Abstract
The present study investigated the effects of a benzodiazepine receptor antagonist, β-carboline ZK 93426 (1, 3 and 10 mg/kg, IP), on scopolamine and nucleus basalis (NB) quisqualic acid lesion-induced neocortical electrocortical activity slowing in rats. Scopolamine induced a dose dependent increase in EEG spectral values and slow delta waves (0.3<0.9=2.7 mg/kg IP). ZK 93426 partially reversed EEG slowing induced by the smallest scopolamine dose (0.3 mg/kg), but had no effect on the EEG changes induced by higher doses. A combination of scopolamine at 0.3 mg/kg and mecamylamine (a centrally active nicotinic antagonist) at 10 mg/kg induced an EEG slowing that was not reversed by ZK 93426. NB lesions markedly decreased cortical choline acetyltransferase (ChAT) activity (−77%) and increased EEG slow waves. ZK 93426 had no effect on the NB lesion-induced slow wave activity increase. The present results support the idea that β-carboline ZK 93426 may increase cortical cholinergic activity by disinhibiting the NB cholinergic neurons. However, if the activity of “NB to cortex” cholinergic system is greatly decreased by either a marked reduction in NB cell number (in NB-lesioned rats), a near complete cortical post-synaptic muscarinic receptor blockade (large scopolamine dose) or by a combination of nicotinic (decrease acetylcholine release) and muscarinic receptor blockade, the effects of β-carboline ZK 93426 on EEG slowing may be negligible.
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Alhainen K, Partanen J, Reinikainen K, Laulumaa V, Soininen H, Airaksinen M, Riekkinen P Sr (1991) Discrimination of tetrahydroaminoacridine responders by a single dose pharmaco-EEG in Alzheimer's disease. Neurosci Lett 127:113–116
Atweh S, Simon JR, Kuhar MJ (1976) Utilization of sodium-dependent high affinity choline uptake in vitro as a measure of the activity of cholinergic neurons in vivo. Life Sci 17:1535–1544
Bartus RT, Dean RL, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric dysfunction. Science 217:408–417
Beani L, Bianchi C, Ferraro L, Nilsson L, Nordberg A, Romanelli L, Spalluto P, Sundwall A, Tanganelli S (1989) Effects of nicotine on the release of acetylcholine and amino acids in the brain. In: Nordberg A, Fuxe K, Holmstedt B, Sundwall A (eds) Nicotine receptors in the CNS: their role in synaptic transmission. Elsevier, Amsterdam
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
Bigl A, Woolf NJ, Butcher LL (1982) Cholinergic projections from basal forebrain to frontal, parietal, temporal, occipital, and cingulate cortices: a combined fluorescent tracer and acetylcholinesterase analysis. Brain Res Bull 8:727–749
Bowen DM, Smith CP, White P, Davinson AN (1976) Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiothrophies. Brain 99:459–496
Buzsáki G, Bickford RG, Ponomareff G, Thal LJ, Mandel G, Gage F (1988) Nucleus basalis and thalamic control of neocortical activity in the freely moving rat. J Neurosci 11:4007–4026
Casamenti F, Deffenu G, Abbamondi AL, Pepeu G (1986) Changes in cortical acetylcholine output induced by modulation of the nucleus basalis. Brain Res Bull 16:589–695
Detari L, Vanderwolf CH (1987) Activity of identified cortically projections and other basal forebrain neurons during large slow waves and cortical activation in anesthetized. Brain Res 437:1–10
Halliwell JV (1986) M-current in human neurocortical neurones. Neurosci Lett 67:1–6
Hedreen JC, Bacon SJ and Price DL (1985) A modified histochemical technique to visualize acetylcholinesterase containing axons. J Histochem Cytochem 33:134–140
Hodges H, Trasher S, Gray JA (1989) Improved radial maze performance induced by the benzodiazepine antagonist ZK93426 in lesioned and alcohol treated rats. Behav Pharmacol 1:45–55
