Mechanism of the Prevention of Nicotine Convulsions by Hexamethonium and by Adrenaline Blocking Agents

Abstract

In a previous paper (Laurence and Stacey, 1952a) we have shown that hexamethonium and pentamethonium protect mice and rats against nicotine convulsions to a marked degree, but that they afford no protection against the action of a number of other convulsants nor against insulin convulsions (Laurence and Stacey, 1952b). In the present work we have sought an explanation for this protection.Hexamethonium does not pass freely into the cerebrospinal fluid (Paton), so that there are good reasons for investigating possible peripheral mechanisms. Evidence has already been advanced for believing that, although violent stimulation of the carotid body may, according to Schmidt and Comroe (1940), lead to convulsions, it is not by blocking afferent impulses from this structure that hexamethonium exerts its protection (Laurence and Stacey, 1952a). Attention was therefore turned to other peripheral actions of nicotine which are modified by hexamethonium. Hexamethonium blocks stimulation of the adrenal medulla by nicotine, and it was thought possible that the adrenaline liberated might play a part in precipitating nicotine convulsions, since adrenaline is known to facilitate spinal reflexes (Bulbring and Burn, 1941) and the passage of impulses across synapses (Bulbring and Burn, 1942), and to potentiate the action of various substances on the central nervous system (Friedemann and Elkeles, 1932). The convulsant action of nicotine was therefore examined under conditions in which the effects of sympathetic stimulation were increased (by simultaneous administration of adrenaline or noradrenaline) or decreased (by blocking agents or adrenalectomy). METHODSMice and rats were used. In each experiment a comparison was made between the convulsion rates in two groups of animals of the same sex, from the same colony, and of similar weights and ages which had received the same dose of a convulsant (either nicotine or leptazol). One group had received previously an injection of a solution of the drug whose anticonvulsant action was being examined, while the other had received an equal volume of solvent. For dibenamine the time interval between the two injections was four hours, for all other drugs 30 minutes.Mice were given nicotine (0.2 mg. base/ml.) or leptazol (2 mg./ml.) into a tail vein, the injection occupying exactly 10 seconds timed by a metronome. Premedication was by intraperitoneal injection. Rats received nicotine (2 mg. base/ml.) subcutaneously or leptazol (25 mg./ml.) intraperitoneally and premedication by subcutaneous injection. Each experiment was repeated after one week with the groups crossed over; the results were then summed. Doses of convulsants were adjusted to give a suitable convulsion rate for the purpose of the experiment. In mice these were: nicotine 0.2-0.4 mg./kg., leptazol 20-40 mg./kg.; and for rats: nicotine 2-3 mg./kg., leptazol 50-70 mg./kg. In the experiments in which adrenaline, noradrenaline, and pitressin were used, these substances were added to the solution of the convulsant and used at once.Adrenale...

Additive deficits in the choice accuracy of rats in the delayed non-matching to position task after cholinolytics and serotonergic lesions are non-mnemonic in nature

“…The ability of hexamethonium dose used (1.5 mg/kg) to block the peripheral nicotinic receptors was confirmed in that this dose of hexamethonium was able to inhibit the effect of nicotine to decrease diastolic blood pressure (data not shown). Moreover, Laurence and Stacey (1953) demonstrated that subcutaneous injection of 2 mg / kg hexamethonium iodide was able to prevent nicotine induced convulsions in rats.…”

The Metabolic Fate of Pentylenetetrazol in the Rat

“…other workers have also reported the facilitation of PTZ convulsions by relatively high doses of epinephrine (80,81,82) (43,90) contradict those on the effect of convulsions by PTZ on the ACh content of the brain (84,85). Although these experiments do not justifiably conclude that PTZ-induced central stimulation is due to cholinergie mechanism, it has been suggested that PTZ, possibly by its analeptic action, May restore the ACh metabolism in brain which had previously been depressed by anaesthesia (2 Although its populari ty seemed to be gradually replaced by the availabi lity of new drugs, its unique position in pharmaco logical research remains unchallen ged.…”

Effects of Acute Administration of Nicotine on Convulsive Movements and Blood Levels of Corticosterone in Old Rats

“…Laurence and Stacey (12) observed that nicotine-induced convulsions were potentiated by the systemic pretreatment with adrenaline or noradrenaline, and they are suppressed by adrenalectomy. In addition, it has been shown that acute administration of nicotine stimulates the release of adrenocorticotropic hormone from the pituitary gland, resulting in the elevation of blood glucocorticoid level (7).…”