Abstract
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.
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