Skip to main content
SpringerLink
Log in

An iontophoretic study of the effects of α-amino-hydroxy-5-methyl-4-isoxazole propionic acid lesions of the nucleus basalis magnocellularis on cholinergic and GABAergic influences on frontal cortex neurones of rats

  • Original Paper
  • Published:
Experimental Brain Research Aims and scope Submit manuscript

Abstract

Unilateral lesions of the nucleus basalis magnocellularis (NBM) produced by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid in rats caused, 8–10 weeks after the lesion, a 94% reduction in cortical acetylcholinesterase fibres and reduced activities of acetylcholinesterase and choline acetyltransferase by 70–80% in the frontal cortex ipsilateral to the lesion. In anaesthetized unlesioned control rats, iontophoretic administration of acetylcholine and carbachol produced atropine-sensitive inhibition and excitation of frontal cortical neurones, effects similar to those produced by electrically stimulating the NBM. The lesion reduced cortical neuronal firing rates but increased the percentage and sensitivity of neurones responding to acetylcholine, the predominant response changing from inhibition to excitation; response duration increased but latency was unaffected. The size of the response of individual neurones to carbachol, but not the percentage of sensitive neurones, was also increased in lesioned animals. The proportion of neurones responding to bicuculline and their individual sensitivities were increased by the lesion, suggesting that the lesion increased GABAergic tone; responses to glutamate were unchanged. The lesion did not affect the proportion of neurones in which acetylcholine modulated neuronal responses but reversed the nature of the modulation to predominantly excitatory; excitation was the predominant response to electrical forepaw stimulation in unlesioned control animals. This suggests a possible interaction between GABAergic and cholinergic mechanisms in selective attention and processing of cognitive information. Acute administration of di-isopropyl fluorophosphate to unlesioned animals significantly increased the number of frontal cortical neurones responding to acetylcholine, without affecting individual neuronal sensitivity or responses to carbachol and glutamate. The similarity of these effects to those of acetylcholine in lesioned animals suggests that the increased sensitivity to acetylcholine in the latter was due to loss of acetylcholinesterase, enabling diffusion of acetylcholine to more distant neurones. However, acetylcholinesterase does not hydrolyse carbachol and therefore it is necessary to postulate a different post-synaptic mechanism to explain the lesion-induced increases in the sensitivities of individual neurones to carbachol and to acetylcholine; interpretation of experimental findings should take these two mechanisms into account.

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

  • Abdulla FA, Calaminici M-R, Gray JA, Sinden JD, Stephenson JD (1992) Chronic hyoscine and oxotremorine treatment alter the sensitivity of rat frontal cortical pyramidal cells to acetyl-choline and carbachol.Br J Pharmacol 106:39P

    Google Scholar 

  • Abdulla FA, Calaminici M-R, Stephenson JD, Sinden JD (1994) Unilateral AMPA lesions of nucleus basalis magnocellularis induce a sensorimotor deficit which is differentially altered by arecoline and nicotine. Behav Brain Res (in press)

  • Altman H, Crossland R, Jenden D, Berman R (1985) Further characterizations of the nature of behavioural and neurochemical effects of lesions to nucleus basalis of Meynert in the rat. Neurobiol Aging 6:125–130

    Google Scholar 

  • Arendt T, Allen Y, Marchbanks RM, Schugens MM, Sinden J, Lantos PL, Gray JA (1989) Cholinergic system and memory in the rat: effects of chronic ethanol, embryonic basal forebrain transplants and excitotoxic lesions of cholinergic basal forebrain projection system. Neuroscience 33:435–462

    Google Scholar 

  • Artola A, Bröcher S, Singer W (1990) Different voltage-dependent thresholds for inducing long-term depression and long-term potentiation in slices of rat visual cortex. Nature 347:69–72

    Google Scholar 

  • Bartus RT, Dean RL, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–417

    Google Scholar 

  • Bartus RT, Flicker C, Dean RL, Pontecorvo MJ, Figuerido JC, Fisher SK (1985) Selective memory loss following nucleus basalis lesions: long term behavioural recovery despite persistent cholinergic deficiencies. Pharmacol Biochem Behav 23:125–135

    Google Scholar 

  • Beaulieu C, Somogyi P (1991) Enrichment of cholinergic synaptic terminals on GABAergic neurons and coexistence of immunoreactive GABA and choline acetyltransferase in the same synaptic terminals in the striate cortex of the cat. J Comp Neurol 304:666–680

