Psychophysiological and psychometric studies after manipulating the GABA system by vigabatrin, a GABA-transaminase inhibitor.
Résumé
This study is concerned with the alterations in central and peripheral psychophysiological measures and psychometric variables after experimental manipulation of the most important inhibitory transmitter system of the CNS, the gamma-aminobutyric acid (GABA) system. Vigabatrin (GVG), a new enzyme-activated, irreversible inhibitor of GABA transaminase, which increases cerebrospinal fluid concentrations of GABA and other substrates of GABA transaminase, was given in single oral doses of 1 g, 2 g and 3 g to 10 normal healthy volunteers. In this double-blind, placebo-controlled crossover study, 3 mg lorazepam was given as reference compound. Blood sampling for vigabatrin kinetics, EEG recordings and evaluation of pulse, blood pressure and side effects were carried out at the hours 0, 1, 2, 4, 6, 8 and 24, and psychometric tests at the same times (except the first hour). Pharmacokinetic analyses demonstrated good absorption of GVG with peak plasma concentrations found within the first two hours, dose-dependent areas under the plasma concentration-time curves and about 65% recovery in the 24-h urine. Computer-assisted spectral analysis of the EEG suggested that GVG produces only small changes in the normal CNS, characterized by an augmentation of total power, absolute and relative power of the beta activity and acceleration of the centroid of the total activity. There was also a trend towards an increase of alpha activity and of the absolute and relative power of the dominant frequency, decrease in the alpha centroid and increase of the centroid of the combined delta and theta activity. Lorazepam 3 mg, in contrast, produced highly significant changes characterized by a decrease of total power, alpha activity, absolute and relative power of the dominant frequency and centroid of the combined delta and theta activity, while beta activity as well as the centroid of the alpha, beta and total activity increased. In the resting condition an additional augmentation of slow activity suggested hypnotic properties of 3 mg lorazepam. The latter changes are typical for anxiolytic sedatives and were also reflected at the behavioral level where psychometric data demonstrated a deterioration in the noo- and thymopsychic parameters and sedative effects in psychophysiological variables. GVG, on the other hand, produced only subtle changes characterized by an improvement of noo- and thymopsychic variables and vegetative activation.