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.
Grilli
M
M
Section of Pharmacology and Toxicology, Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Lagomarsino
F
F
Zappettini
S
S
Preda
S
S
Mura
E
E
Govoni
S
S
Marchi
M
M
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