Time course of prepulse inhibition disruption induced by dopamine agonists and NMDA antagonists: Effects of drug administration regimen

Prepulse inhibition (PPI) of acoustic startle response is impaired in patients with schizophrenia and in animals acutely treated with dopamine agonists and NMDA antagonists. In this study, we investigated the time course of PPI disruption induced by repeated amphetamine, quinpirole, phencyclidine (PCP), and dizocilpine (MK-801) treatment. We focused on how PPI disruption development was influenced by drug administration regimens, comparing a constant versus an escalating dosing regimen. Male Sprague-Dawley rats were repeatedly treated with amphetamine (1.25-5.0 mg/kg, or constant 5.0 mg/kg, sc), PCP (0.50-2.0 mg/kg, or constant 0.5, 1.0 or 2.0 mg/kg, sc), quinpirole (0.03-0.12 mg/kg, or constant 0.12 mg/kg, sc), MK-801 (0.025-0.10 mg/kg, or constant 0.10 mg/kg, sc) or vehicle (saline) and tested for PPI once daily for 6 consecutive days. When amphetamine 5.0 mg/kg or quinpirole 0.12 mg/kg was administrated on a constant dosing schedule, both drugs disrupted PPI upon acute administration, but had no effect after repeated treatment and testing (days 2-5). However, when amphetamine 5.0 mg/kg or quinpirole 0.12 mg/kg was preceded by two lower doses in an escalating dosing regimen, both drugs still disrupted PPI on days 5 and 6 when the constant amphetamine and quinpirole had no effect. For PCP and MK-801, repeated treatment under both regimens produced a stable and persistent disruption of PPI. Startle magnitude increased progressively and dose-dependently under both regimens for all drugs except for quinpirole, which caused a decrease. These results suggest that the drug dosing schedule, rather than the absolute amount of drug that an animal receives, has a greater impact on the development of PPI-disruptive effect of dopamine agonists than NMDA antagonists. Thus, in order to mimic the emerging process of PPI deficit with dopamine agonists, an escalating dosing regimen should be used.