Do alprazolam-induced changes in saccadic eye movement and psychomotor function follow the same time course?
The purpose of this study was to determine whether short-term tolerance develops to GABA-agonist-induced changes in saccadic eye movements (SEMs), and whether the time course for GABA-agonist induced onset and offset of impairment is similar for SEMs and for psychomotor function. An additional goal was to determine whether there are differences in sensitivity between SEMs and psychomotor function. Six healthy volunteers participated in this balanced double-blind, three-way crossover, single-dose study of placebo and two different dosage forms of the GABA-agonist alprazolam: a rapidly absorbed oral 1.5-mg compressed tablet (CT) and a 3.0-mg sustained release (SR) tablet. Treatments were separated by a 7-day washout period. Peak concentrations did not differ between CT and SR treatments, although area under the concentration-time curve (AUC) of alprazolam was greater after administration of SR than after CT, because plateau concentrations were attained after SR. Both SEM and psychomotor tests showed time-dependent responses consistent with the development of tolerance. SEMs discriminated the differences in rate of drug input of the CT and SR formulations, with impairment evident at low concentrations during absorption. SEM impairment also persisted longer than did psychomotor impairment. Peak saccade velocity is a more sensitive indicator of pharmacologic effects mediated by the GABA-benzodiazepine receptor complex than are psychomotor responses. This is probably the result of the very high GABA dependency of SEMs, along with their limited sensitivity to motivation.
Kroboth
P D
PD
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pennsylvania 15261, USA.
Folan
M M
MM
Bauer
K S
KS
Tullock
W
W
Wright
C E
CE
Sweeney
J A
JA
D000328:Adult; D000525:Alprazolam / Q000097:blood / Q000494:pharmacology*; D014151:Anti-Anxiety Agents / Q000097:blood / Q000494:pharmacology*; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D018755:GABA Agonists / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011597:Psychomotor Performance / Q000187:drug effects*; D012438:Saccades / Q000187:drug effects*; D013607:Tablets; D013997:Time Factors
D014151:Anti-Anxiety Agents; D003692:Delayed-Action Preparations; D018755:GABA Agonists; D013607:Tablets; D000525:Alprazolam