Repeated cocaine administration can produce behavioral sensitization to the stimulatory effects of cocaine and other psychomotor stimulants (1,2). This phenomenon is most often demonstrated in laboratory animals by increased locomotor activity or stereotypy across days of repeated drug administration. Another effect that may show sensitization following repeated cocaine use involves its toxic effects. Clinical reports have noted considerable variability in the cocaine dose associated with fatalities (3-6), and prior cocaine usage is a factor. The mechanism of this variation has not been identified, but it most likely involves sensitization to the cardiovascular or convulsant effects of cocaine.
Environmental stress can also increase responsiveness to cocaine. Animals that have received stressful electric shock show increased responses to cocaine (7,8). This cross sensitization has led to speculation that stress can augment some of cocaine's effects and perhaps predispose certain individuals to cocaine addiction. The present study investigated the possibility that stress can also augment the toxic effect of cocaine, by exposing animals to a mild stressor following cocaine injections.
Experimentally naive, male, Long-Evans rats (Harlan Sprague-Dawley, Indianapolis, IN), weighing 320 to 375 g at the beginning of the experiment, were individually housed with food and water available ad libitum except during behavioral testing. The vivarium was maintained at 22° ± 1° C during a 14-hr light/10-hr dark illumination cycle with lights on from 0800 to 2200 hrs. Behavioral testing occurred during the light phase of this cycle (i.e., between 1500 and 1800 hrs). Rats were briefly handled twice before beginning the experiment.
All animals received a daily injection of physiological saline (1 ml/kg, i.p.) or cocaine hydrochloride (30 mg/kg, i.p.) for 5 consecutive days. One group of animals was administered saline (n=12) and another group cocaine (n=12) immediately prior to restraint stress. A third group of animals (n=12) received daily cocaine injections and were returned immediately to their home cages without exposure to the stressor. Animals exposed to restraint stress were placed individually into plastic cylinders (7.6 x 20 cm) for 30 min immediately after their injection. At the end of the 30-min period, fatalities were recorded. All fatalities occurred within 30 min of the cocaine injection. Also noted were convulsive seizures and position reversals during this time. This latter measure indicated that confinement in the restraint cylinder did not prohibit all movement of the subject as demonstrated by the rat reversing its position in the cylinder during testing. This is considerably less restrictive than procedures that totally prevent the animal's movement during restraint and might better be described as confinement stress.
Results & Discussion
The figure shows the cumulative percentage of fatalities across 5 consecutive days of testing. By the third day 50% of the animals in the cocaine-plus-restraint group had died, while only 8% of the animals receiving cocaine and returned to their home cages had died. At the end of the 5-day injection series, 58% of the cocaine-plus-restraint group died, while 17% of the cocaine-only group died. None of the animals in the saline-plus-restraint group died or appeared to have seizures. Most fatalities were preceded by strong convulsive seizures beginning only seconds after the subjects were placed into the cylinders. About half of the fatalities occurred within a few minutes of the cocaine injection, while other fatalities occurred 15 to 20 min post injection with subjects showing intermittent convulsions until death. A few cocaine-plus-restraint subjects had seizures but survived the 5-day testing protocol.
Animals in the saline-plus-restraint group typically reversed their positions in the cylinder one or more times during the 30-min period (e.g., 92% reversed their positions on Day-1); animals in the cocaine-plus-restraint group seldom reversed their positions (e.g., 83% remained in the starting orientation on Day-1). Strong stereotypical head rotations were seen in the cocaine-plus-restraint group, while no stereotypic behaviors were observed in the saline-plus-restraint group. The two animals in the cocaine-only group that died had convulsive seizures within several minutes of the cocaine injection after being returned directly to their home cages.
The cocaine-plus-restraint group had three times as many fatalities as the cocaine-only group. The mechanism responsible for the increased cocaine fatalities was not identified in the present study. One possible mechanism involves the cross sensitization reported between stress and cocaine, and it is possible that a similar mechanism is operative for cocaine's toxic effect. The fact that 25% of the subjects died during the first exposure to cocaine (compared to none of the subjects in the cocaine-only group) appears to suggest an acute stress-cocaine interaction is involved. Stress-induced sensitization could have occurred during delivery from the animal supplier or during the brief handling after arrival. (The rats used in this study had no prior contact with humans [i.e., all equipment used for feeding, watering, and bedding changes is automated at the breeding facility; Harlan Sprague-Dawley, personal communication], and some subjects were particularly difficult to handle during the early phase of the experiment.) The additional fatalities seen across the 5 days of testing are probably related to sensitization (see 9). Another possible factor may involve the neuroendocrinological effects produced both by cocaine and by stress. Corticosterone (10,11) and other hormones may potentiate some psychomotor stimulants effects. Whatever the mechanism, the finding that stress increases cocaine-related fatalities has important implications for the clinical management of cocaine overdose. This finding suggests that restraint during cocaine-induced seizures or motor agitation is strongly contraindicated, and it further suggests that minimizing stress may increase the survival rate following cocaine overdose. It is likely that minimizing other sources of stress may be important in decreasing toxic reactions to cocaine use.
This research was supported by grants from the National Institute on Drug Abuse (DA02285, M.A.B.) and from the Mark Diamond Fund (C.M.P.).
1. R.M. POST and H. ROSE, Nature 260 731-732 (1976).
2. J.S. STRIPLING and E.H. ELLINWOOD, Cocaine and Other Stimulants, E.H. Ellinwood and M.M. Kilbey (eds), 131-167, Raven, New York (1977).
3. J.M. ISNER, N.A. ESTES, P.D. THOMPSON, M.R. COSTANZO-NORDIN, R. SUBRAMANIAN, G. MILLER, G. KATSAS, K. SWEENEY, and W.Q. STURNER, New Eng. J. Med. 315 1438-1441 (1986).
4. J.N. ROGERS, T.E. HENRY, A.M. JONES, R.C. FROEDE, and J.M. BYERS, J. For. Sci. 31 1404-1408 (1986).
5. R.G. SMART and L. ANGLIN, J. For. Sci. 32 303-312 (1987).
6. C.V. WETLI and R.K. WRIGHT, JAMA 241 2519-2522 (1979).
7. A.J. MACLENNAN and S.F. MAIER, Science 219 1091-1093 (1983).
8. B.A. SORG, Ann. New York Acad. Sci. 654 136-144 (1992).
9. Y. ITZHAK and I. STEIN, J. Pharmacol. Exper. Therap. 262 464-470 (1992).
10. M. CADOR, J. DULLUC, and P. MORMÈDE, Neurosci. 56 981-988 (1991).
11. P.V. PIAZZA, S. MACCARI, J.M. DEMIÈNIRE, M. LE MOAL, P. MORMÈDE, and H. SIMON, Proc. Natl. Acad. Sci. USA 88 2088-2092 (1991).
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