We have previously reported that N 6,02'-dibutyryl adenosine 3':5'-cyclic monophosphate (db cyclic AMP) administered intracerebroventricularly (icv) in the rat, shortened amobarbital-induced sleeping time in a dose-related manner. Five neuropharmacologic agents, which included the aliphatic hypnotics chloral hydrate and paraldehyde, the tranquilizer diazeparn, the phencyclidine derivative ketamine, and the inhalation agent halothane, were also tested. Db cyclic AMP shortened, in a dose-related manner, the duration of narcosis of each of these structurally unrelated central nervous system depressants. The purpose of the present research was to determine if db cyclic AMP administered icv protected rats treated with a toxic dose of each of these drugs. Male Sprague-Dawley rats weighing 80-100 g were weighed and one of the central nervous system depressants was injected ip according to the following dose schedule: amobarbital, 175 mg/kg; chloral hydrate (Noctec), 500 mg/kg (diluted 1: 1 in sterile saline), diazepam, 70 mg/kg, and paraldehyde, 1.5 ml/kg. Immediately after the loss of righting reflex, 225 μg of cyclic AMP in 15 μl of 0.001 M potassium phosphate buffer solution, pH 7.5, was administered icv. Our data showed that db cyclic AMP significantly reduced the mortality of amobarbital from LD50 to LD3, chloral hydrate from LD50 to LDl7, and paraldehyde from LD67 to LDl7. Repetitive icv doses of db cyclic AMP were required to decrease the mortality due to ketamine and diazepam. Whereas higher doses of db cyclic AMP (300 μg) given to rats treated with toxic doses of diazepam and ketamine resulted in shortening of the sleeping time, no reduction of the LD50 was observed. Analeptic drugs (methamphetamine, picrotoxin, doxapram, caffeine, theophylline, and strychnine) administered icv did not shorten the sleeping time or reduce the mortality of any of the central nervous system depressants used in this study.