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

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.