ELECTROENCEPHALOGRAPHIC, ELECTROMYOGRAPHIC AND BEHAVIORAL CORRELATES DURING A CYCLE OF SELFMAINTAINED MORPHINE ADDICTION IN THE RAT

¹ Pharmacology Research Laboratories, The Upjohn Company, Kalamazoo, Michigan

A complete cycle of morphine addiction (induction of tolerance and physical dependence, self-maintenance by intravenous injections and abrupt withdrawal) was studied in rats prepared with indwelling venous cannulas, epidural cortical electrodes for electroencephalograms (EEG) and hooks in neck muscles for electromyograms (EMG). The percentages of time in sleep, paradoxical sleep and awake states were evaluated by continuous recording of EEG and EMG. Initially, 2 mg/kg/hr of morphine were administered, and dosage was increased over an 8-day period to 40 mg/kg/hr. At first, sleep was greatly decreased and paradoxical sleep virtually eliminated, but after about 12 hr tolerance gradually developed until, after 3 days, in spite of increasing doses, the amount of sleep was practically normal. The awake cortical EEG tracing showed high-voltage " slow bursts" of 4 to 7 cycles/sec after morphine injections. When addicted rats administered 10 mg/kg of morphine to themselves every 2 to 3 hr, sleep predominated during the 30-min period preceding a voluntary injection, and wakefulness afterward. The total amount of sleep and paradoxical sleep was almost normal. Motivation for morphine appeared unrelated to the agitation present 12 to 24 hr after abrupt withdrawal. The abstinence syndrome had an initial depressed phase and a secondary stimulated phase, thus providing one explanation for conflicting opinions as to whether the rat abstinence syndrome is one of sedation or agitation. The technique of continuous administration of drug and recording the EEG and the EMG was shown useful to demonstrate adaptive mechanisms to a drug affecting the central nervous system.

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