Procognitive 5-HT6 antagonists in the rat forced swimming test: Potential therapeutic utility in mood disorders associated with Alzheimer's disease

Aims: 5-HT6 receptor subtype is predominantly expressed in the brain, and preclinical evidence suggests its potential role in the cognitive function. Brain microdialysis studies demonstrated that 5-HT6 antagonists enhance not only cholinergic but also monoaminergic neurotransmission, a property that may differentiate from acetylcholine esterase (AChE) inhibitors such as donepezil. In this study we compared the antidepressant-like effects of 5-HT6 antagonists with donepezil to determine whether their different effects on monoamines are behaviorally relevant. Main methods: Selective 5-HT6 antagonists (SB-399885 and SB-271046) and donepezil were evaluated in the rat forced swimming test since this is known to identify drugs such as antidepressants which can increase brain monoamine levels. Binding assay was undertaken by using [I-125]SB-258585 to measure brain 5-HT6 receptor occupancy. Key findings: Systemic administration of SB-399885 (3 and 10 mg/kg, i.p.) and SB-271046 (10 and 30 mg/kg, i.p.) produced a significant reduction of immobility time in the rat forced swimming test with a similar profile in terms of 5-HT6 receptor occupancy (62 and 96% for 3 and 10 mg/kg SB-399885 respectively; 56 and 84% for 10 and 30 mg/kg SB-271046 respectively). In contrast, donepezil (0.5 and 1 mg/kg i.p.) did not show any effects in this model. Significance: These data suggest that 5-HT6 antagonists, at doses corresponding to those occupy central 5-HT6 receptors, could have an antidepressive effect in humans. This may differentiate 5-HT6 antagonists from AChE inhibitors with respect to the mood control in the symptomatic treatment of Alzheimer's disease. (C) 2009 Elsevier Inc. All rights reserved.