Ingham CA, Bolam JP, Smith AD (1988) GABA-immunoreactive synaptic boutons in the rat basal forebrain: comparison of neurons that project to the neocortex with pallidosubthalamic neurons. J Comp Neurol 273:263–282
Madison DV, Lancaster B, Nicoll RA (1987) Voltage clamp analysis of cholinergic action in the hippocampus. J Neurosci 7:733–741
Mazurkiewicz MM, Sirviö J, Riekkinen P (1992) Attenuation by the benzodiazepine receptor antagonist, ZK 93426, of the deficit in spatial navigation induced by nucleus basalis lesions. Behav Neural Biol (in press)
McCormick DA (1989) Cholinergic and noradrenergic modulation of thalamocortical processing. TINS 12:215–221
Miller JA, Chmielewski PA (1990) The regulation of high-affinity choline uptake in vitro in rat cortical and hippocampal synaptosomes byβ-carbolines administered in vivo. Neurosci Lett 114:351–355
Paxinos G and Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press, New York
Perry EK, Perry RH, Blessed G, Tomlinson BE (1977) Necropsy evidence of central cholinergic deficits in senile dementia. Lancet i:289
Reinikainen KJ, Riekkinen PJ, Paljärvi L, Soininen H, Helkala E-L, Jolkkonen J, Laakso M (1989) Cholinergic deficit in Alzheimer's disease: a study based on CSF and autopsy data. Neurochem Res 13:135–146
Riekkinen P Jr, Sirviö J, Hannila T, Miettinen T, Riekkinen P (1990a) Effects of quisqualic acid NB lesioning on cortical EEG passive avoiance and water maze performance. Brain Res Bull 24:839–842
Riekkinen P Jr, Sirviö J, Riekkinen P (1990b) Relationship between the cortical ChAT content and EEG delta activity. Neurosci Res 8:12–20
Riekkinen P, Buzsáki G, Riekkinen P Jr, Soininen H, Partanen J, Alhainen K (1991) The cholinergic system and EEG slow waves. Electroencephalogr Clin Neurophysiol 78:89–96
Riekkinen P Jr, Jäkälä P, Sirviö J, Koivisto E, Miettinen R, Riekkinen P (1991) The effects of THA on scopolamine and nucleus basalis lesion-induced EEG slowing. Brain Res Bull 26:633–637
Sarter M, Schneider HH (1988) High density of benzodiazepine binding sites in the substantia innominata of the rat. Pharmacol Biochem Behav 30:679–682
Sarter M, Steckler T (1989) Spontaneous exploration of a 6-arm radial tunnel maze by basal forebrain lesioned rats: effects of the benzodiazepine receptor antagonistβ-carboline ZK 93426. Psychopharmacology 98:193–202
Sarter M, Bodewitz G, Stephens DN (1988) Attenuation of scopolamine-induced impairment of spontaneous alternation behaviour by antagonist but not inverse agonist and agonistβ-carbolines. Psychopharmacology 94:491–495
Sarter M, Bruno JP, Dudchenko P (1990) Activating the damaged basal forebrain cholinergic system: tonic stimulation versus signal amplication. Psychopharmacology 101:1–17
Vizi ES, Kobayashi O, Töröcsik A, Kinjo M, Nagashima H, Manabe N, Goldiner PL, Plotter PE, Foldes FF (1989) Heterogeneity of presynaptic muscarinic receptors involved in modulation or transmitter release. Neuroscience 31:259–267
Zaborski L, Heimer L, Eckenstein F, Lernath C (1986) GABAergic input to cholinergic forebrain neurons: an ultrastructural study using retrograde tracing of HRP and double immunolabeling. J Comp Neurol 250:282–295
Zsilla G, Cheney DL, Costa E (1976) Regional changes in the rats of turnover of acetylcholine in rat brain following diazepam or muscimol. Arch Pharmacol 294:251–255
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Riekkinen, P., Riekkinen, M., Sirviö, J. et al. Effects of ZK 93426 on muscarinic and nicotinic antagonist or nucleus basalis lesioning-induced electrocortical slowing. Psychopharmacology 111, 195–201 (1993). https://doi.org/10.1007/BF02245523
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DOI: https://doi.org/10.1007/BF02245523