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 i s distinguishable from (-)-nicotine on neocortical EEG parameters affected by neuronal nicotinic acetylcholine receptor (nAChR) stimulation.
Acute administration of AKT-418 (0.62-6.2 pmol/kg) did not have a significant effect o n tEG amplitude using FFT frequency band analysis. In contrast, acute administration of (-)-nicotine (1.9 pmol/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 pmol/kg) dose-dependently reduced the incidence of spontaneous €4 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 pmol/kg), consistent with the inhibition of HVS discharges being due to activation of nAChRs. (-)-Nicotine (6.0 pmol/ kg/day) reduced total slow wave sleep (SWS) time during 15 days of subcutaneous infusion. In contrast, ABT-418 (14.0 pmolikgiday) did not affect SWS time on day 1, but did reduce SWS by day 15 of infusion. O n day 15, total SWS duration was reduced 26% and 20% by (-)-nicotine and ABT-418, respectively.
The fewer effects of ABT-418 on neocortical EEC 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. o 1996 W I I ~Y -L I S S , Inc