Vol. 297, Issue 1, 247-253, April 2001

Zolpidem, Triazolam, and Diazepam Decrease Distress Vocalizations in Mouse Pups: Differential Antagonism by Flumazenil and -Carboline-3-carboxylate-t-butyl ester (-CCt)

James K. Rowlett, Walter Tornatzky , James M. Cook, Chunrong Ma¹ and Klaus A. Miczek

Harvard Medical School, New England Regional Primate Research Center, Southborough, Massachusetts (J.K.R., W.T.); Departments of Psychology (W.T., K.A.M.), Psychiatry (K.A.M.), Pharmacology and Experimental Therapeutics (K.A.M.), and Neuroscience (K.A.M.), Tufts University, Medford and Boston, Massachusetts; and Department of Chemistry, University of Wisconsin, Milwaukee, Wisconsin (J.M.C., C.M.)

In response to stressful events, neonatal mice emit ultrasonic vocalizations (USVs), which are suppressed by BZ agonists. The present study examined the role of the benzodiazepine/1 (BZ/1) receptor subtype in the suppression engendered by the BZ/1-preferring agonist zolpidem and the nonselective BZ agonists triazolam and diazepam. The role of BZ receptor subtypes was explored further by conducting antagonism studies using the BZ/1-preferring antagonist -carboline-3-carboxylate-t-butyl ester (-CCt), in comparison with the nonselective BZ antagonist flumazenil. Mouse pups (CFW strain) were separated from their dam and littermates at day 7, and placed for 4 min in a test chamber with reduced ambient temperature (19 ± 1°C) for recording USVs, motor incoordination (measured as a pup rolling on its back per grid cross), and body temperature. Zolpidem, triazolam, and diazepam suppressed USVs in a dose-dependent manner, concomitant with increases in incoordination and augmentation of hypothermia. These effects of the three BZ agonists were blocked by flumazenil in a manner consistent with surmountable antagonism. The ability of zolpidem, but not triazolam or diazepam, to suppress USVs and augment hypothermia was antagonized by -CCt, whereas the increase in motor incoordination engendered by zolpidem, triazolam, and diazepam was not sensitive to -CCt administration. Collectively, these results suggest that zolpidem suppresses distress USVs in mouse pups by a mechanism distinct from that of typical BZs. Furthermore, suppression of distress USVs by zolpidem may involve BZ/1 receptors and a nonanxiolytic mechanism, such as hypothermia.