title: Hemicholinium-3 impairs spatial learning and the deficit is reversed by cholinomimetics.
abstract: The effects of hemicholinium-3 (HC-3) on spatial discrimination 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 micrograms/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 micrograms/rat ICV) 60 min prior to testing and test drugs were injected 15 min before testing. Some doses of physostigmine (46-460 micrograms/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 micrograms/kg/SC) and RS-86 (0.46, 1.0 microgram/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 alpha 2 agonist, clonidine (46, 100 micrograms/kg SC) and the antagonist idazoxan (32, 100 micrograms/kg SC) were also inactive. Learning deficits were not reversed by haloperidol (20, 60 micrograms/kg), amphetamine (0.1, 0.46 mg/kg), the selective 5-HT1A agonist 8-OH-DPAT (30, 100 micrograms/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.
authors.affiliation: Scientific Development Group, Organon International B.V., The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Hagan
authors.forename: J H
authors.initials: JH
authors.lastname: Jansen
authors.forename: C L
authors.initials: CL
authors.lastname: Broekkamp
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D001115:Arecoline / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects; D006426:Hemicholinium 3 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007858:Learning / Q000187:drug effects*; D008297:Male; D010095:Oxotremorine / Q000494:pharmacology; D010277:Parasympathomimetics / Q000494:pharmacology*; D010830:Physostigmine / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D051381:Rats; D013028:Space Perception / Q000187:drug effects*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D010277:Parasympathomimetics; D013764:Tetrahydronaphthalenes; D010862:Pilocarpine; D006426:Hemicholinium 3; D001115:Arecoline; D010095:Oxotremorine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D010830:Physostigmine