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 muM) caused a concentration-dependent increase in 5-HT release. This effect was antagonised by mecamylamine (0.5 muM), indicating an action at nicotinic receptors. Nicotine-evoked 5-HT release was not affected by tetrodotoxin (3 muM), cadmium chloride (0.1 mM), or the absence of Ca2+ or Nai in the superfusion medium. Unexpectedly, higher concentrations of mecamylamine alone (1-50 muM) 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 muM) on 5-HT release was reduced by the muscarinic M-1 receptor agonist, McN-A-343 (100 muM), but pirenzepine(0.005-1 muM), which blocks M-1 receptors, alone increased 5-HT release. Hippocampal serotonergic neurones are known to possess both excitatory nicotinic receptors and inhibitory M-1 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 muM) 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.