Procognitive 5-HT6 antagonists in the rat forced swimming test: potential therapeutic utility in mood disorders associated with Alzheimer's disease.
OBJECTIVE
5-HT(6) 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-HT(6) 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-HT(6) antagonists with donepezil to determine whether their different effects on monoamines are behaviorally relevant.


METHODS
Selective 5-HT(6) 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 [(125)I]SB-258585 to measure brain 5-HT(6) receptor occupancy.


RESULTS
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-HT(6) 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.


CONCLUSIONS
These data suggest that 5-HT(6) antagonists, at doses corresponding to those occupy central 5-HT(6) receptors, could have an antidepressive effect in humans. This may differentiate 5-HT(6) antagonists from AChE inhibitors with respect to the mood control in the symptomatic treatment of Alzheimer's disease.
Hirano
Kazufumi
K
Cognition & Neurodegeneration Centre, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, #03-01/02, The Helios, 11 Biopolis Way, Singapore. kazufumi.2.hirano@gsk.com
Piers
Thomas M
TM
Searle
Kirsten L
KL
Miller
Neil D
ND
Rutter
A Richard
AR
Chapman
Paul F
PF
D000544:Alzheimer Disease / Q000378:metabolism / Q000523:psychology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D008297:Male; D019964:Mood Disorders / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000523:psychology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D013550:Swimming; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use
D010879:Piperazines; D011985:Receptors, Serotonin; C503990:SB 399885; D012702:Serotonin Antagonists; D013449:Sulfonamides; D013876:Thiophenes; C097216:serotonin 6 receptor; C117443:SB 271046