The effect of 'two hit' neonatal and young-adult stress on dopaminergic modulation of prepulse inhibition and dopamine receptor density.

BACKGROUND AND PURPOSE: A combination of early neurodevelopmental insult(s) and young-adult stress exposure may be involved in the development of schizophrenia. We studied prepulse inhibition (PPI) regulation in rats after an early stress, maternal deprivation, combined with a later stress, simulated by chronic corticosterone treatment, and also determined whether changes in brain dopamine receptor density were involved. EXPERIMENTAL APPROACH: Rats were subjected to either 24 h maternal deprivation on postnatal day 9, corticosterone treatment from 8 to 10 weeks of age, or both. At 12 weeks of age, the rats were injected with 0.1, 0.3 or 1.0 mg.kg(-1) of apomorphine or 0.5 or 2.5 mg.kg(-1) of amphetamine and PPI was determined using automated startle boxes. Dopamine D(1) and D(2) receptor levels were assessed in the nucleus accumbens and caudate nucleus using receptor autoradiography. KEY RESULTS: Young-adult treatment with corticosterone resulted in attenuated disruption of PPI by apomorphine and amphetamine. In some rats, maternal deprivation resulted in reduced baseline PPI which added to the effect of corticosterone treatment. There was no down-regulation of dopamine D(1) or D(2) receptors. CONCLUSIONS AND IMPLICATIONS: These results confirm and extend our finding of an inhibitory interaction of developmental stress on dopaminergic regulation of PPI. No corresponding changes in dopamine receptor density were observed in brain regions with a major involvement in PPI regulation, suggesting long-lasting desensitization of dopamine receptor signalling or indirect changes in PPI regulation.