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Anxiolytic-Like Effects of Perospirone, a Novel Serotonin-2 and Dopamine-2 Antagonist (SDA)-Type Antipsychotic Agent

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Abstract

We examined the anxiolytic potential of perospirone, a novel serotonin-2 and dopamine-2 antagonist (SDA)-type antipsychotic agent, and compared its effects with those of the standard anxiolytic diazepam and the conventional antipsychotic haloperidol by using conditioned defensive burying (CDB) and social interaction (SI) tests in rats. The tests were conducted 1 h after oral administration of the drug. Diazepam inhibited CDB specifically directed toward a probe previously associated with brief electric shock and increased the time spent in SI by pairs of naive rats in a brightly illuminated novel environment. Perospirone mimicked the effects of diazepam by dose dependently suppressing CDB and facilitating SI. In contrast, haloperidol failed to inhibit CDB or increase SI. Thses results suggested that, unlike the conventional antipsychotic haloperidol, perospirone exerts anxiolytic-like effects in animal models with different motivational and emotional states. A braoder efficacy of perospirone for the treatment of anxiety and related symptoms in schizophrenia is discussed.

Section snippets

Subjects

The subjects were male Lister hooded rats (Nihon Dobutu, Japan), each weighing 180.5–317.5 g at the beginning of the experiments. The rats were group housed in a ventilated, temperature (23 ± 2°C)- and humidity (55 ± 10%)-controlled animal care room under a standard 12 L:12 D cycle (lights on at 0800 h, lights off at 2000 h), with free access to food and water. The housing conditions of the rats complied with the institutional guidelines of Sumitomo Pharmaceuticals Research Center.

Apparatus

The CDB test

Conditioned Defensive Burying Test

As shown in Fig. 1, there was a significant dose-related differential response to the shock and shock-control probes in animals treated with the anxiolytic diazepam [dose × probe type interaction: F(4, 90) = 3.316, p < 0.0139]. The time spent in burying the shock probe was dose dependently decreased by diazepam, F(4, 45) = 4.284, p < 0.0051, whereas that of the shock-control probe was not affected. Diazepam did not depress the motility (Fig. 2). Thus, diazepam dose dependently inhibited CDB at

Discussion

The principle findings of the present study were three fold: (a) the anxiolytic diazepam significantly inhibited CDB of the probe previously paired with the aversive stimulus (i.e., shock probe) and significantly prolonged the time spent in active SI between naive rats in the brightly illuminated, novel environment; (b) the SDA-type antipsychotic perospirone, but not the conventional antipsychotic haloperidol, mimicked the effects of diazepam by significantly inhibiting CDB at 0.3 and 1 mg/kg,

Acknowledgements

The authors thank Yoko Ueda, Hitomi Ohki, and Yasuyo Ogiu for their technical and administrative assistance.

References (43)

  • S.M. Korte et al.

    Neuroendocrine and behavioral responses during conditioned active and passive behavior in the defensive burying/probe avoidance paradigmEffects of ipsapirone

    Physiol. Behav.

    (1992)
  • R.G. Lister

    Ethologically based animal models of anxiety disorders

    Pharmacol. Ther.

    (1990)
  • Y. Ohno et al.

    Evaluation of bradykinesia induction by SM-9018, a novel 5-HT2 and D2 receptor antagonist, using the mouse pole test

    Pharmacol. Biochem. Behav.

    (1994)
  • L.J. Terlecki et al.

    Conditioned and unconditioned defensive burying in the rat

    Learn. Motiv.

    (1979)
  • D. Treit et al.

    Conditioned defensive buryingA new paradigm for the study of anxiolytic agents

    Pharmacol. Biochem. Behav.

    (1981)
  • D. Treit

    Animal models for the study of anti-anxiety agentsA review

    Neurosci. Behav. Rev.

    (1985)
  • J.L. Wiley et al.

    Effects of four antipsychotics on punished responding in rats

    Pharmacol. Biochem. Behav.

    (1993)
  • K.D. Wilner et al.

    Anxiolytic effects of ziprasidone compared with diazepam and placebo prior to dental surgery

    Eur. Neuropsychopharmacol.

    (1996)
  • American Psychiatric Association

    Diagnostic and statistical manual of mental disorders

    (1994)
  • N.C. Andreasen et al.

    Negative vs. positive schizophreniaDefinition and validation

    Arch. Gen. Psychiatry

    (1982)
  • M.J. Benvenga et al.

    Olanzapine, an atypical antipsychotic, increases rates of punished responding in pigeons

    Psychopharmacology (Berlin)

    (1995)
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