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Effects of the cholinergic channel activator ABT‐418 on cortical EEG: Comparison with (−)‐nicotine
Author(s) -
Radek Richard J.,
Briggs Clark A.,
Sullivan James P.,
Kang ChaeHee,
Arneric Stephen P.
Publication year - 1996
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199602)37:2<73::aid-ddr2>3.0.co;2-i
Subject(s) - nicotine , nicotinic agonist , cholinergic , mecamylamine , chemistry , stimulation , acetylcholine , acetylcholine receptor , endocrinology , nicotinic acetylcholine receptor , medicine , electroencephalography , pharmacology , anesthesia , psychology , neuroscience , receptor , biochemistry
ABT‐418[(S)‐3‐methyl‐5‐(1‐methyl‐2‐pyrrolidinyl)isoxazole] is a novel cholinergic channel activator (ChCA) and, like the prototypic ChCA (−)‐nicotine, has cognition enhancing and anxiolytic effects. It appears, however, to have fewer central nervous system (CNS) or peripheral side effects compared to (−)‐nicotine. The purpose of this study was to determine whether ABT‐418 also is distinguishable from (−)‐nicotine on neocortical EEG parameters affected by neuronal nicotinic acetylcholine receptor (nAChR) stimulation. Acute administration of ABT‐418 (0.62–6.2 μmol/kg) did not have a significant effect on EEG amplitude using FFT frequency band analysis. In contrast, acute administration of (−)‐nicotine (1.9 μmol/kg) produced a sustained EEG desynchronization which was reflected in significantly lowered EEG amplitude, an effect indicative of generalized cortical stimulation. Like (−)‐nicotine, however, ABT‐418 (0.62–6.2 μmol/kg) dose‐dependently reduced the incidence of spontaneous 6–8 Hz neocortical spike wave discharges (high voltage spindles, HVS) in awake 12‐month‐old rats. The HVS effect of ABT‐418 was blocked by the nicotinic antagonist mecamylamine (5.0 μmol/kg), consistent with the inhibition of HVS discharges being due to activation of nAChRs. (−)‐Nicotine (6.0 μmol/kg/day) reduced total slow wave sleep (SWS) time during 15 days of subcutaneous infusion. In contrast, ABT‐418 (14.0 μmol/kg/day) did not affect SWS time on day 1, but did reduce SWS by day 15 of infusion. On day 15, total SWS duration was reduced 26% and 20% by (−)‐nicotine and ABT‐418, respectively. The fewer effects of ABT‐418 on neocortical EEG and sleep distinguishes this compound from (−)‐nicotine. This study suggests that the previously reported behavioral effects ABT‐418 may not be a simple consequence of neocortical activation, as ABT‐418 did not induce EEG activation at doses which have been found to evoke behavioral responses. © 1996 Wiley‐Liss, Inc.