Specific inhibitory effect of amyloid-b on presynaptic muscarinic receptor subtypes modulating neurotransmitter release in the rat nucleus accumbens

In this study we investigate on the effect of amyloid-beta1-40 (Ab1-40) on the oxotremorine (OXO)-induced release of [3H] dopamine (DA), [3H]GABA and [3H]acetylcholine (ACh) from synaptosomes in the rat nucleus accumbens (NAc). OXO in presence of himbacine (HIMBA) was able to increase the basal release of [3H]GABA. The OXO-elicited [3H]GABA overflow was significantly antagonized by atropine (A; 94%), by the M3 antagonists DAU5884 (96%) and 4-DAMP (70%), and by Ab1-40 (65%). Exposure of NAc synaptosomes to OXO produced a dose-dependent increase of [3H]DA overflow which was antagonized by A, partially inhibited by Ab1-40 (100 nM) but unaffected by DAU5884 and 4-DAMP. The K+-evoked [3H]ACh overflow was inhibited by OXO. This effect was counteracted by the M2 antagonist AFDX-116 but not by the selective M4 antagonist mamba toxin 3 (MT3). The K+-evoked [3H]GABA overflow was also inhibited by OXO but conversely, this effect was counteracted by MT3 and not by AFDX-116. Ab1-40 (100 nM) did not modify the inhibitory effect of OXO both on the K+-evoked [3H]ACh and [3H]GABA overflow. The results show that in the rat NAc, Ab1-40 selectively inhibits the function of the muscarinic subtypes which stimulate neurotransmitter release and not those which modulate negatively the stimulated release.