Therapeutic effect of THA on hemicholinium-3-induced learning impairment is independent of serotonergic and noradrenergic systems.
Tetrahydroaminoacridine (THA: Tacrine) has previously been shown to reverse deficits in spatial discrimination learning induced by hemicholinium-3 (HC-3). In the present experiments the effects of prior depletion of serotonin (5-HT) or noradrenaline (NA) on this reversal were examined. In the first experiment 5-HT lesions were made by injecting 5,7-DHT (2 x 50 micrograms/5 microliters) into the lateral ventricles of rats pretreated with desmethylimipramine (DMI 25 mg/kg IP). A permanently indwelling guide tube was then implanted over the right lateral ventricle. Subsequent testing under drug-free conditions, revealed no effect of the lesion on the number of trials needed to attain criterion (nine consecutive correct choices) in two-platform spatial discrimination learning in a watermaze. Using a latin square design rats were then tested for the effects of HC-3 and THA. HC-3 (5 micrograms/5 microliters ICV) or placebo (CSF) were injected 60 min before the start of a 30-trial training session. THA (4.6, 10 mg/kg SC) or placebo were then injected 15 min before training. Choice accuracy but not choice latency was significantly impaired by HC-3 and the effect was reversed by THA in both sham operated and 5-HT lesioned rats. In the second experiment two injections of DSP-4 (50 mg/kg IP) were given, following cannulation, to deplete forebrain NA. The lesion had no effect on spatial learning under drug-free conditions and failed to block the THA-induced reversal of spatial discrimination learning deficits following HC-3. These results confirm that forebrain Ach depletion by HC-3 impairs spatial discrimination learning and that the deficit is reversed by THA.(ABSTRACT TRUNCATED AT 250 WORDS)
Hagan
J J
JJ
Scientific Development Group, Organon International B.V., OSS, The Netherlands.
Jansen
J H
JH
Nefkens
F E
FE
de Boer
T
T
D015116:5,7-Dihydroxytryptamine / Q000633:toxicity; D000609:Aminoacridines / Q000627:therapeutic use*; D000818:Animals; D001596:Benzylamines / Q000633:toxicity; D003891:Desipramine / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects; D006426:Hemicholinium 3 / Q000037:antagonists & inhibitors*; D007276:Injections, Intraventricular; D007859:Learning Disabilities / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D008297:Male; D009638:Norepinephrine / Q000502:physiology*; D051381:Rats; D012701:Serotonin / Q000502:physiology*; D013028:Space Perception / Q000187:drug effects; D013619:Tacrine / Q000627:therapeutic use*
D000609:Aminoacridines; D001596:Benzylamines; D006426:Hemicholinium 3; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D013619:Tacrine; C012102:DSP 4; D003891:Desipramine; D009638:Norepinephrine