    Google Scholar 

  • Ben-Ari Y, Krnjevic K, Reiffenstein RJ, Reinhardt W (1981) Inhibitory conductance changes and action of γ-aminobutyrate in rat hippocampus. Neuroscience 6:2445–2463

    Google Scholar 

  • Ben-Barak J, Gazit H, Silman I, Dudai Y (1981) In vivo modulation of the number of muscarinic receptors in rat brain by cholinergic ligands. Eur J Pharmacol 74:73–81

    Google Scholar 

  • Benson D M, Blitzer RD, Haroutunian V, Landau EM (1989) Functional muscarinic supersensitivity in denervated rat hippocampus. Brain Res 478:399–402

    Google Scholar 

  • Bird SJ, Aghajanian GK (1975) Denervation supersensitivity in the cholinergic septo-hippocampal pathway: a microiontophoretic study. Brain Res 100:355–370

    Google Scholar 

  • Bowen DM, Smith CB, White P, Davison AN (1976) Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 99:459–496

    Google Scholar 

  • Buzsáki G, Bicford RG, Ponomareff G, Thal L, Mandel R, Gage H (1988) Nucleus basalis and thalamic control of neocortical activity in the freely moving rat. J Neurosci 8:4007–4026

    Google Scholar 

  • Candy JM, Perry RH, Perry EK, Irving D, Blessed G, Fairbarn AF, Tomlinson BE (1983) Pathological changes in the nucleus of Meynert in Alzheimer's and Parkinson's diseases. J Neurol Sci 59:277–289

    Google Scholar 

  • Coyle JT, Schwarcz R (1983) The use of excitatory amino acids as selective neurotoxins. In: Björklund A, Hokfeldt I (eds) Handbook of chemical neuroanatomy: methods in chemical neuroanatomy, vol 1. Elsevier, New York, pp 508–527

    Google Scholar 

  • Davies P, MaLoney AJF (1976) Selective loss of cholinergic neurons in Alzheimer's disease. Lancet 2:1403

    Google Scholar 

  • Dawson VL, Hunt ME, Wamsley JK (1992) Alteration in cortical muscarinic receptors following cholinotoxin (AF64A) lesion of the rat nucleus basalis magnocellularis. Neurobiol Aging 13:25–32

    Google Scholar 

  • Dunnett SB, Toniolo G, Fine A, Ryan CN, Björklund 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 16:787–797

    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 

  • Dunnett SB, Everitt B, Robbins TW (1991) The basal forebraincortical system: interpreting the functional consequences of excitotoxic lesion. Trends Neurosci 14:494–501

    Google Scholar 

  • Dutar P, Bassant MH, Lamour Y (1990) Effects of tetrahydro-9-aminoacridine on cortical and hippocapal neurons in the rat: an in vivo and in vitro study. Brain Res 527:32–40

    Google Scholar 

  • Eckenstein F, Thoenen H (1983) Cholinergic neurones in the rat cerebral cortex demonstrated by immunohistochemical localization of choline acetyltransferase. Neurosci Lett 36:211–215

    Google Scholar 

  • Fine A, Dunnett SB, Björklund A, Clarke D, Iversen SD (1985) Transplantation of embryonic ventral forebrain neurons to the neocortex of rats with lesions of nucleus basalis magnocellularis. I. Biochemical and anatomical observation. Neuroscience 16:769–786

    Google Scholar 

  • Fisher RS, Buchwald NA, Hull CD, Levine MS (1988) GABAergic basal forebrain neurons project to the neocortex: the localization of glutamic acid decarboxylase and choline acetyltransferase in feline corticopetal neurons. J Comp Neurol 272:489–502

    Google Scholar 

  • Fonnum F (1975) A rapid radiochemical method for the determination of choline acetyltransferase. J Neurochem 24:407–409

    Google Scholar 

  • Freund TF, Meskenaite V (1992) γ-Aminobutyric acid-containing basal forebrain neurons innervate inhibitory interneurons in the neocortex. Proc Natl Acad Sci USA 89:738–742

    Google Scholar 

  • Geula C, Mesulam M-M (1989) Cortical cholinergic fibers in aging and Alzheimer's disease: a morphometric study. Neuroscience 33:469–481

    Google Scholar 

  • Hall RD, Lindholm EP (1974) Organization of motor and somatosensory neocortex in the albino rat. Brain Res 66:23–38

    Google Scholar 

  • Hallanger AE, Wainer BH, Rye DB (1986) Colocalization of gamma-aminobutyric acid and acetylcholinesterase in rodent cortical neurons. Neuroscience 19:763–769

