Effects of Clozapine, Haloperidol, and Fluoxetine on the Reversal of Cocaine-Induced Locomotor Sensitization

OBJECTIVE Repeated treatment with psychostimulants induces sensitization of the dopaminergic system in the brain. Dopaminergic sensitization has been proposed as a mechanism of psychosis. Although antipsychotics block the expression of sensitized behavior, they are ineffective for reversing the sensitized state. We investigated the effect of clozapine, haloperidol, and fluoxetine on the reversal of cocaine-induced behavioral sensitization. METHODS Male ICR mice were sensitized to cocaine with repeated treatment. Animals were then split into four groups, and each group was treated with vehicle or one of the above drugs for 5 days. After a 3-day drug washout, locomotor activity was assessed before and after a cocaine challenge. RESULTS Clozapine reversed the sensitized state, whereas haloperidol did not. Fluoxetine seemed to reverse the sensitization partially. CONCLUSION We confirmed that D2 blockade was not effective for reversing sensitization. The reversal by clozapine is partially explained in terms of its strong 5-HT2 and weak D2 affinity. The partial reversal by fluoxetine seemed to be related to its serotonin-augmenting action.