Haloperidol (but not ziprasidone) withdrawal potentiates sensitization to the hyperlocomotor effect of cocaine in mice

One important contributing factor in the high prevalence of drug abuse disorders seen among schizophrenic patients seems to be related to chronic treatment with typical neuroleptics. We have previously demonstrated that withdrawal from long-term treatment with the typical neuroleptic haloperidol, but not the atypical neuroleptic ziprasidone, potentiated the hyperlocomotor effect induced by a single cocaine injection and cocaine-induced conditioned place preference in mice. In the present study we investigated whether withdrawal from long-term treatment with these same neuroleptics would also modify cocaine-induced hyperlocomotion sensitization, which has been proposed as an animal model for the intensification of drug craving in cocaine addiction. Swiss male mice were i.p. treated with haloperidol (1.0 mg/kg) or ziprasidone (4.0 mg/kg) for 15 days. Twenty-four hours after the last injection, animals received an i.p. injection of cocaine (10 mg/kg) for 5 consecutive days, being placed after each injection in the open-field apparatus in order to perform a drug-environment conditioning. Seven days after the last drug-environment conditioning procedure, the animals were challenged with an i.p. injection of cocaine (10 mg/kg), placed in the open-field apparatus and had their locomotor activity quantified. Withdrawal from haloperidol (but not ziprasidone) potentiated cocaine-induced behavioral sensitization. These results are suggested to be a consequence of the development of the dopaminergic supersensitivity phenomenon by long-term treatment with the typical compound. Our findings provide additional support for the use of atypical agents like ziprasidone in the treatment of schizophrenic patients with comorbid substance abuse disorder.