Specific inhibitory effect of amyloid-beta 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 (A beta 1-40) on the oxotremorine (OXO)-induced release of [(3)H] dopamine (DA), [(3)H]GABA and [(3)H]acetylcholine (ACh) from synaptosomes in the rat nucleus accumbens (NAc). OXO in presence of himbacine (HIMBA) was able to increase the basal release of [(3)H]GABA. The OXO-elicited [(3)H]GABA overflow was significantly antagonized by atropine (A; 94%), by the M3 antagonists DAU5884 (96%) and 4-DAMP (70%), and by A beta 1-40 (65%). Exposure of NAc synaptosomes to OXO produced a dose-dependent increase of [(3)H]DA overflow which was antagonized by A, partially inhibited by A beta 1-40 (100 nM) but unaffected by DAU5884 and 4-DAMP. The K(+)-evoked [(3)H]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 [(3)H]GABA overflow was also inhibited by OXO but conversely, this effect was counteracted by MT3 and not by AFDX-116. A beta 1-40 (100 nM) did not modify the inhibitory effect of OXO both on the K(+)-evoked [(3)H]ACh and [(3)H]GABA overflow. The results show that in the rat NAc, A beta 1-40 selectively inhibits the function of the muscarinic subtypes which stimulate neurotransmitter release and not those which modulate negatively the stimulated release.
Section of Pharmacology and Toxicology, Department of Experimental Medicine, University of Genoa, Genoa, Italy.
M
M
Grilli
F
F
Lagomarsino
S
S
Zappettini
S
S
Preda
E
E
Mura
S
S
Govoni
M
M
Marchi
D000109:Acetylcholine / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D010095:Oxotremorine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000502:physiology*; D017661:Receptors, Presynaptic / Q000502:physiology*; D013574:Synaptosomes / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D016229:Amyloid beta-Peptides; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D018377:Neurotransmitter Agents; D010446:Peptide Fragments; D011976:Receptors, Muscarinic; D017661:Receptors, Presynaptic; C078592:amyloid beta-protein (1-40); D005680:gamma-Aminobutyric Acid; D010095:Oxotremorine; D000109:Acetylcholine; D004298:Dopamine