A study of the localization of the site of action of central nervous system depressants and convulsants

This study involved the investigation of two techniques for the "in vivo" localization of Central Nervous System stimulants and depressants. One method was a biochemical analysis of a metabolite of the brain tissue, while the other was a physiological method, that of evaluating the pharmacological activities produced by direct brain injections. The experimental animals used were adult male and female white rats of the Sprague Dawley strain. The biological method was the determination of glycogen in sanpies of brain tissues obtained from rats injected intraperitoneally with the drugs. The animals were killed at the peak of drug activity by cervical dislocation and immediately decapitated before onset of convulsions. Stabilization of the samples was accomplished by freezing with liquid air. Brain samples were divided in cortical mesencephalic and rhombencephalic portions from which glycogen was extracted and spectrophotometrically analyzed as glucose. The physiological method consisted of momentarily anesthetizing the rat with ethyl chloride and injecting the drug into the cortex, the hypothalamus and the medulla. The injectionswere made with a 30 gauge needle after the rat had recovered from anesthesia. Observations on heart rate, respiratory rate, pupil size and autonomic manifestations were recorded. The drugs investigated by both methods were pentamethylene tetrazol, pentobarbital sodium, chlorpromazine and reserpine. The glycogen was also determined on control rats and rats injected with morphine and methamphetamine. Saline, air, and a citric acid placebo were injected in the brain area as controls for the physiological method. From a correlation of the results obtained, the following conclusions were made: the main site of action of pentamethylene tetrazol is the hypothalamus; pentobarbital sodium acts on the whole brain, predominantly on the medulla, then on the cortex; chlorpromazine acts on the whole brain but selectively on the medulla; reserpine's tranquilizing action is at the cortical level. Discussion is made of the possibilities and limitations of these techniques as pharmacological screening methods. It appears that drug stimulation of the brain areas is concomitant with decreases in the glycogen stores whereas depression increases the glycogen.