Linopirdine (DuP 996) improves performance in several tests of learning and memory by modulation of cholinergic neurotransmission.
The actions of linopirdine (DuP 996; 3,3-bis[4-pyrindinylmethyl]-1-phenylindolin-2-one) were evaluated in rats and mice in several cognitive behavioral tests, and for its effects on hippocampal acetylcholine (ACh) overflow in rats. Using mice treated with the muscarinic receptor antagonist, scopolamine, we studied the effects of linopirdine on retention of a passive avoidance task. Linopirdine (0.1 and 1 mg/kg) ameliorated the scopolamine-induced deficit, but at doses ranging from 0.01-1 mg/kg, it did not affect passive avoidance retention in normal (untreated) mice. In a scopolamine-induced hyperactivity test, linopirdine (1 mg/kg) decreased the motoric stimulation associated with the cholinergic hypofunction, without affecting locomotor activity on its own. Using rats, we studied the effects of linopirdine on performance in the Morris water maze spatial memory task. Young rats treated with atropine (30 mg/kg), a muscarinic receptor antagonist, took significantly longer to locate the submerged platform across 12 trials. Linopirdine (0.01 and 0.1, but not 1 mg/kg) ameliorated the atropine deficit. In addition, linopirdine (0.1 mg/kg) ameliorated the deficit in cognition-impaired aged rats (23-24 mo), but did not affect unimpaired aged rats. In terms of neurochemical action, linopirdine (1, 10, and 100 microM) produced a concentration-dependent increase in K(+)-evoked ACh overflow from superfused rat hippocampal slices. Also, linopirdine (10 microM) similarly increased ACh release in young control rats and cognition-impaired and nonimpaired aged rats. Our results confirm and extend findings from other studies that demonstrate the cognition-enhancing action of linopirdine in rodent models.(ABSTRACT TRUNCATED AT 250 WORDS)
Fontana
D J
DJ
Department of Neurosciences, Syntex Discovery Research, Palo Alto 94304.
Inouye
G T
GT
Johnson
R M
RM
D000375:Aging / Q000523:psychology; D000818:Animals; D001285:Atropine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007858:Learning / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010275:Parasympathetic Nervous System / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012601:Scopolamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*
D007211:Indoles; D011725:Pyridines; D001285:Atropine; D012601:Scopolamine; C061017:linopirdine