Potentiation by DSP-4 of EEG slowing and memory impairment in basal forebrain-lesioned rats.
The effects of cholinergic and noradrenergic depletion, alone and in combination, on spatial memory and electroencephalogram (EEG) activity were investigated. Basal forebrain-lesioned rats exhibited a significant decrease in cortical choline acetyltransferase activity and spatial memory impairment. In the cortical EEG, the basal forebrain lesion induced EEG slowing such as an increase in delta power activity and a decrease in beta power activity. Noradrenergic depletion following a treatment with DSP-4 (N-2-(chloroethyl)-N-ethyl-2-bromobenzylamine) had no effect on cortical choline acetyltransferase activity and spatial memory, but it aggravated the cognitive impairment induced by the basal forebrain lesion. DSP-4 itself increased delta power activity in non-lesioned rats, whereas DSP-4 potentiated the EEG slowing induced by the basal forebrain lesions. Systemic administration of tetrahydroaminoacridine at 1 or 3 mg/kg, i.p., ameliorated the memory deficits and EEG slowing induced by the basal forebrain lesion. However, the drug could not attenuate the EEG slowing and memory impairment in rats that had received a combination of DSP-4 and basal forebrain lesion. These results suggest that noradrenergic depletion aggravated the EEG slowing and the spatial memory impairment induced by cholinergic dysfunction and may decrease the efficacy of an anticholinesterase agent in reversing the cortical cholinergic hypofunction.
Abe
K
K
Department of Pharmacology, Shionogi and Co. Ltd., Osaka, Japan.
Horiuchi
M
M
Yoshimura
K
K
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D001927:Brain Diseases / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D004569:Electroencephalography / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000378:metabolism*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000172:deficiency / Q000378:metabolism; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013619:Tacrine / Q000494:pharmacology
D001596:Benzylamines; D002800:Cholinesterase Inhibitors; D014179:Neurotransmitter Uptake Inhibitors; D013619:Tacrine; D002795:Choline O-Acetyltransferase; C012102:DSP 4; D009638:Norepinephrine