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Therapeutic effect of THA on hemicholinium-3-induced learning impairment is independent of serotonergic and noradrenergic systems

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Abstract

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 (2×50 µg/5 µl) 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 µg/5 µl 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. However, concommitant depletion of forebrain 5-HT or NA does not block the ameliorative effect of THA.

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  1. Scientific Development Group, Organon International B.V., P.O. Box 20, NL-5340 BH OSS, The Netherlands

    J. J. Hagan, J. H. M. Jansen, F. E. W. Nefkens & T. de Boer

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  1. J. J. Hagan
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  2. J. H. M. Jansen
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  3. F. E. W. Nefkens
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  4. T. de Boer
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Hagan, J.J., Jansen, J.H.M., Nefkens, F.E.W. et al. Therapeutic effect of THA on hemicholinium-3-induced learning impairment is independent of serotonergic and noradrenergic systems. Psychopharmacology 101, 376–383 (1990). https://doi.org/10.1007/BF02244057

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  • DOI: https://doi.org/10.1007/BF02244057

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