Conditioned ultrasonic distress vocalizations in adult male rats as a behavioural paradigm for screening anti-panic drugs

Abstract

Rats may produce ultrasonic vocalizations (USV) in threatening situations. USV of adult male rats in association with aversive stimulation was evaluated as a screening method for anxiolytic drugs. The triazolobenzodiazepine alprazolam, the 5-HT uptake inhibitors fluvoxamine and clomipramine, the mixed 5-HT/NA uptake inhibitor imipramine, the full 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan, the partial 5-HT1A receptor agonists buspirone, ipsapirone and BMY 7378, the alpha 2-adrenoceptor agonist clonidine and the alpha 2-adrenoceptor antagonist yohimbine reduced conditioned USV. The classical benzodiazepines (BZD) diazepam and chlordiazepoxide were ineffective or had a very low potency to decrease USV. The partial BZD receptor agonists bretazenil, alpidem and zolpidem, the BZD receptor antagonist flumazenil, the NA uptake inhibitors desipramine and maprotiline, and the 5-HT3 receptor antagonist ondansetron had no effect on conditioned USV. The dopamine-D2 receptor antagonist haloperidol reduced USV at a very high dose. In separate experiments the effects of these drugs on locomotor activity were assessed. There was, however, no direct relationship between effects on motor behaviour and USV. In conclusion, the sensitivity of conditioned USV to 5-HT uptake inhibitors and alprazolam versus the insensitivity to classical benzodiazepines and NA uptake inhibitors provides a very interesting profile, which closely resembles the psychopharmacology of panic disorder. Also the face validity of conditioned USV towards situational panic attacks is high. We therefore propose conditioned USV in adult male rats as a novel behavioural paradigm to screen for anti-panic drugs.

The Gerbil Elevated Plus-Maze I Behavioral Characterization and Pharmacological Validation

“…Similarly, fluoxetine and paroxetine did not exhibit any anxiolyticlike activity in rat and mouse elevated plus-maze, and in fact produced anxiogenic effects (Silva et al 1999;Kurt et al 2000;Silva and Brandao 2000;Koks et al 2001). However, in contrast to the data generated in rat and mouse elevated plus-mazes, imipramine, fluoxetine, and paroxetine have been shown to produce anxiolytic-like actions in a number of other animal models of anxiety, including rat social interaction (Lightowler et al 1994), shock-or separation-induced vocalizations in rats and guinea pigs (Molewijk et al 1995;Molewijk et al 1996;Kramer et al 1998;Schreiber et al 1998;Podhorna and Brown 2000), and the four-plate test in mice (Hascoet et al 2000). Therefore, it is of interest that the gerbil elevated plus-maze appears to corroborate the anxiolytic findings with antidepressants in other invivo anxiety models and the recent findings in human patients.…”

Mouse defensive behaviors: pharmacological and behavioral assays for anxiety and panic

“…Molewijk et al [72] suggested that conditioned ultrasonic vocalizations (USV) elicited by reintroducing adult rats into the environment in which they previously received inescapable footshocks may serve as a screening method for panicmodulating drug effects. However, as can be seen in Table 2, major discrepancies between animal studies and clinical ®ndings have been found with this model.…”

“…Instead, panic may even be exacerbated by buspirone or esinoxan [23,42,74,102]. Moreover, a single administration of clomipramine, imipramine,¯uvoxamine, mCPP and yohimbine, which have all demonstrated panicogenic properties following acute treatment, produced clear antipaniclike activity in the USV [72,91]. Taken as a whole, these ®ndings strongly question the predictive validity of USV as an animal model of panic.…”

Effect of Anxiolytic Drugs on Air-Puff-Elicited Ultrasonic Vocalization in Adult Rats

“…3). The anxiolytic effects of many benzodiazepines on USVs have been previously shown in adult rats [1,2,10,16] and in rat pups [3,4,20], though the active doses were close to those that produce muscle relaxation and sedation. The dosage of diazepam (0.25-1.0 mg/kg, s.c.) used in the present study was supposed to have an anxiolytic effect, with neither muscle relaxation nor sedation occurring.…”

“…In view of the behavioral contexts in which USV are emitted, they are often interpreted as expressions of "fear" or "anxiety" [1,8]. Many attempts have been made to develop animal models to test the anxiolytic effects of drugs [2,6,10,16]. Suppression by anxiolytics of electric shockelicited or acoustic startle-elicited USV in adult rats have been proposed as animal models of psychopharmacology of anxiolytic action which are behaviorally compatible with human anxiolytic function.…”