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Effects of clozapine, haloperidol, and fluoxetine on the reversal of cocaine-induced locomotor sensitization.

Cha SK, Kang UG - Psychiatry Investig (2014)

Bottom Line: Although antipsychotics block the expression of sensitized behavior, they are ineffective for reversing the sensitized state.Clozapine reversed the sensitized state, whereas haloperidol did not.We confirmed that D2 blockade was not effective for reversing sensitization.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Republic of Korea.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Effects of drugs on sensitized locomotor activity, comparison between pre- and post-treatment. A: Post-cocaine: day 23 stimulated locomotor activity was significantly reduced by clozapine treatment (t=3.259, df=9, p=0.010). B: Pre-cocaine: day 23 baseline locomotor activity was significantly increased by haloperidol (t=-3.162, df=9, p=0.038) and vehicle (t=-2.431, df=8, p=0.041) treatments. *significant difference compared to day 5 in each drug at p=0.05 (not corrected for multiple testing).
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Figure 4: Effects of drugs on sensitized locomotor activity, comparison between pre- and post-treatment. A: Post-cocaine: day 23 stimulated locomotor activity was significantly reduced by clozapine treatment (t=3.259, df=9, p=0.010). B: Pre-cocaine: day 23 baseline locomotor activity was significantly increased by haloperidol (t=-3.162, df=9, p=0.038) and vehicle (t=-2.431, df=8, p=0.041) treatments. *significant difference compared to day 5 in each drug at p=0.05 (not corrected for multiple testing).

Mentions: We also examined changes in post-cocaine locomotor activity on day 23 from day 5 (sensitized) in each group using a paired t-test. The change was significant in the clozapine group (t=3.259, df=9, p=0.010), but not in the fluoxetine (t=-0.722, df=9, p=0.489), haloperidol (t=-1.535, df=9, p=0.159) or vehicle (t=0.956, df=8, p=0.367) groups. This shows that the sensitized state was altered by clozapine (Figure 4A).


Effects of clozapine, haloperidol, and fluoxetine on the reversal of cocaine-induced locomotor sensitization.

Cha SK, Kang UG - Psychiatry Investig (2014)

Effects of drugs on sensitized locomotor activity, comparison between pre- and post-treatment. A: Post-cocaine: day 23 stimulated locomotor activity was significantly reduced by clozapine treatment (t=3.259, df=9, p=0.010). B: Pre-cocaine: day 23 baseline locomotor activity was significantly increased by haloperidol (t=-3.162, df=9, p=0.038) and vehicle (t=-2.431, df=8, p=0.041) treatments. *significant difference compared to day 5 in each drug at p=0.05 (not corrected for multiple testing).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4225210&req=5

Figure 4: Effects of drugs on sensitized locomotor activity, comparison between pre- and post-treatment. A: Post-cocaine: day 23 stimulated locomotor activity was significantly reduced by clozapine treatment (t=3.259, df=9, p=0.010). B: Pre-cocaine: day 23 baseline locomotor activity was significantly increased by haloperidol (t=-3.162, df=9, p=0.038) and vehicle (t=-2.431, df=8, p=0.041) treatments. *significant difference compared to day 5 in each drug at p=0.05 (not corrected for multiple testing).
Mentions: We also examined changes in post-cocaine locomotor activity on day 23 from day 5 (sensitized) in each group using a paired t-test. The change was significant in the clozapine group (t=3.259, df=9, p=0.010), but not in the fluoxetine (t=-0.722, df=9, p=0.489), haloperidol (t=-1.535, df=9, p=0.159) or vehicle (t=0.956, df=8, p=0.367) groups. This shows that the sensitized state was altered by clozapine (Figure 4A).

Bottom Line: Although antipsychotics block the expression of sensitized behavior, they are ineffective for reversing the sensitized state.Clozapine reversed the sensitized state, whereas haloperidol did not.We confirmed that D2 blockade was not effective for reversing sensitization.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Republic of Korea.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus