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In this study, rats were tested in behavioural paradigms relevant to schizophrenia during withdrawal from two different administration schedules of amphetamine (Amph). One of the escalating administration schedules, which has been employed in previous studies, consisted of three daily injections for 6 d with increasing dosages from 1 to 5 mg/kg Amph (Esc-5) and was compared to a hitherto never examined escalating administration schedule [three injections per day for 6 d escalating from 1 to 8 mg/kg Amph (Esc-8)]. Control animals received an equivalent volume of saline (Sal) injections according to the same schedule. Whereas rats treated with Esc-5, as reported before, failed to show an effect on prepulse inhibition (PPI), the Esc-8-treated rats exhibited a long-lasting disruption of PPI in a drug-free state on days 6, 13 and 55 of withdrawal. The Amph-pretreated animals demonstrated a similar magnitude of behavioural sensitization following an Amph challenge on withdrawal day 58 irrespective of the administration schedule. To evaluate if the withdrawal from the two Amph schedules led to a change in brain monoamine levels, a subgroup of animals was neurochemically examined in post-mortem for eight parameters in seven brain regions on withdrawal day 55. Withdrawal from the Esc-8 schedule induced reduced dopamine levels in the caudate putamen. Only this neurochemical finding and the PPI attenuation differentiated the Esc-8 animals from the Esc-5 and Sal animals. These data suggest that, based on the endogenous sensitization hypothesis of schizophrenia, the persistent disruption of PPI observed in animals withdrawn from Esc-8 can be used as a valid animal model of specific symptoms of schizophrenic patients.

Differential effects on prepulse inhibition of withdrawal from two different repeated administration schedules of amphetamine