A Quantitative Study of the Effect of Cocaine on the Response of the Cat Nictitating Membrane to Nerve Stimulation and to Injected Noradrenaline

Abstract

Results are reported of a quantitative study of the potentiating effect of cocaine on the responses of the cat nictitating membrane to intravenously and intra-arterially injected noradrenaline, as well as to different types of sympathetic nerve stimulation. Responses of the membrane to noradrenaline were potentiated more with intravenous than with close-arterial injections. From studies of the responses of the nictitating membrane to various forms of sympathetic nerve stimulation before and after injection of cocaine, conclusions are drawn as to the extent to which the transmitter amine liberated by nerve activity is normally removed and its effect t~hereby limited in duration and extent. This uptake was greatest at low stimulus frequencies. The mechanism by which cocaine potentiates sympathetic responses is discussed.It has been known for over fifty years that cocaine increases the responses of various tissues to some sympathomimetic amines; the voluminous literature has recently been reviewed by Trendelenburg (1963). There is evidence that the noradrenaline-potentiating effect of cocaine is due to its ability to block the uptake of the amine by sympathetic nerve endings (Whitby, Hertting & Axelrod, 1960;Burn & Burn, 1961;Hertting, Axelrod & Patrick, 1961 ;Muscholl, 1961 ; Iversen & Whitby, 1962; Kopin, Hertting & Gordon, 1962;Wolfe, Potter, Richardson & Axelrod, 1962).The quantitative aspect of the potentiation of noradrenaline by cocaine has been little studied. We considered this side of the problem to be of interest for the following reason. Measurements of the uptake of noradrenaline by tissues before and after administration of cocaine and the failure of tyramine to produce sympathomimetic effects on various organs after appropriate doses of cocaine (unpublished experiments on strips of cat isolated spleen) indicate that cocaine can inhibit almost completely the usual uptake of the amine by sympathetically innervated tissues. A quantitative evaluation of the potentiation phenomenon would permit an estimation of the usual uptake of noradrenaline.In the investigation described here the effects of cocaine on the responsiveness to noradrenaline of a typical sympathetically innervated organ were studied quantitatively. By this indirect approach it was possible to determine approximately to what extent uptake into sympathetic nerve endings usually limits the response

Preferential secretion of adrenaline or noradrenaline by the cat adrenal in vivo in response to different stimuli

“…In order to determine whether such a reuptake mechanism is of significance in the adrenal medulla we performed the experiments with cocaine, which is an effective inhibitor of the reuptake mechanism in sympathetic nerve endings (Haefely, Hurlimann & Thoenen, 1964;Whitby, Axelrod & Weil-Malherbe, 1961). But as seen in Table 4, no significant increase of catecholamine secretion rate was found after the injection of cocaine, nor was there any change of the ratio of adrenaline to noradrenaline.…”

An Analysis of the Sympathomimetic Effects of Acetylcholine on the Rat Ileum

“…Cocaine has been reported to potentiate the response to sympathetic nerve stimulation (Haefely, Hurlimann & Thoenen, 1964). However, cocaine had no significant effect on the responses of the rat ileum to acetylcholine.…”

Studies on the peripheral pharmacology of fenazoxine, a potential antidepressant drug

“…This action resemibled that of cocaine and DMI. Cocaine (Haefely et al, 1964;de la Lande, Frewin & Waterson, 1967) and DMI (Callingham, 1967) potentiate the action of noradrenaline on various peripheral tissues. Further, cocaine and DMI are potent inhibitors of the uptake of labelled noradrenaline into isolated perfused rat heart (Iversen, 1965), suggesting that these drugs potentiate the actions of noradrenaline by inhibiting its uptake into adrenergic nerve endings.…”