Ontogeny of phencyclidine and apomorphine-induced startle gating deficits in rats.

NMDA antagonists and dopamine agonists produce behavioral and neuropathological changes in rats that may model schizophrenia symptoms. In adult rats, both drug types disrupt sensorimotor gating measured by prepulse inhibition (PPI), mirroring PPI deficits seen in schizophrenia patients. High doses of NMDA antagonists also cause limbic system pathology similar to schizophrenia neuropathology. In 16-day-old rat pups, both the NMDA antagonist phencyclidine (PCP) and the dopamine agonist apomorphine disrupted PPI, showing early developmental functionality of the underlying substrates. However, PCP-induced neurotoxicity was only observed in adult rats, indicating that brain mechanisms responsible for PPI disruption and neurotoxicity are dissociable across development.

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Abstract

NMDA antagonists and dopamine (DA) agonists produce neuropathological and/or behavioral changes in rats that may model specific abnormalities in schizophrenia patients. In adult rats, NMDA antagonists and DA agonists disrupt sensorimotor gating-measured by prepulse inhibition (PPI)-modeling PPI deficits in schizophrenia patients. In addition, high doses of NMDA antagonists produce limbic system pathology that may model neuropathology in schizophrenia patients. We examined these behavioral and neuropathological models across development in rats. Both the NMDA antagonist phencyclidine (PCP) and the DA agonist apomorphine disrupted PPI in 16 day pups, demonstrating early developmental functionality in substrates regulating these drug effects on PPI. In contrast, PCP neurotoxicity was evident only in adult rats. Brain mechanisms responsible for the PCP disruption of PPI, and PCP-induced neurotoxicity, are dissociable across development.