Skip to main content
SpringerLink
Log in

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

  • Original Investigations
  • Published:
Psychopharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Albin RL, Young AB, Penney JB (1988) Tetrahydro-9-aminoacridine (THA) interacts with the phencyclidine (PCP) receptor side. Neurosci Lett 88:303–307

    Google Scholar 

  • Becker RE, Giacobini E (1988) Mechanisms of cholinesterase inhibition in senile dementia of the Alzheimer type: clinical, pharmacological and therapeutic aspects. Drug Dev Res 12:163–195

    Google Scholar 

  • Bevan KA, Patterson JC, Templeton WW (1988) Classification of muscarinic receptor subtypes in the conscious mouse. Br J Pharmacol 93: 174p

  • Bruno G, Mohr E, Gillespie M, Fedio P, Chase TN (1986) Muscarinic agonist therapy of Alzheimer's disease. Arch Neurol 43:659–661

    Google Scholar 

  • Caine ED (1980) Cholinomimetic treatment fails to improve memory disorders. N Engl J Med 303:585–586

    Google Scholar 

  • Caulfield MP, Fortune DH, Roberts PM, Stubley JK (1981) Intracerebroventricular hemicholinium-3 (HC-3) impairs learning of a passive avoidance task in mice. Br J Pharmacol 74: 865 p

    Google Scholar 

  • Christie JE, Shering A, Ferguson J, Glen AIM (1981) Physostigmine and arecoline: effects of intravenous infusions in Alzheimer's presenile dementia. Br J Psychiatry 138:46–50

    Google Scholar 

  • Collerton D (1986) Cholinergic function and intellectual decline in Alzheimer's disease. Neuroscience 19:1–28

    Google Scholar 

  • Cortes R, Palacios JM (1986) Muscarinic cholinergic receptor subtypes in the rat brain: I Quantitative autoradiographic studies. Brain Res 362:227–238

    Google Scholar 

  • Domino EF, Cassano GB, Placidi GF (1974) Autoradiographic distribution of 14C-Hemicholinium-3 in mouse whole body and dog brain. J Pharmacol Exp Ther 188:77–85

    Google Scholar 

  • Dunnett SB, Toniolo G, Fine A, Ryan CN, Bjorklund A, Iversen SD (1985) Transplantation of embryonic ventral forebrain neurons to the neocortex of rats with lesions of nucleus basalis magnocellularis: II Sensorimotor and learning impairments. Neuroscience 16:787–799

    Google Scholar 

  • Dunnett SB, Whishaw IQ, Jones GH, Bunch ST (1987) Behavioural, biochemical and histochemical effects of different neurotoxic amino acids injected into nucleus basalis magnocellularis of rats. Neuroscience 20:653–669

    Google Scholar 

  • Flood JF, Cherkin A (1986) Scopolamine effects on memory retention in mice: a model of dementia? Behav Neurol Biol 45:169–184

    Google Scholar 

  • Flood JF, Landry DW, Jarvik ME (1981) Cholinergic receptor interactions and their effects on long-term memory processing. Brain Res 215:177–185

    Google Scholar 

  • Franklin SR, Sethy VH, Tang AH (1986) Amnesia produced by intracerebroventricular injections of hemicholinium-3 in mice was prevented by pretreatment with piracetam-like compounds. Pharmacol Biochem Behav 25:925–927

    Google Scholar 

  • Freedman LS, Backman MZ, Quartermain D (1979) Clonidine reverses the amnesia induced by dopamine beta hydroxylase inhibition. Pharmacol Biochem Behav 11:259–263

    Google Scholar 

  • Freedman SB, Harley EA, Iversen LL (1988) Relative affinities of drugs acting at cholinoceptors in displacing agonist and antagonist radioligands: the NMS/Oxo-M ratio as an index of efficacy at cortical muscarinic receptors. Br J Pharmacol 93:437–445

    Google Scholar 

  • Freeman JJ, Macri JR, Choi RG, Jenden DJ (1979) Studies on the behavioral and biochemical effects of hemicholinium in vivo. J Pharmacol Exp Ther 210:91–97

    Google Scholar 

  • Hagan JJ, Tweedie F, Morris RGM (1986) Lack of task specificity and absence of post training effects of atropine on learning. Behav Neurosci 100:483–493

    Google Scholar 

  • Hagan JJ, Tonnaer JADM, Rijk H, Broekkamp CLE, Van Delft AML (1987a) Facilitation of amphetamine-induced rotation by muscarinic antagonists is correlated with M2 receptor affinity. Brain Res 410:69–73

    Google Scholar 

  • Hagan JJ, Jansen JHM, Broekkamp CLE (1987b) Blockade of spatial learning by the M1 muscarinic antagonist pirenzepine. Psychopharmacology 93:470–476

