title: Flunitrazepam-induced changes in neurophysiological, behavioural, and subjective measures used to assess sedation.
abstract: BACKGROUND
  Certain features of event-related potentials (ERPs), electroencephalographic (EEG), and behavioural measures vary with differing states of alertness and/or sedation.
  
  
  OBJECTIVE
  This study was conducted to investigate changes in several measures usually viewed as reflecting states of sedation/sleepiness associated with the use of a range of doses of the hypnotic benzodiazepine (BZD) flunitrazepam (FNZ).
  
  
  METHODS
  This was a double blind, independent group design study of the effects of acute oral doses of FNZ in young healthy volunteers. Forty-eight subjects were randomly allocated to one of four groups-FNZ (0.6, 0.8, and 1.0 mg) and placebo (PLAC)-and tested prior to treatment and then in a posttreatment session close to the theoretical peak plasma concentration. ERP latencies and amplitudes were measured at midfrontal (Fz), midcentral (Cz), and midparietal (Pz) using a standard auditory oddball paradigm. EEG changes were assessed at Pz. Behavioural measures included the digit-symbol substitution test (DSST), a cancellation task (CT), and subjective ratings of alertness and attentiveness by the subjects (SUB) and the experimenter (EXP).
  
  
  RESULTS
  FNZ led to psychomotor impairments and decreased alertness and attention; these effects were consistent with previous findings. A progressive, dose-related increase in P3 latency occurred in Fz, Cz, and Pz, and there was an increase in N1 (Fz, Cz) and N2 (Fz). N2-P3 amplitude decreased in Fz. EEG power bands beta 1 increased for the two highest doses, but no significant differences were noted in theta, delta, and alpha bands. P3 latencies, experimenter-rated levels of alertness, and DSST scores differentiated all three doses of FNZ from PLAC.
  
  
  CONCLUSIONS
  The most sensitive measures used were P3 latencies of the ERPs (which varied with FNZ dose), DSST, and the experimenter-rated levels of alertness. However, we found no evidence for the assumption that one single phenomenon was reflected in all measures and different mechanisms were probably involved. Further experiments will be needed for more in-depth probing of the finer mechanisms underlying sedation/sleepiness and how they affect behavioural and eletrophysiological measures of the central nervous system (CNS) function.
authors.affiliation: Department of Psychobiology, Universidade Federal de São Paulo, R. Napoleão de Barros, 925 V. Clementino, CEP: 04024-002, São Paulo, SP, Brazil. ligia@psicobio.epm.br
authors.forename: Lígia M
authors.initials: LM
authors.lastname: Lucchesi
authors.forename: Sabine
authors.initials: S
authors.lastname: Pompéia
authors.forename: Gilberto M
authors.initials: GM
authors.lastname: Manzano
authors.forename: André F
authors.initials: AF
authors.lastname: Kohn
authors.forename: José C F
authors.initials: JC
authors.lastname: Galduroz
authors.forename: Orlando F A
authors.initials: OF
authors.lastname: Bueno
authors.forename: Sérgio
authors.initials: S
authors.lastname: Tufik
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D001288:Attention / Q000187:drug effects / Q000502:physiology; D004311:Double-Blind Method; D004569:Electroencephalography / Q000187:drug effects* / Q000706:statistics & numerical data; D005072:Evoked Potentials, Auditory / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005445:Flunitrazepam / Q000494:pharmacology*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D011594:Psychometrics; D011597:Psychomotor Performance / Q000187:drug effects*; D018709:Statistics, Nonparametric
chemical_list: D006993:Hypnotics and Sedatives; D005445:Flunitrazepam