Attenuation of serotonin-suppressed [3H]acetylcholine release by tetrahydroaminoacridine and dendrotoxin: interaction with minaprine binding site.
5-Hydroxytryptamine (5-HT) inhibited K(+)-induced [3H]acetylcholine ([3H]ACh) release from rat hippocampal slices dose-dependently. Minaprine [3-(2-morpholino-ethylamino)-4-methyl-6-phenylpyridazine] and 9-amino-1,2,3,4-tetrahydroacridine (THA) attenuated the inhibition of [3H]ACh release by 5-HT. A neurotoxin isolated from the venom of Dendroaspis snake, dendrotoxin (DTX), also attenuated the 5-HT inhibited [3H]ACh release from hippocampal slices dose-dependently at doses of more than 3 x 10(-7) g/ml (about 42 nM). Specific binding of [3H]minaprine to hippocampal membrane was dose-dependently inhibited by THA and DTX. The IC50 of THA and DTX for the [3H]minaprine binding were about 32 and 0.7 mu M, respectively. Scatchard plot analyses showed that the inhibitory effects of THA and DTX were noncompetitive for [3H]minaprine binding. THA and DTX inhibited [3H]ketanserin binding with IC50 of 28.8 and 26.2 mu M, respectively. These results suggest that THA and DTX attenuate the 5-HT-inhibited [3H]ACh release by blocking a voltage-dependent K+ current, and that they interact with the binding site of minaprine in the hippcampus.
Muramatsu
M
M
Department of Pharmacology, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Chaki
S
S
Usuki-ito
C
C
Otomo
S
S
D000109:Acetylcholine / Q000378:metabolism*; D000609:Aminoacridines / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004546:Elapid Venoms / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D015221:Potassium Channels / Q000502:physiology; D011724:Pyridazines / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013619:Tacrine / Q000494:pharmacology*
D000609:Aminoacridines; D004546:Elapid Venoms; D015221:Potassium Channels; D011724:Pyridazines; D012702:Serotonin Antagonists; C006149:minaprine; D013619:Tacrine; C020273:dendrotoxin; D000109:Acetylcholine