Administration of ziprasidone for 10 days increases cocaine toxicity in mice

Long-term treatment with antipsychotic medications alters the regional density of several of the neurotransmitter receptors that mediate cocaine toxicity. However, the effect of either up- or down-regulation of the neurotransmitter receptors on cocaine toxicity is unknown. In this study, we determined if subacute administration of the atypical antipsychotic ziprasidone altered the toxic effects of cocaine in mice. Ziprasidone (4 mg/kg) or placebo was administered to the first two groups of CF-1 mice for 10 days and, then on day 10, an estimated LD50 dose of cocaine (102 mg/kg) was given to these mice. In a third group, in order to produce a ziprasidone withdrawal state, we administered ziprasidone for 10 days, followed by no treatment for 2 days before cocaine administration. There was no significant difference among the three groups in overall survival: 63% in the treatment group, 60% in the withdrawal group, and 80% in the placebo group. Survival time was significantly shorter for the withdrawal group than for the control group. Our study may have been limited by lower than expected serum ziprasidone concentrations and lower than expected lethality from cocaine. However, our findings suggest that administration of an atypical antipsychotic for 10 days may increase the toxic effects of cocaine.