DIAZEPAM WITHDRAWAL - EFFECTS OF DIAZEPAM AND GEPIRONE ON ACOUSTIC STARTLE-INDUCED 22 KHZ ULTRASONIC VOCALIZATIONS

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and the putative anxiolytic gepirone with aff inity for 5-hydroxytryptamine (5-HT1A) receptors in naive and diazepam -withdrawn subjects.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 Gepirone (0.1-1 mg/kg IP), but not diazepam (3-20 mg/kg IP) antagonized the increased rate of USV in rats withdrawn from 10 mg/kg b.i.d. diazepam. Diazepam (2.5-10 mg/kg IF) antagonized the increased rate of USV in rats withdrawn from 2.5 mg/kg b.i.d. diazepam.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.