facilitating opioid self-administration in formerly-dependent organisms.
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References
Akera, T. and Brody, T. M.: The addiction cycle to narcotics in the rat and its relation to catecholamines. Biochem. Pharmacol.17, 675–688, 1968.
Andersson, B. and Larsson, B.: Influence of local temperature changes in the preoptic area and rostral hypothalamus on the regulation of food and water intake. Acta Physiol. Scand.52, 75–89, 1961.
Bhargava, H. N.: Rapid induction and quantitation of morphine dependence in the rat by pellet implantation. Psychopharmacology52, 55–62, 1977.
Giantusos, G., Drawbaugh, R., Hynes, M. and Lal, H.: The narcotic withdrawal syndrome in the rat.In Ehrenpreis, S. and Neidle, A. (eds.): Methods of Narcotic Research. New York, Marcel Dekker, 1975, pp. 293–309.
Gibaldi, M. and Perrier, D.: Pharmacokinetics. New York, Marcel Dekker, 1975.
Goode, P. G.: An implanted reservoir of morphine solution for rapid induction of physical dependence in rats. Br. J. Pharmacol.41, 558–566, 1971.
Hosoya, E.: Screening of dependence liability of drugs using rats.In Ehrenpreis, S. and Neidle, A. (eds.): Methods in Narcotic Research. New York, Marcel Dekker, 1975 (pp. 261–291).
Jones, B. E. and Prada, J. A.: Relapse to morphine use in dog. Psychopharmacologia30, 1–12, 1973.
Jones, B. E. and Prada, J. A.: Drug-seeking behavior in the dog: lack of effect of prior passive dependence on morphine. Drug Alcohol Depend.2, 287–294, 1977.
Kumar, R. and Stolerman, I. P.: Resumption of morphine self-administration by ex-addict rats: an attempt to modify tendencies to relapse. J. Comp. Physiol. Psychol.78, 457–465, 1972.
Lorenzetti, D.J. and Sancilio, L. F.: Morphine dependent rats as a model for evaluating potential addiction liability of analgesic compounds. Arch. Int. Pharmacodyn. Ther.183, 391–402, 1970.
Martin, W. R.: Pathophysiology of narcotic addiction: possible roles of protracted abstinence in relapse.In Zarafonetis, C. J. D. (ed.): Drug Abuse, Proceedings of the International Conference. Philadelphia, Lea and Febiger, 1972 (pp. 153–159).
Martin, W. R. and Sloan, J. W.: The pathophysiology of morphine dependence and its treatment with opioid antagonists. Pharmacopsychiat. Neuropsychopharmacol.1, 260–270, 1968.
Martin, W. R., Wikler, A., Eades, C. G. and Pescor, F. T.: Tolerance to and physical dependence on morphine in rats. Psychopharmacologia4, 247–260, 1963.
Miller, D., Dougherty, J. A. and Wikler, A.: Interoceptive conditioning through repeated suppression of morphine abstinence. II. Relapse-testing. Pavlov. J. Biol. Sci.14, 170, 1979.
Moreton, J. E., Young, G., Meltzer, L. and Khazan, N.: The effects of subcutaneous pellets on relapse to morphine self-administration in post-addict rats. Res. Comm. Chem. Pathol. Pharmacol.11, 209–219, 1975.
Mushlin, B. E., Grell, R. and Cochin, J.: Studies on tolerance. I. The role of the interval between doses on the development of tolerance to morphine. J. Pharmacol. Exp. Ther.196, 280–287, 1976.
Nakamura, H., Ishii, K. and Shimizu, M.: Some altered responses in rats formerly dependent on morphine. Psychopharmacology56, 269–277, 1978.
Nichols, J. R., Headlee, Cp. P. and Coppock, H. W.: Drug addiction. I. Addiction by escape training. J. Am. Pharmaceut. Assoc. (Sci. ed.)45, 788–791, 1956.
Pickens, R. and Dougherty, J.: A method for chronic intravenous infusion of fluids in unrestrained rats. Report No. PR-72-1, Research Laboratories of the Department of Psychiatry, University of Minnesota, Minneapolis, 1972.
Siegel, P. S. and Stuckey, H. L.: The diurnal course of water and food intake in the normal mature rat. J. Comp. Physiol. Psychol.40, 365–370, 1947.
Siegel, S.: Nonparametric Statistics. New York, McGraw-Hill, 1956.
Teiger, D. G.: Induction of physical dependence on morphine, codeine and meperidine in the rat by continuous infusion. J. Pharmacol. Exp. Ther.190, 408–415, 1974.
Thompson, T. and Ostlund, W.: Susceptibility to re-addiction as a function of the addiction and withdrawal environment. J. Comp. Physiol. Psychol.59, 388–392, 1965.
Wei, E., Loh, H. H. and Way, E. L.: Quantitative aspects of precipitated abstinence in morphinedependent rats. J. Pharmacol. Exp. Ther.184, 398–403, 1973.
Wikler, A.: Recent progress in research on the neurophysiological basis of morphine addiction. Am. J. Psychiat.105, 329–338, 1948.
Wikler, A.: On the nature of addiction and habituation. Br. J. Addict.57, 73–80, 1961.
Wikler, A.: Conditioning factors in opiate addiction and relapse.In Wilner, D. I. and Kassebaum, G.G. (eds). Narcotics. New York, McGraw-Hill, 1965 (pp. 85–100).
Wikler, A., Green, P. C., Smith, H. D. and Pescor, F. T.: Use of a dilute aqueous solution (5 mcg/ml) of a benzimidazole derivative with potent morphine-like actions orally as a presumptive reinforcing agent in conditioning of drug-seeking behavior in the rat. Fed. Proc.19, 22, 1960.
Wikler, A., Martin, W. R., Pescor, F. T. and Eades, C. G.: Factors regulating oral consumption of an opioid (etonitazene) by morphine-addicted rats. Psychopharmacologia5, 55–70, 1963.
Wikler, A. and Pescor, F. T.: Classical conditioning of a morphine-abstinence phenomenon, reinforcement of opioid-drinking behavior and “relapse” in morphine-addicted rats. Psychopharmacologia10, 255–284, 1967.
Wikler, A. and Pescor, F. T.: Persistence of “relapsetendencies” of rats previously made physically dependent on morphine. Psychopharmacologia16, 375–384, 1970.
Wikler, A., Pescor, F. T., Miller, D. and Norrell, H.: Persistent potency of a secondary (conditioned) reinforcer following withdrawal of morphine from physically dependent rats. Psychopharmacologia20, 103–117, 1971.
Wikler, A., Norrell, H. and Miller, D.: Limbic system and opioid addiction in the rat. Exp. Neurol.34, 543–547, 1972.
Winter, C. A.: Measurement of an analgesic effect: the tail-flick method.In Minutes of the 12th Meeting, Committee on Drug Addiction and Narcotics, NASNRC, Boston, Massachusetts, Nov. 6–7, 1953 (Appendix A, pp. 577–591).
Youth, R. A., Simmerman, R., Newell, R. and King, R. A.: Ketamine anesthesia for rats. Physiol. Behav.10, 633–636, 1973.
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This research was supported by the Medical Research Service of the Veterans Administration and by N.I.D.A. Grant No. DA-01131, awarded to A. Wikler.
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Dougherty, J.A., Miller, D.B. & Wikler, A. Interoceptive conditioning through repeated suppression of morphine-abstinence. Pav. J. Biol. Sci.. 14, 160–169 (1979). https://doi.org/10.1007/BF03001977
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DOI: https://doi.org/10.1007/BF03001977