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SCIENCE, VOL. 216, 23 APRIL 1982
437

tion of the contribution of contextual stimuli to tolerance (10, 15).

Opiate-inexperienced male rats (Wistar-derived, 90 to 110 days old) with permanent jugular cannulas (16) were intravenously injected with diacetylmorphine hydrochloride (heroin) 15 times, one injection every other day. The dose was increased according to the following schedule: first injection, 1 mg/kg; second and third injections, 2 mg/kg; fourth through seventh injections, 4 mg/kg; and eighth through fifteenth injections, 8 mg/kg. Each rat also received on volumetrically equated injection of the vehicle (5 percent dextrose solution) on days when it was not injected with heroin.

The injections were given in two different environments. One was the colony, where the rats were individually housed. The animal was removed from its cage, injected, and returned to its cage. The other environment was a different room with constant white noise (60 dB SPL). Rats were injected 15 minutes after being transferred to this room and were kept there for an additional 2 hours. One group of rats received heroin in the distinctive room and dextrose in the colony; a second group received heroin in the colony and dextrose in the distinctive room. Finally, the subjects in each group were placed in one of the two environments and injected with 15 mg of heroin per kilogram. This procedure permitted evaluation of the effects of a high dose of heroin in the context of cues that had previously signaled lower doses of the drug [similary tested (ST) rats] and in the context of cues not previously associated with the drug [differently tested (DT) rats]. It should be emphasized that, throughout the study, both experimental groups were injected an equal number of times with the same doses of heroin at the same intervals between injections [results obtained from the two counterbalanced conditions were not significantly different (17)]. A third group received 30 daily injections of dextrose in each of the two environments on an alternating schedule and then an injection of heroin (15 mg/kg) in one of the two environments. Thus the control rats had no experience with the opiate before the final session.

Chi-square analysis indicates that mortality differed significantly among groups (P [???] .001) (18). Both groups with pretest experience with sublethal doses of heroin were more likely to survive the highest dose than control animals (P [???] .002), suggesting that tolerance resulted from the sublethal heroin injection associated with those injections. However, mortality was significantly higher in DT than in ST rats (P [???] .001), indicating that identical pretest pharmacological histories do not necessarily result in the display of equivalent tolerance to the lethal effect of heroin. The experiment was conducted in six replications (three involving testing in each of the two environments), and in every replication a greater proportion of DT than ST rats died (P [???] .02, binomial test). The combined results for all replications are summarized in Table 1.

In conclusion, groups of rats with the same pharmacological history of heroin administration can differ in mortality following administration of a high dose of the drug: rats that received the potentially lethal dose in the context of cues previously associated with sublethal doses were more likely to survive than animals that received teh dose in the context of cues not previously associated with the drug.

Shepard Siegel
Department of Psychology,
McMaster University,
Hamilton, Ontario L8S 4K1, Canada

Riley E. Hinson
Department of Psychology,
University of Western Ontario,
London, Ontario N6A 5C2