    Google Scholar 

  • Hartgraves SL, Mensah PL, Kelly PH (1982) Regional decreases of cortical acetyltransferase after lesions of the septal area and in the area of nucleus basalis magnocellularis. Neuroscience 7:2369–2376

    Google Scholar 

  • Hodges H, Alien Y, Kershaw T, Lantos PL, Gray JA, Sinden J (1991) Effects of cholinergic-rich neural grafts on radial maze performance of rats after excitotoxic lesions of the forebrain cholinergic projection system. I. Amelioration of cognitive deficits by transplants into cortex and hippocampus but not into basal forebrain. Neuroscience 45:587–607

    Google Scholar 

  • Katayama S, Kito S, Yamamura Y (1990) Increase of muscarinic receptor following kainic acid lesions of nucleus basalis magnocellularis in rat brain: an autoradiographic study. Res Commun Chem Pathol Pharmacol 68:391–394

    Google Scholar 

  • Krnjevic K, Phillis JW (1963) Acetylcholine-sensitive cells in the cerebral cortex. J Physiol (Lond) 166:296–327

    Google Scholar 

  • Lamour Y, Dutar P, Jobert A (1982) Spread of acetylcholine sensitivity in the neocortex following lesion of the nucleus basalis. Brain Res 252:377–381

    Google Scholar 

  • Lamour Y, Dutar P, Jobert A. Dykes RW (1988) An iontophoretic study of single somatosensory neurons in rat granular cortex serving the limbs: a laminar analysis of glutamate and acetylcholine effects on receptive-field properties. J Neurophysiol 60:725–750

    Google Scholar 

  • Levey AI, Wainer BH, Rye DB, Mufson EJ, Mesulam M-M (1984) Choline acetyltransferase-immunoreactive neurons intrinsic to rodent cortex and distinction from acetylcholinesterase-positive neurons. Neuroscience 13:341–353

    Google Scholar 

  • Lysakowski A, Wainer, BH, Bruce G, Hersh LB (1989) An atlas of the regional and laminar distribution of choline acetyltransferase immunoreactivity in rat cerebral cortex. Neuroscience 28:291–336

    Google Scholar 

  • Mash DC, Flynn DD, Potter LT (1985) Loss of M2 muscarine receptors in the cerebral cortex in Alzheimer's disease and experimental denervation. Science 228:1115–1117

    Google Scholar 

  • McCormick DA, Prince DA (1985) Two types of muscarinic response to acetylcholine in mammalian cortical neurones. Proc Natl Acad Sci USA 82:6344–6348

    Google Scholar 

  • McCormick DA, Prince DA (1986) Mechanisms of action of acetylcholine in the guinea pig cerebral cortex, in vitro. J Physiol (Lond) 375:169–194

    Google Scholar 

  • McKinney M, Coyle JT (1982) Regulation of neocortical muscarinic receptors: effects of drug treatment and lesions. J Neurosci 2:97–105

    Google Scholar 

  • McKinney M, Coyle JT, Hedreen JC (1983) Topographic analysis of innervation of the rat neocortex and hippocampus by the basal forebrain cholinergic system. J Comp Neurol 217:103–121

    Google Scholar 

  • Müller CM, Singer W (1989) Acetylcholine-induced inhibition in the cat visual cortex is mediated by a GABAergic mechanism. Brain Res 487:335–342

    Google Scholar 

  • Page KJ, Everitt BJ, Robbins TW, Marston HM, Wilkinson LS (1991) Dissociable effects on spatial maze and passive avoidance acquisition and retention following AMPAand ibotenic acid-induced excitotoxic lesions of the basal forebrain in rats: differential dependence on cholinergic neuronal loss. Neuroscience 43:457–472

    Google Scholar 

  • Pellegrino LJ, Pellegrino AS, Cushman AJ (1979) A stereotaxic atlas of the rat brain, 2nd edn. Plenum, New York

    Google Scholar 

  • Phillis JW, York DH (1967) Cholinergic inhibition in the cerebral cortex. Brain Res 5:517–520

    Google Scholar 

  • Raulli RE, Arendash G, Crews F (1989) Effects of nBM lesions on muscarinic stimulation of phosphoinositide hydrolysis. Neurobiol Aging 10:191–197

    Google Scholar 

  • Robbins TW, Everitt BJ, Ryan CN, Marston HM, Jones GH, Page KJ (1989a) Comparative effects of quisqualic and ibotenic acid-induced lesions of the substantia innominata and globus pallidus on the acquisition of a conditioned visual discrimination: differential effects on cholinergic mechanisms. Neuroscience 28:337–352

