Ja. Vivian et al., DIAZEPAM WITHDRAWAL - EFFECTS OF DIAZEPAM AND GEPIRONE ON ACOUSTIC STARTLE-INDUCED 22 KHZ ULTRASONIC VOCALIZATIONS, Psychopharmacology, 114(1), 1994, pp. 101-108
It has proven difficult to demonstrate and study the ''anxiogenic'' qu
ality of drug withdrawal states in animals. Ultrasonic vocalizations (
USV) in response to acoustic startle stimuli have shown promise as a m
easure of affect and may represent ''distress'' responses during diaze
pam withdrawal. Three experiments evaluated the association between US
V and ''distress'' by comparing the effects of diazepam as a prototypi
c benzodiazepine agonist and the putative anxiolytic gepirone with aff
inity for 5-hydroxytryptamine (5-HT1A) receptors in naive and diazepam
-withdrawn subjects. Adult male Long-Evans rats were exposed to acoust
ic startle sessions consisting of nine 105 dB and nine 115 dB stimuli.
USV at 20-30 kHz were readily emitted during startle and often commen
ced after the third or fourth stimulus presentation. Acutely, intraper
itoneal (IP) administration of diazepam (0.1-3 mg/kg) and gepirone (0.
1-1 mg/kg) decreased USV dose-dependently without affecting the startl
e reflex; gepirone also decreased tail flick latency. Startle-induced
USV were also sensitive to the ''anxiogenic'' effects of withdrawal fr
om diazepam exposure (0, 2.5, 5, 10 mg/kg b.i.d. IP x 5 days). Twenty-
four hours after the last diazepam injection, rats were hyperreactive
to startle stimuli and doubled their rate of USV over vehicle-treated
controls. Gepirone (0.1-1 mg/kg IP), but not diazepam (3-20 mg/kg IP)
antagonized the increased rate of USV in rats withdrawn from 10 mg/kg
b.i.d. diazepam. Diazepam (2.5-10 mg/kg IF) antagonized the increased
rate of USV in rats withdrawn from 2.5 mg/kg b.i.d. diazepam. USV indu
ced by acoustic startle stimuli are sensitive to the anxiolytic effect
s of benzodiazepine and 5-HT1A receptor agonists and permit the assess
ment of the ''anxiogenic'' properties of diazepam withdrawal. The pote
nt effect of gepirone on USV suggests a serotonergic amelioration of t
he ''anxiogenic'' aspects of diazepam withdrawal.