Andrew R Abela1,2,3, Xiao Dong Ji4, Zhaoxia Li4, Anh D Lê4,5, Paul J Fletcher4,6,7. 1. Preclinical Research and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St, Toronto, Ontario, M5T 1R8, Canada. andrew.abela@camh.ca. 2. Department of Psychiatry, University of Toronto, Toronto, ON, Canada. andrew.abela@camh.ca. 3. Department of Neuroscience, Centre for Addiction and Mental Health, 33 Russell Street, Toronto, ON, M5T 1R8, Canada. andrew.abela@camh.ca. 4. Preclinical Research and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St, Toronto, Ontario, M5T 1R8, Canada. 5. Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada. 6. Department of Psychiatry, University of Toronto, Toronto, ON, Canada. 7. Department of Psychology, University of Toronto, Toronto, ON, Canada.
Abstract
RATIONALE AND OBJECTIVES: Although clozapine is effective in treating schizophrenia, it is associated with adverse side effects including weight gain and metabolic syndrome. Despite this, the role of clozapine on feeding behaviour and food intake has not been thoroughly characterised. Clozapine has a broad pharmacological profile, with affinities for several neurotransmitter receptors, including serotonin (5-hydroxytriptamine, 5-HT) and histamine. Given that the serotonin 5-HT2C receptor and histaminergic H1 receptor are involved in aspects of feeding behaviour, the effect of clozapine on feeding may be linked to its action at these receptors. METHODS: We assessed, in rats, the effect of acute and subchronic administration of clozapine on responding for food under a progressive ratio (PR) schedule under conditions of food restriction and satiety. We also examined the effect of antagonists of the serotonin 5-HT2C and histaminergic H1 receptors on the same schedule. Clozapine reliably increased responding for food, even when rats had ad libitum access to food. The effect of clozapine on responding for food was reproduced by combined (but not individual) antagonism of the serotonin 5-HT2C and histaminergic H1 receptors. CONCLUSION: These findings show that clozapine enhances the motivation to work for food, that this effect is stable over repeated testing, and is independent of hunger state of the animal. This effect may relate to a combined action of clozapine at the serotonin 5-HT2C and histaminergic H1 receptors.
RATIONALE AND OBJECTIVES: Although clozapine is effective in treating schizophrenia, it is associated with adverse side effects including weight gain and metabolic syndrome. Despite this, the role of clozapine on feeding behaviour and food intake has not been thoroughly characterised. Clozapine has a broad pharmacological profile, with affinities for several neurotransmitter receptors, including serotonin (5-hydroxytriptamine, 5-HT) and histamine. Given that the serotonin 5-HT2C receptor and histaminergic H1 receptor are involved in aspects of feeding behaviour, the effect of clozapine on feeding may be linked to its action at these receptors. METHODS: We assessed, in rats, the effect of acute and subchronic administration of clozapine on responding for food under a progressive ratio (PR) schedule under conditions of food restriction and satiety. We also examined the effect of antagonists of the serotonin 5-HT2C and histaminergic H1 receptors on the same schedule. Clozapine reliably increased responding for food, even when rats had ad libitum access to food. The effect of clozapine on responding for food was reproduced by combined (but not individual) antagonism of the serotonin 5-HT2C and histaminergic H1 receptors. CONCLUSION: These findings show that clozapine enhances the motivation to work for food, that this effect is stable over repeated testing, and is independent of hunger state of the animal. This effect may relate to a combined action of clozapine at the serotonin 5-HT2C and histaminergic H1 receptors.
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