Seung Keun Cha1, Ung Gu Kang2. 1. Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Republic of Korea. 2. Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Republic of Korea. ; Institute of Human Behavioral Medicine, Seoul National University College of Medicine, 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.
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.
Authors: Taline V Khroyan; Dennis Yasuda; Lawrence Toll; Willma E Polgar; Nurulain T Zaveri Journal: Biochem Pharmacol Date: 2015-08-07 Impact factor: 5.858