B. Olivier et al., RAT PUP ULTRASONIC VOCALIZATION - EFFECTS OF BENZODIAZEPINE RECEPTOR LIGANDS, European journal of pharmacology, 358(2), 1998, pp. 117-128
The involvement of the GABA(A)-enzodiazepine receptor complex in rat p
up ultrasonic vocalisations was studied by testing benzodiazepine rece
ptor ligands with varying intrinsic activity and selectivity for benzo
diazepine subtype receptors. Ultrasonic vocalisations were recorded un
der two temperature conditions (37 degrees C and 18 degrees C), presum
ably reflecting a low and high stress state. The latency to the negati
ve geotaxis response, a measure of motor coordination and the rectal t
emperature were determined to assess putative side effects of drugs. T
he full, non-selective benzodiazepine receptor agonists diazepam, chlo
rdiazepoxide, alprazolam and oxazepam suppressed ultrasonic vocalisati
ons both at 37 degrees C and 18 degrees C conditions, although more ef
ficaciously at 37 degrees C. The partial, non-selective benzodiazepine
receptor agonist bretazenil and the partial benzodiazepine(1) selecti
ve receptor agonist alpidem significantly reduced ultrasonic vocalisat
ions at 37 degrees C, but not at 18 degrees C. The full benzodiazepine
(1) selective receptor agonist zolpidem behaved like other fun, non-se
lective benzodiazepine receptor agonists by reducing ultrasonic vocali
sations under both high and low temperature. The effects of zolpidem i
ndicate that activation of benzodiazepine(1) receptors alone already s
uffices to suppress ultrasonic vocalisations. The non-selective, benzo
diazepine receptor antagonist flumazenil and the partial, non-selectiv
e benzodiazepine receptor inverse agonist FG 7142 (N'-methyl-beta-carb
oline-3-carboxamide) and the full, non-selective benzodiazepine recept
or inverse agonist DMCM ,7-dimethoxy-4-ethyl-beta-carboline-3-carboxyl
ate) had no significant effect on ultrasonic vocalisations under both
temperature conditions. The involvement of benzodiazepine receptors in
rat pup ultrasonic vocalisations (37 degrees C-condition) was confirm
ed by antagonism of the ultrasonic vocalisations reducing effects of c
hlordiazepoxide by flumazenil (1 or 3 mg/kg). Using the rat pup ultras
onic vocalisations paradigm under 18 degrees C and 37 degrees C condit
ions combined with measurements of negative geotaxis-latencies and rec
tal temperatures it is possible to (1) distinguish benzodiazepine rece
ptor agonists from other anxiolytics because of dissimilar dose respon
se curves at 37 degrees C and 18 degrees C, (2) differentiate partial
from full receptor agonists by absence of effects at the 18 degrees C
condition, (3) suggest a key role for benzodiazepine, receptors in the
modulation of ultrasonic vocalisations. These data contribute to the
predictive validity of pup vocalizations as an animal model of anxiety
. (C) 1998 Elsevier Science B.V. All rights reserved.