    Google Scholar 

  • Hagan JJ, Morris RGM (1988) The cholinergic hypothesis of memory: A review of animal experiments. In: Snyder, S, Iversen LL, Iversen SD (eds) The handbook of psychopharmacology vol 20. Plenum, New York, pp 237–323

    Google Scholar 

  • Hagan JJ, Salamone JD, Simpson J, Iversen SD, Morris RGM (1988) Place navigation in rats is impaired by lesions of medial septum and diagonal band but not nucleus basalis magnocellularis. Behav Brain Res 27:9–20

    Google Scholar 

  • Hagan JJ, Van der Heijden B, Broekkamp CLE (1988) The relative potencies of cholinomimetics and cholinergic antagonists on the rat iris in vivo: Effects of pH on potency of pirenzepine and telenzepine. Naunyn-Schmiedebergs Arch Pharmacol 338:476–483

    Google Scholar 

  • Haroutunian V, Kanof P, Davis KL (1985) Pharmacological alleviation of cholinergic lesion induced memory deficits in rats. Life Sci 37:945–952

    Google Scholar 

  • Heilbron E (1961) Inhibition of cholinesterase by tetrahydroaminoacridine. Acta Chem Scand 15:1386

    Google Scholar 

  • Hepler DJ, Olton DS, Wenk GL, Coyle JT (1985) Lesions in the nucleus basalis magnocellularis and medial septal area of rats produce qualitatively similar memory impairments. J Neurosci 5:866–873

    Google Scholar 

  • Hollander E, Davidson M, Mohs RC, Horvath TB, Davis BM, Zemishlany Z, Davis KL (1987) RS86 in the treatment of Alzheimer's disease: cognitive and biological effects. Biol Psychiatry 22:1067–1078

    Google Scholar 

  • Hunter AJ, Roberts FF (1988) The effects of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on spatial learning in the Morris Water Maze task. In: Dourish CT, Ahlenius S, Hutson PH (eds) Brain 5HT1A receptors: behavioural and neurochemical pharmacology. VCH and Horwood, pp 278-286

  • Hunter AJ, Murray TK, Cross AJ, Osborne JA, Green AR (1988) Behavioural and biochemical actions of the cholinesterase inhibitor tetrahydroaminoacridine. Br J Pharmacol 93: 175 p

    Google Scholar 

  • Hurlbut BJ, Lubar JF, Switzer R, Dougherty J, Eisentstadt ML (1987) Basal forebrain infusion of HC-3 in rats: maze learning deficits and neuropathology. Physiol Behav 39:381–393

    Google Scholar 

  • Jensen LH, Stephens DN, Sarter M, Petersen EN (1987) Bidirectional effects of β-carbolines and benzodiazepines on cognitive processes. Brain Res Bull 19:359–364

    Google Scholar 

  • Knowlton B, Wenk GL, Olton DS, Coyle JT (1985) Basal forebrain lesions produce a dissociation of trial-dependent and trial-independent memory performance. Brain Res 345:315–321

    Google Scholar 

  • Kolb B, Sutherland RJ, Whishaw IQ (1983) A comparison of the contribution of the frontal and parietal association cortex to spatial localization in rats. Behav Neurosci 97:13–27

    Google Scholar 

  • Mair RG, McEntee WJ (1986) Cognitive enhancement in Korsakoff's psychosis by clonidine: A comparison with l-dopa and ephedrine. Psychopharmacology 88:374–380

    Google Scholar 

  • Martinez JL, Jensen RA, Messing RB, Vasquez B, Soumireu-Mourat B, Geddes D, Liang KC, McGaugh JL (1980) Central and peripheral actions of amphetamine on memory storage. Brain Res 182:157–166

    Google Scholar 

  • McGurk S, Levin ED, Butcher LL (1988) Cholinergic-dopaminergic interactions in radial-arm maze performance. Behav Neural Biol 49:234–239

    Google Scholar 

  • M'Harzi M, Willig F, Costa JC, Delacour J (1988) d-Amphetamine enhances memory performance in rats with damage to the fimbria. Physiol Behav 42:575–579

    Google Scholar 

  • Morris RGM (1981) Spatial localisation does not depend on the presence of local cues. Learn Motiv 12:239–260

    Google Scholar 

  • Morris RGM, Hagan JJ, Rawlins JNP (1986) Allocentric spatial learning by hippocampectomised rats: a further test of the “spatial mapping” and “working memory” theories of hippocampal function. J Exp Psychol 38B:365–395

    Google Scholar 

  • Murray CL, Fibiger HC (1985) Learning and memory deficits after lesions of the nucleus basalis magnocellularis: reversal by physostigmine. Neuroscience 14:1025–1032

    Google Scholar 

  • Murray CL, Fibiger HC (1986) Pilocarpine and physostigmine attenuate spatial memory impairments produced by lesions of the nucleus basalis magnocellularis. Behav Neurosci 100:23–32

