Nicotinic-receptor potentiator drugs, huprine X and galantamine, increase ACh release by blocking AChE activity but not acting on nicotinic receptors

The main goal of the present study was to analyse the effects of (±)-huprine X ((±)-HX) and galantamine (GAL), with potentiating action on nicotinic receptors, and huperzine A (HPA), devoid of nicotinic activity, on [3H]-acetylcholine ([3H]-ACh) release in striatal slices of rat brain. All compounds are non-covalent and reversible inhibitors of AChE. Addition of (±)-HX (0.01 μM), GAL (10 μM) and HPA (0.1 μM) to the superfusion medium decreased the release of the ACh neurotransmitter to a similar extent: 36%, 30% and 34%, respectively (P < 0.01). This effect was reverted in the presence of atropine (ATR; 0.1 μM), which blocks the pre-synaptic muscarinic M2 receptor. After that, a wide range of concentrations of drugs, concomitantly with ATR (0.1 μM), was studied in the presence of haloperidol (HAL; 0.01μM), a dopamine D2 antagonist. In these conditions, a dose-dependent increase of [3H]-ACh release was observed in the presence of (±)-HX, GAL and HPA. To test the role of nicotinic receptors in the drugs' effects on [3H]-ACh release, mecamylamine (MEC) 100 μM was used to block such receptors. MEC alone significantly decreased neurotransmitter release by 18% (P < 0.05), but no change was obtained in the presence of both ATR and MEC. Under these conditions, (±)-HX, GAL and HPA increased the release of [3H]-ACh by 37%, 25% and 38%, respectively (P < 0.01). Taking into account all of these data, the present results suggest that the effects induced by (±)-HX and GAL nicotinic-receptor potentiators seem to be mainly due to their ability in inhibiting acetylcholinesterase activity, but not by interaction on the nicotinic receptors.