    Google Scholar 

  • Robbins TW, Everitt BJ, Marston HM, Wilkinson J, Jones GH, Page KJ (1989b) Comparative effects of ibotenic acid and quisqualic acid-induced lesions of the substantia innominata on attentional function in the rat: further implication for the role of cholinergic neurones of neucleus basalis in cognitive processes. Behav Brain Res 35:221–241

    Google Scholar 

  • Ruberg M, Mayo W, Brice A, Duyckaerts C, Hauw JJ, Simon H, Le Moal M, Agid Y (1990) Choline acetyltransferase activity and [3H]vesamicol binding in the temporal cortex of patients with Alzheimer's disease, Parkinson's disease, and rats with basal forebrain lesions. Neuroscience 35:327–333

    Google Scholar 

  • Saper CB (1984) Organization of cerebral cortical afferent systems in the rat. II. Magnocellular basal nucleus. J Comp Neurol 222:313–342

    Google Scholar 

  • Sarter M, Schneider HH, Stephens DN (1988) Treatment strategies for senile dementia: antagonist β-carbolines. Trends Neurosci 11:13–17

    Google Scholar 

  • Sato H, Hata Y, Hagihara K, Tsumoto T (1987) Effects of cholinergic depletion on neuron activities in the cat visual cortex. J Neurophysiol 58:781–794

    Google Scholar 

  • Shoham S, Newman ME, Wertman E, Ebstein RP (1990) Cortical second messengers after NBM damage: no change in response to cholinergic agonists. Pharmacol Biochem Behav 36:507–513

    Google Scholar 

  • Spehlmann R, Daniels JC, Smathers CC Jr (1971) Acetylcholine and the synaptic transmission of specific impulses to the visual cortex. Brain 94:125–138

    Google Scholar 

  • Szabadi E, Bradshaw CM, Bevan P (1977) Excitatory and depressant responses to noradrenaline, 5-hydroxytryptamine and mescaline: the role of the baseline firing rate. Brain Res 126:580–583

    Google Scholar 

  • Szabadi E, Bradshaw CM, Bevan P (1978) Relation betweeen baseline firing rate and the direction of neuronal responses to noradrenaline: a species comparison. J Pharm Pharmacol 30:392–393

    Google Scholar 

  • Tremblay N, Warren RA, Dykes RW (1990) Electrophysiological studies of acetylcholine and the role of the basal forebrain in the somatosensory cortex of the rat. I. Cortical neurons excited by glutamate. J Neurophysiol 64:1199–1211

    Google Scholar 

  • Watson M, Vickroy TW, Fibiger HC, Roeske WR, Yamamura HI (1985) Effects of bilateral ibotenate-induced lesions of nucleus basalis magnocellularis upon selective cholinergic biochemical markers in the anterior cerbral cortex. Brain Res 346:387–391

    Google Scholar 

  • Wenk G, Markowska AL, Olton DS (1989) Basal forebrain lesions and memory: alterations in neurotensin not acetylcholine may cause amenesia. Behav Neurosci 103:765–769

    Google Scholar 

  • Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, De-Long MR (1982) Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science 215:1237–1239

    Google Scholar 

  • Woolf NJ, Eckenstein F, Butcher LL (1983) Cholinergic projections from the basal forebrain to the frontal cortex: a combined fluorescent tracer and immunohistochemical analysis in the rat. Neurosci Lett 40:93–98

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychology, Institute of Psychiatry, De Crespigny Park, SE5 8AF, London, UK

    F. A. Abdulla & J. D. Sinden

  2. Department of Neuroscience, Institute of Psychiatry, De Crespigny Park, SE5 8AF, London, UK

    M. -R. Calaminici & J. D. Stephenson

  3. Institute of Higher Nervous Activity and Neurophysiology, 5a Butlerov Street, 117865, Moscow, Russia

    V. V. Raevsky

Authors
  1. F. A. Abdulla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. -R. Calaminici
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V. V. Raevsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. D. Sinden
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. A. Gray
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. D. Stephenson
    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

Abdulla, F.A., Calaminici, M.R., Raevsky, V.V. et al. An iontophoretic study of the effects of α-amino-hydroxy-5-methyl-4-isoxazole propionic acid lesions of the nucleus basalis magnocellularis on cholinergic and GABAergic influences on frontal cortex neurones of rats. Exp Brain Res 98, 441–456 (1994). https://doi.org/10.1007/BF00233982

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00233982

Key words

Search

Navigation