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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

Experimental schedule. Cocaine was administered for 5 consecutive days (days 1-5), and locomotor activity was measured on days 1 and 5. The maintenance of sensitization was confirmed by a cocaine challenge on day 13, and animals were grouped according to locomotor activity. Subsequently, clozapine, haloperidol, fluoxetine, or vehicle were administered for 5 days from days 16 to 20. The final cocaine challenge was performed on day 23.
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Figure 1: Experimental schedule. Cocaine was administered for 5 consecutive days (days 1-5), and locomotor activity was measured on days 1 and 5. The maintenance of sensitization was confirmed by a cocaine challenge on day 13, and animals were grouped according to locomotor activity. Subsequently, clozapine, haloperidol, fluoxetine, or vehicle were administered for 5 days from days 16 to 20. The final cocaine challenge was performed on day 23.

Mentions: Thirty-nine male ICR mice (Orient, Seoul, Korea) weighing approximately 20 g were used. The mice were maintained under a 12/12-h dark/light cycle, and food and water were available ad libitum. All animal procedures were conducted in accordance with NIH Guidelines for the Use of Laboratory Animals. In order to reduce the number of animals, we did not use a separate control group for cocaine-induced sensitization. The mice were given 20 mg/kg cocaine-HCl dissolved in 0.9% NaCl intraperitoneally (Belgopia, Louvain-La-Neuve, Belgium) for 5 consecutive days. Locomotor activity was measured after the first (day 1) and last (day 5) treatments. Injections on days 2, 3, and 4 were administered in their home cages. One week after the last treatment, another dose of cocaine was given, and locomotor activity was measured to confirm that the sensitized state was maintained (day 13). The animals were then split into four groups based on locomotor activity on that day, in a manner in which the mean activity for each group was similar. Allocation of a specific drug to each group was determined randomly. Drug treatments began 3 days later, and the animals were given clozapine (5 mg/kg), fluoxetine (10 mg/kg), haloperidol (2 mg/kg), or vehicle (0.3% tartaric acid, pH adjusted to 5.0) for 5 consecutive days. After a 3-day washout period, the animals were finally challenged with the same dose of cocaine, and their locomotor activities were measured (day 23) (Figure 1).


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

Cha SK, Kang UG - Psychiatry Investig (2014)

Experimental schedule. Cocaine was administered for 5 consecutive days (days 1-5), and locomotor activity was measured on days 1 and 5. The maintenance of sensitization was confirmed by a cocaine challenge on day 13, and animals were grouped according to locomotor activity. Subsequently, clozapine, haloperidol, fluoxetine, or vehicle were administered for 5 days from days 16 to 20. The final cocaine challenge was performed on day 23.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Experimental schedule. Cocaine was administered for 5 consecutive days (days 1-5), and locomotor activity was measured on days 1 and 5. The maintenance of sensitization was confirmed by a cocaine challenge on day 13, and animals were grouped according to locomotor activity. Subsequently, clozapine, haloperidol, fluoxetine, or vehicle were administered for 5 days from days 16 to 20. The final cocaine challenge was performed on day 23.
Mentions: Thirty-nine male ICR mice (Orient, Seoul, Korea) weighing approximately 20 g were used. The mice were maintained under a 12/12-h dark/light cycle, and food and water were available ad libitum. All animal procedures were conducted in accordance with NIH Guidelines for the Use of Laboratory Animals. In order to reduce the number of animals, we did not use a separate control group for cocaine-induced sensitization. The mice were given 20 mg/kg cocaine-HCl dissolved in 0.9% NaCl intraperitoneally (Belgopia, Louvain-La-Neuve, Belgium) for 5 consecutive days. Locomotor activity was measured after the first (day 1) and last (day 5) treatments. Injections on days 2, 3, and 4 were administered in their home cages. One week after the last treatment, another dose of cocaine was given, and locomotor activity was measured to confirm that the sensitized state was maintained (day 13). The animals were then split into four groups based on locomotor activity on that day, in a manner in which the mean activity for each group was similar. Allocation of a specific drug to each group was determined randomly. Drug treatments began 3 days later, and the animals were given clozapine (5 mg/kg), fluoxetine (10 mg/kg), haloperidol (2 mg/kg), or vehicle (0.3% tartaric acid, pH adjusted to 5.0) for 5 consecutive days. After a 3-day washout period, the animals were finally challenged with the same dose of cocaine, and their locomotor activities were measured (day 23) (Figure 1).

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