Marvin D. Krank
Jane McCully
Department of Psychology,
McMaster University

References and Notes
1. C. C. Hug, in Chemical and Biological Aspects of Drug Dependence, S. J. Mule and H. Brill, Eds. (CRC Press, Cleveland, 1972), pp. 307-358.
2. D. B. Louria, T. Hensle, J. Rose, Ann. Intern. Med. 67, 1 (1967); P. Mason, Mt. Sinai Hosp. J. N. Y. 34, 4 (1967); D. W. Maurer and V. H. Vogel, Narcotics and Narcotic Addiction (Thomas, Springfield, Ill., 1973), p. 101.
3. P. H. Abelson, Science 168, 1289 (1970); M. Helpern, Hum. Pathol. 3, 13 (1972).
4. J. H. Jaffe and W. R. Martin, in The Pharmacological Basis of Therapeutics, A. G. Gilman, L. S. Goodman, A. Gilman, Eds. (Macmillan, New York, ed. 6, 1980), pp. 494-534.
5. J. L. Duberstein and D. M. Kaufman, Am. J. Med. 51, 704 (1971).
6. D. W. Fraser, J. Am. Med. Assoc. 217, 1387 (1971); J. C. Garriott and W. Q. Sturner, N. Engl. J. Med. 289 1276 (1973); D. H. Huber, J. Am. Med. Assoc. 229, 689 (1974).
7. E. M. Brecher, Licit and Illicit Drugs (Little, Brown, Boston, 1972), pp. 101-114; T. Reed, Int. J. Addict. 15, 359 (1980).
8. Final Report of the Commission of Inquiry into the Non-Medical Use of Drugs (Information Canada, Ottawa, 1973), pp. 310-315.
9. A. B. Light and E. B. Torrance, Arch. Intern. Med. 44, 1 (1929).
10. S. Siegel, in Psychopathology in Animals: Research and Clinical Applications, J. D. Keehn, Ed. (Academic Press, New York, 1979), pp. 143-168; Fed. Pro. Fed Am. soc. Exp. Biol., in press; in Research Advances in Alcohol and Drug Problems, Y. Israel et al., Eds. (Plenum, New York, in press).
11. I. P. Pavlov, Conditioned Reflexes (Oxford Univ. Press, London, 1927), pp. 35-37.
12. F. Obal, Acta Physiol. Acad. Sci. Hung. 30, 15 (1966); A. Wikler, Cond. Reflex 8, 193 (1973).
13. C. Advokat, Behav. Neural Biol. 29, 385 (1980); R. K. Ferguson and C. L. Mitchell, Clin. Pharmacol. Ther. 10, 372 (1969); G. J. LaHoste, R. D. Olson, G. A. Olson, A. J. Kastin, Pharmacol. Biochem. Behav. 13, 799 (1980); R. F. Mucha, C. Volkovskis, H. Kalant, J. Comp. Physiol. Psychol. 95, 351 (1981); S. Siegel, Science 193, 323 (1976); J. Comp. Physiol. Psychol. 92, 1137 (1978); S. T. Tiffany and T. B. Baker, J. Comp. Physiol. Psychol. 95, 747 (1981).
14. S. Siegel, R. E. Hinson, M. D. Krank, Behav. Neural Biol. 25, 257 (1979).
15. R. L. Hayes and D. J. Mayer, Science 200, 343 (1978).
16. The cannula was a modified version of that described by R. J. Brown and C. B. Breckenridge [Biochem. Med. 13, 280 (1975)]. Subjects were cannulated 1 week before the experiment. The rate of injection was controlled by infusing the injected substance at a rate of 0.005 ml/sec through the intravenous cannula with a Harvard model 902 infusion pump. The concentration of heroin (in sterile 5 percent dextrose) was 3.125, 6.250, 12.500, 25.000, and 50.000 mg/ml for the doses of 1, 2, 4, 8, and 15 mg/kg, respectively. Thus the duration of the infusion for all rats at all dose levels was equivalent (about 1 min/kg).
17. Of the 37 ST rats, 17 were injected with heroin in the distinctive room and 20 were injected with heroin in the colony. Half of the 42 DT rats were injected with heroin in each of the environments.
18. For subjects that died as a result of the injection of heroin at 15 mg/kg, the median times for the start of the injection until death (as determined by lack of heartbeat) in ST, DT, and control groups were 187, 174, and 164 seconds, respectively. Thus these animals died soon after the start of the lethal injection (differences between groups were insignificant), as is frequently the case of human victims of drug overdose (7, 8).
19. Supported by grants from the Natural Sciences and Engineering Research Council of Canada and the National Institute on Drug Abuse. The assistance of D. Mitchell and W. Stephaniv is gratefully acknowledged.
30 November 1981

Tumor Rejection in Rats After Inescaapable or Escapable Shock

Abstract. Rats experienced inescapable, escapable, or no electric shock 1 day after being implanted with a Walker 256 tumor preparation. Only 27 percent of the rats receiving inescapable shock rejected the tumor, whereas 63 percent of the rats receiving escapable shock and 54 percent of the rats receiving no shock rejected the tumor. These results imply that lack of control over stressors reduces tumor rejection and decrease survival.

Psychological states involving the loss of control, such as helplessness, bereavement, and depression, are associated with an increase incidence of cancer (1). The influence that psychological variables may have on the development and maintenance of malignancies is difficult to determine from correlational studies of humans: the psychological states may have preceded cancer onset, resulted from it, or occurred at the same time. Therefore, animal studies in which psy-