    Google Scholar 

  • Palacios JM, Pazos A, Hoyer D (1987) Characterization and mapping of 5-HT1A sites in the brain of animals and man. In: Dourish CT, Ahlenius S, Hutson PH (eds) Brain 5-HT1A receptors: behavioural and neurochemical pharmacology. Horwood, Chichester

    Google Scholar 

  • Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH (1978) Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J 2:1457–1459

    Google Scholar 

  • Pirozzolo FJ, Baskin DS, Swhihart AA, Appel SH (1987) Oral tetrahydroaminoacridine in the treatment of senile dementia, Alzheimer's type. N Engl J Med 316:1603 (see also following correspondence)

    Google Scholar 

  • Raaijmakers WGM (1983) Lasting hippocampal cholinergic deficit and memory impairment in the rat. Neurosci Lett [Suppl] 14:S294

    Google Scholar 

  • Reavill C, Spivak CE, Stolerman IP, Waters JA (1987) Isoarecolone can inhibit nicotine binding and produce nicotine-like discriminative stimulus effects in rats. Neuropharmacology 26:789–792

    Google Scholar 

  • Ridley RM, Barratt NG, Baker, HF (1984) Cholinergic learning deficits in the marmoset produced by scopolamine and ICV hemicholinium. Psychopharmacology 83:340–345

    Google Scholar 

  • Ridley RM, Baker HF, Drewett B (1987) Effects of arecoline and pilocarpine on learning ability in marmosets pretreated with hemicholinium-3. Psychopharmacology 91:512–514

    Google Scholar 

  • Ridley RM, Murray TK, Johnson JA, Baker HF (1986) Learning impairment following lesion of the basal nucleus of Meynert in the marmoset: modification by cholinergic drugs. Brain Res 376:108–116

    Google Scholar 

  • Russell RW, Macri J (1978) Some behavioral effects of suppressing choline transport by cerebroventricular injection of Hemicholinium-3. Pharmacol Biochem Behav 8:399–403

    Google Scholar 

  • Sahakian BJ (1988) Cholinergic drugs and human cognitive performance: clinical aspects. Psychopharmacology 96, S67

    Google Scholar 

  • Salamone JD, Beart PM, Alpert JE, Iversen SD (1984) Impairment in T-maze reinforced alternation performance following nucleus basalis magnocellularis lesions in rats. Behav Brain Res 13:63–70

    Google Scholar 

  • Sara SJ, Deweer B (1982) Memory retrieval enhanced by amphetamine after a long retention interval. Behav Neural Biol 36:146–160

    Google Scholar 

  • Sarter M, Schnieder HH, Stephens DN (1988) Treatment strategies for senile dementia: antagonist β-carbolines. TINS 11:13–16

    Google Scholar 

  • Schauf CL, Sattin A (1987) Tetrahydroaminoacridine blocks potassium channels and inhibits sodium inactivation in myxicola. J Pharmacol Exp Ther 243:609–613

    Google Scholar 

  • Schenk F, Morris RGM (1985) Dissociation between components of spatial memory in rats after recovery from the effects of retrohippocampal lesions. Exp Brain Res 58:11–28

    Google Scholar 

  • Siegel S (1956) Non parametric statistics for the behavioral sciences. McGraw-Hill, Kogakusha Ltd

  • Stevens DR, Cotman CW (1987) Excitatory actions of tetrahydro-9-aminoacridine (THA) on hippocampal pyramidal neurons. Neurosci Lett 79:301–305

    Google Scholar 

  • Summers WK, Majovski LV, Marsh GM, Tachiki K, Kling A (1986) Oral tetrahydroaminoacridine in long term treatment of senile dementia, Alzheimer type. N Engl J Med 315:1241–1245

    Google Scholar 

  • Tonnaer JADM, Van Vugt MA, De Boer Th, De Graaf JS (1987) Differential interaction of muscarinic drugs with binding sites of [3H]pirenzepine and [3H]quinuclidinyl benzilate in rat brain tissue. Life Sci 40:1981–1987

    Google Scholar 

  • Wess J, Lambrecht G, Moser U, Mutschler E (1987) Stimulation of ganglionic muscarinic M1 receptors by a series of tertiary arecaidine and isoarecaidine esters in the pithed rat. Eur J Pharmacol 134:61–67

    Google Scholar 

  • Whittaker VP (1988) The storage and release of acetylcholine. TIPS 7:312–315

    Google Scholar 

Download references

Author information

Authors and Affiliations

  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 & C. L. E. Broekkamp

Authors
  1. J. J. Hagan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. H. M. Jansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. L. E. Broekkamp
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hagan, J.J., Jansen, J.H.M. & Broekkamp, C.L.E. Hemicholinium-3 impairs spatial learning and the deficit is reversed by cholinomimetics. Psychopharmacology 98, 347–356 (1989). https://doi.org/10.1007/BF00451686

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00451686

Key words

Search

Navigation