1 The effect of acute and chronic (16 days) administration of nicotine on cortical acetylcholine (ACh) release, gross behaviour and brain nicotinic binding sites was investigated in rats and guinea-pigs.2 The drug, injected either subcutaneously (0.45-0.90mgkg-1) or intracerebroventricularly (1, 3 and 5 ig) increased the cortical ACh release, in a dose-dependent manner, through mecamylaminesensitive receptors for 1-2 h in both species. 3 Chronic treatment significantly increased basal ACh release in the rat and slightly lowered it in the guinea-pig, but the response to a challenging dose of nicotine was proportionally maintained in both species. 4 The number of nicotinic receptors was four times higher in the rat than in the guinea-pig and was not dependent on the radioligand used ([3H]-nicotine or [3H]-ACh, in the presence of atropine) to determine this. The nicotinic binding sites showed an apparent increase in chronically treated rats but no change in guinea-pigs. 5 Tolerance to the inhibitory effect of the drug, assessed with the T maze test, was found in the rat. No apparent change in gross behaviour was detected in the guinea-pig. 6 It is concluded that chronic nicotine treatment causes evident tolerance to its inhibitory effect on behaviour in the rat, but no adaptation to its excitatory properties on the cholinergic brain structures in rats and guinea-pigs.

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.

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