The effect of nicotine and cytisine on3H-acetylcholine release from cortical slices of guinea-pig brain

Abstract

Nicotine 1.8 X 10(-5)-1.8 X 10(-4) mol/l enhanced the spontaneous 3H-efflux from guinea-pig cortical slices preloaded with 3H-choline and perfused in the presence of hemicholinium (HC-3). The facilitation of tritium outflow was prevented by tetrodotoxin 5 X 10(-7) mol/l and by D-tubocurarine 4.5 X 10(-6) mol/l. Nicotine 1.8 X 10(-6)-1.8 X 10(-4) mol/l, and the agonist cytisine 5 X 10(-7)-5 X 10(-5) mol/l increased, in a concentration-dependent way, 3H-efflux from electrically-stimulated slices (0.2 Hz). The concentration-response curves of both drugs were parallelly shifted to the right by D-tubocurarine 4.5 X 10(-6) mol/l. The EC50 values (i.e. the concentrations required to cause a 50% increase in the S2/S1 ratio) changed for nicotine from 5.58 X 10(-5) to 4.34 X 10(-4) and for cytisine from 6.3 X 10(-6) to 2.75 X 10(-4) mol/l in the absence and in the presence of the antagonist, respectively. In the range of 0.2-2 Hz the magnitude of the effect of nicotine was inversely related to the rate of stimulation. The response to nicotine was subject to rapidly developing tachyphylaxis; it was resistant to atropine. It is concluded that nicotine and cytisine facilitate 3H-efflux from the cholinergic nerve endings of guinea-pig cerebral cortex. This effect involves sodium-dependent mechanisms and is due to an interaction of the drugs with receptors showing affinity for D-tubocurarine.

Do tetrahydroaminoacridine (THA) and physostigmine restore acetylcholine release in Alzheimer brains via nicotinic receptors?

“…A positive correlation between number of high affinity nicotinic receptors and 3H-ACh release has also been observed (Nordberg et al, 1987 a). It is known from studies on animal tissues that the effect of agonist activity on nicotinic receptors can only be measured after short exposure time, since longer exposure times cause a desensitization of the nicotinic receptors (Beani et al, 1985). In control human brain tissue, an increased ACh content in the synaptic cleft induced by cholinesterase inhibitors, may induce desensitization of the presynaptically located nicotinic receptors.…”

“…Interestingly, the facilitating effect on 3H-ACh release elicited by physostigmine 10 -4 M in AD/SDAT brain tissue, was partially blocked in the presence of d-tubocurarine 10 -6 M, indicating that the enhanced release might be induced via nicotinic receptors. This assumption is supported by the finding that nicotinic agonists can induce an increased release of 3H-ACh by stimulating nicotinic receptors (Beani et al, 1985). Presynaptic nicotinic receptors mediating a postive feedback on ACh release at the muscle endplate have also been suggested (Wessler et al, 1986;Vizi et al, 1987).…”

Effect of acute and subchronic nicotine treatment on cortical acetylcholine release and on nicotinic receptors in rats and guinea‐pigs

“…It has been suggested that this latter type of receptors might be present on the intracortical cholinergic nerve endings (Rowell & Winkler, 1984;Araujo et al, 1987). However, the antagonism by tetrodotoxin of the effect of nicotine on unstimulated guinea-pig cortical slices (Beani et al, 1985), together with some negative results on binding and biochemical studies on synaptosomes after lesioning of the subcortical cholinergic nuclei of the rat (Schwartz et al, 1984;Meyer et al, 1987), cast some doubts about such definite or exclusive localization. Further studies are needed to clarify if these supposed autoreceptors are also upstream (i.e.…”

“…Autoreceptors too seem to exist. This inference is based on binding studies carried out in human brains with spontaneous lesions of the basal cholinergic nuclei (Whitehouse et al, 1986;Nordberg & Winblad, 1986) and on neurochemical investigations performed in animal brain synaptosomes (Rowell & Winkler, 1984;Moss & Wonnacott, 1985) and cortical slices (Beani et al, 1985;Araujo et al, 1987). The actual relevance of nicotine-induced facilitation of acetylcholine (ACh) release remains, however, to be firmly established in physiological, integrated models.…”

5‐Hydroxytryptamine‐mediated effects of nicotine on endogenous GABA efflux from guinea‐pig cortical slices

“…These effects are most likely due to its interaction with specific brain receptors, which increase the firing rate and secretion of many neurones (Balfour, 1982). Nicotine increases 5-hydroxytryptamine (5-HT) and dopamine release (Westfall et al, 1983;Imperato et al, 1986;Balfour, 1989;Carboni et al, 1989;Riberio et al, 1993;Nisell et al, 1994) as well as acetylcholine release (Beani et al, 1985;Nordberg et al, 1989) both in vivo and in vitro preparations. Moreover, the drug increases excitatory amino acid outflow in vivo (Garza De La et al, 1989;Beani et al, 1991;Toth et al, 1993) and in vitro (Perez de la Mora et al, 1991).…”