Brain Research, 78 (1974) 331-334 331 ~ Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands Modification of the morphine withdrawal syndrome in rats ALLEN P. FERTZIGER, JAMES J. LYNCH AND ELLIOT STEIN University of Maryland Medical School, Departments of Physiology and Psychiatry attd Human Behavior, Balt#nore, Md. 21201 (U.S.A.) (Accepted June 15th, 1974) The narcotic abstinence syndrome in both man and animals represents a fun- damental feature of the addictive process. This syndrome can be elicited in narcotic dependent animals either by abrupt drug withdrawal or by the injection of a narcotic antagonist. Most clinically relevant examples of narcotic withdrawal generally in- volve a rebound or overshoot reaction of some kind, in which those systems depressed by the narcotic in question become exaggerated above normal levels during with- drawal 1°. Thus, for example, the depression of flexor and crossed extensor reflexes elicited by morphine in the spinal dog is transformed into a hyperreflexia during morphine withdrawaP 9. Similarly, the morphine-elicited fall in blood pressure and pupillary miosis are transformed to a rise in blood pressure 2° and pupillary mydri- asis12,t3, respectively, during morphine withdrawal. For these reasons, one might expect a central nervous system depressant such as morphine to elicit an increase in neuronal excitability when abruptly withdrawn from a dependent animal. That this is the case in the morphine-dependent laboratory rat has been suggested by a series of well known observations during precipitated and naturally occurring morphine withdrawal 21. Typically one observes a generalized increase in motor activity, body or 'wet dog' shakes, escape attempts, teeth chattering, facial tremors, diarrhea, and diffuse restlessness in the rat undergoing withdrawal. We have attempted to determine whether this withdrawal-induced rebound hyperexcitability can be modified by a known antagonist of neuronal hyperexcitability, the anticonvulsant drug, diphenylhydantoin (DPH). Morphine dependence was induced in 30 male Sprague-Dawley rats (150- 200 g) according to a schedule slightly modified fromthat of Wikler et al. 21. Injections of morphine sulfate (MS) in saline, were administered i.p. twice daily, at 0900 and 1600 h. The initial dose level of 15 mg/kg/injection was increased by 15 mg/kg every 3 days until a level of 180 mg/kg/day was reached. Animals were then maintained at this level for the duration of the study. Smaller groups of rats were stabilized at 200, 210 and 220 mg/kg/day. No significant behavioral differences were observed in any of these groups and all data to be presented are pooled from these 4 groups. Twenty of these 30 rats were injected i.m. twice daily with DPH (prepared in an aqueous solution of 10 ~ ethanol and 40 ~ propylene glycol). One group of 10 received a dose of 15 mg/kg/injection of DPH, while a second group of 10 received 30 mg/kg/injection of DPH. DPH injections were administered at the same time as the morphine in-