title: An iontophoretic study of the effects of alpha-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.
abstract: Unilateral lesions of the nucleus basalis magnocellularis (NBM) produced by alpha-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.
authors.affiliation: Department of Psychology, Institute of Psychiatry, London, UK.
authors.forename: F A
authors.initials: FA
authors.lastname: Abdulla
authors.forename: M R
authors.initials: MR
authors.lastname: Calaminici
authors.forename: V V
authors.initials: VV
authors.lastname: Raevsky
authors.forename: J D
authors.initials: JD
authors.lastname: Sinden
authors.forename: J A
authors.initials: JA
authors.lastname: Gray
authors.forename: J D
authors.initials: JD
authors.lastname: Stephenson
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D005625:Frontal Lobe / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D007478:Iontophoresis; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D010275:Parasympathetic Nervous System / Q000502:physiology*; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D005971:Glutamates; D007555:Isoxazoles; D011422:Propionates; C081662:alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D002217:Carbachol; D000109:Acetylcholine; D001640:Bicuculline