Rat pup ultrasonic vocalization: effects of benzodiazepine receptor ligands.
The involvement of the GABA(A)-benzodiazepine receptor complex in rat pup ultrasonic vocalisations was studied by testing benzodiazepine receptor ligands with varying intrinsic activity and selectivity for benzodiazepine subtype receptors. Ultrasonic vocalisations were recorded under two temperature conditions (37 degrees C and 18 degrees C), presumably reflecting a low and high stress state. The latency to the negative geotaxis response, a measure of motor coordination and the rectal temperature were determined to assess putative side effects of drugs. The full, non-selective benzodiazepine receptor agonists diazepam, chlordiazepoxide, alprazolam and oxazepam suppressed ultrasonic vocalisations both at 37 degrees C and 18 degrees C conditions, although more efficaciously at 37 degrees C. The partial, non-selective benzodiazepine receptor agonist bretazenil and the partial benzodiazepine, selective receptor agonist alpidem significantly reduced ultrasonic vocalisations at 37 degrees C, but not at 18 degrees C. The full benzodiazepine, selective receptor agonist zolpidem behaved like other full, non-selective benzodiazepine receptor agonists by reducing ultrasonic vocalisations under both high and low temperature. The effects of zolpidem indicate that activation of benzodiazepine, receptors alone already suffices to suppress ultrasonic vocalisations. The non-selective, benzodiazepine receptor antagonist flumazenil and the partial, non-selective benzodiazepine receptor inverse agonist FG 7142 (N'-methyl-beta-carboline-3-carboxamide) and the full, non-selective benzodiazepine receptor inverse agonist DMCM (6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) 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 confirmed by antagonism of the ultrasonic vocalisations reducing effects of chlordiazepoxide by flumazenil (1 or 3 mg/kg). Using the rat pup ultrasonic vocalisations paradigm under 18 degrees C and 37 degrees C conditions combined with measurements of negative geotaxis-latencies and rectal temperatures it is possible to (1) distinguish benzodiazepine receptor agonists from other anxiolytics because of dissimilar dose response 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.
Olivier
B
B
CNS Research, Solvay Pharmaceuticals, Weesp, The Netherlands. berend.olivier@solvay.com
Molewijk
E
E
van Oorschot
R
R
van der Heyden
J
J
Ronken
E
E
Mos
J
J
D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000188:drug therapy; D001010:Anxiety, Separation; D001831:Body Temperature; D004195:Disease Models, Animal; D005260:Female; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006112:Gravitation; D007274:Injections, Intraperitoneal; D008024:Ligands; D008297:Male; D009949:Orientation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000145:classification; D015203:Reproducibility of Results; D013696:Temperature; D014465:Ultrasonics; D014828:Vocalization, Animal / Q000187:drug effects*
D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008024:Ligands; D011963:Receptors, GABA-A