Abstracts

Talampanel (LY 300164) is a potent and selective, orally active noncompetitive AMPA receptor antagonist with anticonvulsant and neuroprotective properties. We sought to identify human neurophysiological parameters [(EEG and TMS (transcranial magnetic stimulation)] sensitive to blockade of AMPA receptors that can be used to functionally monitor synaptic AMPA receptors during treatment trials with AMPA receptor antagonists. Six healthy volunteers were given single oral doses of talampanel (25 or 50 mg) or placebo. An 18-lead EEG recording was acquired for 1h before treatment and for 3 h after treatment. Averaged 1 min epochs were analyzed for [alpha], [beta], and [gamma] activity by FFT. Single and paired magnetic pulses were applied over the scalp to activate the abductor pollicis brevis muscle. Resting and active motor thresholds, recruitment curves and intracortical inhibition/facilitation were determined. Talampanel treatment was associated with a dose-dependent increase in [beta] (fast, [gt]13 Hz) activity (peaking at 1 h) with no change in [alpha]. In the TMS studies, resting and active motor thresholds were elevated by talampanel, and the recruitment curve gradient was decreased, particularly at stimulation intensities close to the threshold value, suggesting that AMPA receptors are critical to motor unit recruitment at lower stimulation intensities. Talampanel was not associated with any consistent change in intracortical inhibition or facilitation. Placebo treatment failed to affect any of the EEG or TMS parameters. Blockade of brain AMPA receptors causes an increase in EEG [beta] activity. The resting and active thresholds for TMS-evoked motor activity are highly sensitive to AMPA receptor blockade and there are also specific changes in the recruitment curve. These parameters can be used to monitor in real time the extent of blockade of synaptic AMPA receptors during treatment trials with AMPA receptor antagonists. (Supported by National Institute of Neurological Disorders and Stroke, NIH)