Abstract
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/α1 (BZ/α1) receptor subtype in the suppression engendered by the BZ/α1-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/α1-preferring antagonist β-carboline-3-carboxylate-t-butyl ester (β-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 β-CCt, whereas the increase in motor incoordination engendered by zolpidem, triazolam, and diazepam was not sensitive to β-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/α1 receptors and a nonanxiolytic mechanism, such as hypothermia.
Footnotes
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Send reprint requests to: James K. Rowlett, Ph.D., New England Regional Primate Research Center, Harvard Medical School, One Pine Hill Dr., Box 9102, Southborough, MA 01772-9102. E-mail:james_rowlett{at}hms.harvard.edu
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↵1 Current address: Pfizer International-La Jolla, 10777 Science Center Dr., San Diego, CA 92121.
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This research was supported by U.S. Public Health Service Grants DA11792 (to J.K.R.), MH46851 (to J.M.C.), and RR00168 (administered to the New England Regional Primate Research Center).
- Abbreviations:
- BZ
- benzodiazepine
- β-CCt
- β-carboline-3-carboxylate-t-butyl ester
- USV
- ultrasonic vocalization
- 5-HT
- 5-hydroxytryptamine
- CI
- confidence interval
- Received November 20, 2000.
- Accepted December 21, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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