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

Abstract

ObjectiveRepeated 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.MethodsMale 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.ResultsClozapine reversed the sensitized state, whereas haloperidol did not. Fluoxetine seemed to reverse the sensitization partially.ConclusionWe 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.

Evaluation of multitarget drugs on the expression of cocaine-induced locomotor sensitization in male rats: A comparative study

“…Regarding cocaine locomotor sensitization, our results show that the administration of MIR, PIN, FLX, RIS, TRZ, ZPR, OND, or PRZ in the previously described dose ranges generated a significant attenuation of cocaine locomotor sensitization. The results are consistent with previous results, which showed that, at the dose mentioned above, MIR [ 50 , 53 ], FLX [ 71 , 74 ], RIS [ 56 ], ZPR [ 75 , 76 ], OND [ 64 , 77 ], and PRZ [ [78] , [79] , [80] ] reduce hyperactivity induced by COC; decrease cocaine self-administration and attenuate the induction and expression of cocaine sensitization.…”

High affinity α3β4 nicotinic acetylcholine receptor ligands AT-1001 and AT-1012 attenuate cocaine-induced conditioned place preference and behavioral sensitization in mice

“…6B). These effects of AT-1001 are distinctly unlike the effects of antipsychotics such as haloperidol, which block cocaine-induced locomotor sensitization but also attenuate cocaine-induced locomotor activity at the same doses [45, 46]. …”

Reversal of Dopamine Supersensitivity as a Mechanism of Action of Clozapine

“…In a similar study that compared clozapine with haloperidol, only clozapine was found to reverse cocaine-induced locomotor sensitization [8]. However, in another study, haloperidol partially reversed D 2…”