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Psychopharmacology

, Volume 98, Issue 3, pp 347–356 | Cite as

Hemicholinium-3 impairs spatial learning and the deficit is reversed by cholinomimetics

  • J. J. Hagan
  • J. H. M. Jansen
  • C. L. E. Broekkamp
Original Investigations

Abstract

The effects of hemicholinium-3 (HC-3) on spatial discriminaton learning were studied. Rats were equipped with indwelling cannulae in the right lateral ventricle and, following recovery, were trained on a two platform spatial discrimination task in a water maze. In this task a visible escape platform remains in a fixed position in the pool during a single training session, whilst the location of an identical “float” (which affords no escape) is randomly varied. For each session the location of the fixed escape platform was changed and the rats were retrained to criterion following pretreatment either with artificial cerebrospinal fluid (CSF) or HC-3 (2.5, 5.0 μg/rat/ICV) 1 h before training. Each rat received every treatment according to a latin square design. The results showed that spatial learning was dose dependently impaired by HC-3, choice accuracy being reduced to chance levels by the higher dose. There was no evidence of motoric difficulty, as choice latencies were not significantly increased. Experiments were then conducted to test for reversal of the deficit using a range of psychotropic drugs. Rats were treated with CSF or HC-3 (5 μg/rat ICV) 60 min prior to testing and test drugs were injected 15 min before testing. Some doses of physostigmine (46–460 μg/kg/SC) and tetrahydroaminoacridine (THA) (2.2–10 mg/kg/SC) reversed the spatial learning deficit. The muscarinic agonists arecoline (0.046–1 mg/kg/SC), aceclidine (1–10 mg/kg/SC), oxotremorine (30–100 μg/kg/SC) and RS-86 (0.46, 1.0 μg/kg/SC) were also effective. Pilocarpine (0.22–2.2 mg/kg/SC) showed marginal activity and isoarecoline (4.6–10 mg/kg/SC) was inactive. Nicotine (0.32, 1, 3.2 mg/kg/SC) and piracetam (10, 30, 100 mg/kg IP) were also inactive. The α2 agonist, clonidine (46, 100 μg/kg SC) and the antagonist idazoxan (32, 100 μg/kg SC) were also inactive. Learning deficits were not reversed by haloperidol (20, 60 μg/kg), amphetamine (0.1, 0.46 mg/kg), the selective 5-HT1A agonist 8-OH-DPAT (30, 100 μg/kg) or by the benzodiazapine antagonist ZK 93426 (1, 3.2, 10 mg/kg). The results show that forebrain Ach depletion by HC-3 impairs spatial discrimination learning and these deficits are reversed by cholinesterase inhibitors and some muscarinic receptor agonists. Some degree of pharmacological selectivity is indicated by the failure of a range of other drugs to reverse the impairments.

Key words

Spatial discrimination Hemicholinium-3 Rats Cholinesterase inhibitors Muscarinic agonists 

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Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • J. J. Hagan
    • 1
  • J. H. M. Jansen
    • 1
  • C. L. E. Broekkamp
    • 1
  1. 1.Scientific Development GroupOrganon International B. V.OSSThe Netherlands

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