From M.A. Bozarth and R.A. Wise (1985). Toxicity associated with long-term intravenous heroin and cocaine self-administration in the rat. Journal of the American Medical Association, 254, 81-83.
Michael A. Bozarth & Roy A. Wise
Studies involving intravenous (IV) drug self-administration in laboratory animals have typically limited access to drug during the experimental session. One reason for this is that early tests of cocaine self-administration with unlimited access resulted in a high subject fatality rate.
While this observation is sufficient to prompt investigators to limit periods of drug access during experimental testing of stimulant drugs, there has not been a systematic comparison of the toxicity of cocaine and heroin during continuous access. The present study reports tests where animals were allowed continuous access to either IV cocaine hydrochloride or heroin hydrochloride for 30 days. The hourly drug intake was measured for each 24-hour period of testing, and observations were made regarding the general health of the animals.
The rats were randomly divided into two groups and placed in standard operant test chambers with food and water available ad libitum. One group of subjects (n = 12) had access to cocaine hydrochloride, 1 mg/kg per infusion, while the other group (n = 11) had access to heroin hydrochloride, 100 m g/kg per infusion. Both drugs were dissolved in a physiological saline containing 0.3% sodium metabisulfite and sterilized by filtration. Each IV catheter was connected to a 50-mL syringe by polyethylene tubing, and a fluid commutator located between the subject and the infusion pump permitted unrestricted movement of the animal during testing. Pressing a lever activated a motor-driven syringe pump that delivered 0.25 mL of drug solution over 10 s. Pressing the lever during the infusion interval had no scheduled effect, but rats could self-administer another infusion of drug immediately after completion of an injection. Testing for drug self-administration continued 24 hours a day for a maximum of 30 days. The hourly drug intake was measured for each rat.
Animals self-administering heroin showed a gradual increase in 24-hour
drug intake during the first two weeks of testing (Fig 1). After this time,
the mean daily intake of heroin remained constant through the remaining
weeks of testing, with no evidence of further learning or tolerance to
the rewarding effects of the drug injections. Rats in the heroin group
tended to take approximately the same number of injections each day and
to distribute their responding evenly throughout the 24 hours of testing.
Body weights of these subjects remained stable during the 30 days of testing.
The group tested for cocaine self-administration demonstrated erratic
patterns of drug intake across days of testing. Many rats would take large
amounts of drug during one 24-hour period and much less during the next
period (Fig 2). The episodic pattern of responding developed early and
continued throughout the 30 days of testing. Cocaine self-administration
was associated with a reduction in body weight (mean loss, 29%), and several
animals lost about 40% of their pretesting body weight. Grooming behavior
diminished over days of testing, and there was an obvious deterioration
in the animals general health. Several animals displayed full, clonicotonic
seizures during testing but would reinitiate drug self-administration as
soon as the convulsions subsided. The pattern of drug self-administration
and the behavioral effects of chronic intake have been reported in detail
One of the most striking differences in the effects of continuous drug access in animals self-administering cocaine or heroin was the mortality rate (Fig 3). By the end of the second week of testing, 60% of the subjects self-administering cocaine had died, while only 9% of those self-administering heroin had died (c 2 = 37.7, p < .005). At the completion of the 30-day test protocol, the mortality rate for the cocaine group was 90% and the mortality rate for the heroin group was 36% (c 2 = 23.1, p < .005). Animals in the heroin group surviving the full 30 days of testing were still in good health, while the surviving animal in the cocaine group showed marked deterioration (e.g., 32% weight loss).
Figure 3: Cumulative number of fatalities from intravenous cocaine hydrochloride and heroin hydrochloride self- administration during unlimited access to drug. Percentage of animals lost are depicted as function of days of continuous testing. Subject attrition due to catheter failure is not shown. Solid circles indicate deaths in cocaine group; solid squares, deaths in heroin group.
Cocaine self-administration was accompanied by a substantially higher incidence of mortality than was heroin self-administration. This is reflected both by the number of days necessary to produce a 50% mortality rate and by the number of animals surviving the 30-day testing protocol. Rats terminally deprived of food have been reported to die after a loss of about 40% of their pretreatment body weight. In the present study, 56% of the subjects responding for cocaine died after a loss of less than 30% of their pretesting body weight. This suggests that the mortality associated with long-term cocaine use was not merely the result of a reduction of body weight; the high mortality rate is likely to be related to other factors, possibly the toxic effects of cocaine and its depression of medullary function.
The fact that the number of fatalities following unlimited access to cocaine was over twice that following unlimited access to heroin has obvious implications for human drug abuse. While many drug users recognize the inherent danger of opiate addiction, they fail to recognize the potential danger of long-term cocaine use. The facts that cocaine is usually not available to humans in unlimited quantities and that the available cocaine tends to be of low purity probably account for the relatively few deaths associated with its use. As the intake of cocaine increases and the concentration of this compound becomes greater (through the availability of higher-purity drug, by IV injections, or by "free-basing") the number of fatalities associated with cocaine abuse is likely to increase.
This research was supported in part by grants from the Medical Research Council (Canada) and by the National Institute on Drug Abuse. The technical assistance of Aileen Murray is gratefully acknowledged. Dr. Bozarth is a University Research Fellow sponsored by the Natural Sciences and Engineering Research Council of Canada.
1. Abelson PH: Death from heroin. Science 1970;168:1289.
2. Jaffe JH: Drug addiction and drug use, in Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics. New York, Macmillan Publishing Co Inc, 1975, pp 284-324.
3. Finkle BS, McCloskey KL: The forensic toxicology of cocaine, in Petersen RC, Stillamn RC (eds): Cocaine: 1977. Washington, DC, National Institute on Drug Abuse, 1977, pp 153-178.
4. Adams EH, Durell, J: Cocaine: A growing public health problem, in Grabowski J (ed): Cocaine: Pharmacology, Effects, and Treatment of Abuse. Washington, DC, National Institute on Drug Abuse, 1984, pp 9-14.
5. Deneau GW, Yanagita T, Seevers MH: Self-administration of psychoactive substances by the monkey: A measure of psychological dependence. Psychopharmacology 1969;16:30-48.
6. Johanson CE, Balster RL, Bonese K: Self-administration of psychomotor stimulant drugs: The effects of unlimited access. Pharmacol Biochem Behav 1976;4:45-51.
7. Pickens R, Thompson T: Characteristics of stimulant reinforcement, in Thompson T, Pickens R (eds): Stimulus Properties of Drugs. New York, Appleton-Century-Crofts, 1971, pp 177-192.
8. Campbell BA, Teghtsoonian R, Williams RA: Activity, weight loss, and survival time of food-deprived rats as a function of age. J Comp Physiol Psychol 1961;54:216-219.
9. Ritchie JM, Cohen PJ: Local anesthetics, in Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics. New York, Macmillan Publishing Co Inc, 1975, pp 379-403.
10. Evans Ma, Dwivedi C, Harbison RD: Enhancement of cocaine-induced lethality by phenobarbital, in Ellinwood EH, Kilbey MM (eds): Cocaine and Other Stimulants. New York, Plenum Press, 1977, pp 253-267.
©1985 American Medical Association