Evidence for a complex influence of nicotinic acetylcholine receptors on hippocampal serotonin release

The effects of nicotine on 5-hydroxytryptamine (5-HT) release from serotonergic nerve endings in rat dorsal hippocampal slices were studied. Nicotine (50-500 μM) caused a concentration-dependent increase in 5-HT release. This effect was antagonised by mecamylamine (0.5 μM), indicating an action at nicotinic receptors. Nicotineevoked 5-HT release was not affected by tetrodotoxin (3 μM), cadmium chloride (0.1 mM), or the absence of Ca²⁺ or Na⁺ in the superfusion medium. Unexpectedly, higher concentrations of mecamylamine alone (1-50 μM) increased 5-HT release. This suggested the presence of inhibitory input to 5-HT neurones and that these inhibitory neurones possess tonically active nicotinic receptors. The effect of mecamylamine (50 μM) on 5-HT release was reduced by the muscarinic M₁ receptor agonist, McN-A-343 (100 μM), but pirenzepine (0.005-1 μM), which blocks M₁ receptors, alone increased 5-HT release. Hippocampal serotonergic neurones are known to possess both excitatory nicotinic receptors and inhibitory M₁ receptors. Although there may be several explanations for our results, one possible explanation is that nicotine stimulates 5-HT release by activating nicotinic heteroreceptors on 5-HT terminals. Mecamylamine (0.5 μM) antagonises this effect, but higher concentrations increase 5-HT release indirectly by blocking the action of endogenous acetylcholine on nicotinic receptors situated on cholinergic neurones that provide muscarinic inhibitory input to 5-HT neurones.