Phencyclidine supersensitivity in rats with neonatal dopamine loss

Rationale: Disruption in brain dopamine function early in life can lead to enhanced susceptibility to the effects of NMDA receptor antagonists in adulthood, suggesting that animals given neonatal 6-OHDA treatment might provide a model for the altered NMDA receptor function associated with human disease. Objective: The present study investigated whether neonatal dopamine lesions lead to supersensitivity to the stimulant effects of two NMDA antagonists, phencyclidine (PCP) and ketamine. Methods: Sprague-Dawley rats, given dopamine or sham lesions on day 3 of life, were tested as adults for locomotor changes following treatment with NMDA antagonists. Results: Lesioned rats were more sensitive to the stimulant effects of PCP and ketamine than controls. Enhanced sensitivity to PCP emerged in the male lesioned animals following a brief priming regimen with a D-1-dopamine receptor agonist. Sensitization was also induced by repeated treatments with PCP (5 mg/kg), given at weekly intervals across 4 weeks, with progressive increases in activity significantly enhanced in the lesioned animals. Sensitization to PCP was still evident 3 weeks following chronic PCP treatment. The high rates of PCP-induced locomotion in the lesioned animals were not attenuated by pretreatment with a dopamine antagonist selective for the D-1-dopamine receptor site (SCH-23390, 0.3 mg/kg) or with haloperidol (0.5 mg/kg), in comparison to controls. Olanzapine (5 mg/kg), an atypical antipsychotic, significantly reduced the response to PCP (5 mg/kg) in lesioned and control animals. Conclusions: This work confirms that rats with neonatal dopamine loss show enhanced sensitivity to NMDA antagonists, and may provide an animal model for the altered NMDA receptor function observed in human clinical syndromes.