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The 5-HT1A receptor agonist MKC-242 reverses isolation rearing-induced deficits of prepulse inhibition in mice

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Abstract

Rationale

Prepulse inhibition (PPI) of startle provides an operational measure of sensorimotor gating in which a weak stimulus presented prior to a startling stimulus reduces the startle response. PPI deficits observed in schizophrenia patients can be modeled in rats by individual housing from weaning until adulthood. The deficits in PPI produced by isolation rearing can be reversed by antipsychotics. We previously found that (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242), a highly potent 5-HT1A receptor agonist, reduced aggressive behavior selectively in isolation-reared mice.

Objective

This study examines whether isolation rearing of mice produces PPI deficits and whether PPI deficits are attenuated by 5-HT1A receptor activation.

Methods

Male ddY mice, 4 weeks old, were housed for more than 6 weeks singly or in groups of five or six. The PPI of the acoustic startle response was measured using SR-LAB systems.

Results

The PPI was less in isolation-reared mice than in group-reared mice. Oral administration of MKC-242 at 0.1–0.3 mg/kg reversed PPI deficits in isolation-reared mice, although it did not affect PPI in group-reared mice. MKC-242 did not affect MK-801-induced and apomorphine-induced PPI deficits in group-reared mice. The reversal by MKC-242 of isolation-induced PPI deficits was antagonized by the 5-HT1A receptor antagonist WAY100635 at low doses.

Conclusion

These results suggest that isolation rearing produces deficits in sensorimotor gating in mice that are reversible by activation of 5-HT1A receptors, probably somatodendritic 5-HT1A autoreceptors.

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Acknowledgements

This work was supported by grants from Grant-in-Aid for Scientific Research and Mitsubishi Pharma Co. We acknowledge the donation of MKC-242 and WAY100635 from Dr. M. Egawa (Mitsubishi Pharma Co.).

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Authors and Affiliations

  1. Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1–6 Yamada-oka, Suita 565-0871, Osaka, Japan

    Masaki Sakaue & Akemichi Baba

  2. Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1–6 Yamada-oka, Suita 565-0871, Osaka, Japan

    Yukio Ago & Toshio Matsuda

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  1. Masaki Sakaue
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  2. Yukio Ago
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  3. Akemichi Baba
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  4. Toshio Matsuda
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Correspondence to Toshio Matsuda.

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Sakaue, M., Ago, Y., Baba, A. et al. The 5-HT1A receptor agonist MKC-242 reverses isolation rearing-induced deficits of prepulse inhibition in mice. Psychopharmacology 170, 73–79 (2003). https://doi.org/10.1007/s00213-003-1515-x

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  • DOI: https://doi.org/10.1007/s00213-003-1515-x

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