Date of Award
M.A. in Psychology
Dr. Thomas W. Lombardo
Dr. Mary Jeanne Kallman
Dr. Stan L. O'Dell
Dr. Stephen C. Fowler
University of Mississippi
Benzodiazepines are a class of drugs that have several actions including hypnotic features, anti-convulsant features, and anxiolytic features. Midazolam (MZ), a short acting benzodiazepine, is of special interest because of its probable high abuse potential and its efficacy as a preanesthetic.
Tolerance to drug effect has been found for both the hypnotic and anti-convulsant activity of benzodiazepines. Tolerance to the anxiolytic activity of benzodiazepines, however, is less clear. Evidence suggests that the time course for the development of tolerance associated with the anxiolytic action of MZ is slower than the time course associated with tolerance to the sedative and anticonvulsant actions of MZ (Griffiths and Goudie, 1987).
Previous work suggests that acoustic startle is sensitive to behavioral dimensions (ie: anxiety) thought to be related to benzodiazepine effects. Pilot data (Mirabella, Kallman, and Fowler, 1988, 1989a, 1989b, unpublished) utilizing a force platform dynamometer have shown that the device is sensitive to drug effects (pentylenetetrazol and d-amphetamine) and may in fact be more sensitive than other methods (e.g., schedule controlled behavior; direct observation) presently utilized. This being the case, the force platform appears to be a useful device for measuring auditory startle that at the same time in the same subject may be capable of detecting tolerance to drug effect; and the occurrence and intensity of seizures.
The present experiment was designed to examine and assess: the presence and extent of tolerance to the chronic 30 day oral exposure of MZ, startle responses, and/or audiogenic seizures in rats induced by pulses of intense white noise with the use of a force platform dynamometer. Withdrawal was assessed at 2, 4, 8, 12, 24, 46.5 and 76 hrs., and 15 days following the removal of MZ from the drinking water. Four groups (N=8/group) of rats were exposed to successive blocks (20 trials/block) of acoustic startle stimuli (115 dB bursts of white noise) before, during, and after chronic exposure to MZ (control, 15 mg/kg, 30 mg/kg, and 60 mg/kg). Dependent measures for acoustic startle were peak amplitudes of X, Y, and Z axial forces, and the intertrial activity measures (VFx, VFy, and VFz). Fluid intakes for the 30 and 60 mg/kg groups were reduced to 69% and 66% of baseline levels on the first exposure day. Within seven days, both groups returned to baseline fluid intake levels. The actual drug exposure for the three dosing groups across the exposure duration were 13.88, 26.12, and 55.37 mg/kg. Acoustic startle was relatively insensitive to tolerance to MZ after 30 days of chronic oral exposure. The only drug effects observed was a drug x hours x trials effect on the Fx measure following drug removal. Within-session habituation occurred primarily in the first 5 trials. Short-term habituation was observed for trials less than 24 hours apart. Intertrial interval activity measures revealed increasing levels of activity across trials and sessions.
Mirabella, Robert Francis, "The Effect of Repetitive Midazolam Treatment on Acoustical Startle in Rats" (1990). Electronic Theses and Dissertations. 2466.