Acute onset by 5-HT(6)-receptor activation on rat brain brain-derived neurotrophic factor and activity-regulated cytoskeletal-associated protein mRNA expression.
A number of previous studies have shown that chronic but not acute treatment with antidepressant drugs targeting the central 5-HT system, enhances mRNA expression for a number of genes including, brain-derived neurotrophic factor (BDNF) and the effector immediate early gene (IEG), activity-regulated, cytoskeletal-associated protein (Arc). The present study investigated the effects of 5-HT(6)-receptor activation on hippocampal and cortical levels of mRNA expression of BDNF and Arc in the rat. The selective 5-HT(6)-receptor agonist LY-586713 was administered acutely (0.1-10 mg/kg, s.c.) and mRNA levels of BDNF and Arc were measured 18 h later. Administration of LY-586713 caused a bell-shaped dose response on hippocampal BDNF mRNA expression, having no effect at 0.1 mg/kg, a significant up-regulation at 1 mg/kg and no effect at 10 mg/kg. The up-regulation in BDNF expression observed at 1 mg/kg was completely blocked by pre-treatment with the selective 5-HT(6)-receptor antagonist SB-271046 (10 mg/kg, s.c.). The effective dose (1 mg/kg) of LY-586713 on the induction of BDNF expression was also tested on Arc expression. Acute administration of LY-586713 at this dose caused marked increases of the Arc mRNA levels in cortical and hippocampal regions. These increases were also attenuated by SB-271046 (10 mg/kg) in all regions of the hippocampus, as well as the parietal cortex. However, in frontal cortical regions there was no attenuation by the antagonist. Moreover, SB-271046 alone increased Arc expression in these regions. The results presented here provide the first evidence for the involvement of the 5-HT(6) receptor in regulating BDNF and Arc mRNA expression, suggesting that LY-586713 has potential effects on neuronal plasticity. Overall, these findings suggest that, as opposed to more general 5-HT receptor activation by, for example, antidepressants, direct 5-HT(6)-receptor activation results in a more rapid rise in BDNF and Arc mRNA expression which does not require repeated administration.
de Foubert
G
G
Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, The Gateway, Leicester, UK.
O'Neill
M J
MJ
Zetterström
T S C
TS
D000818:Animals; D001345:Autoradiography; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage; D013449:Sulfonamides / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
D019208:Brain-Derived Neurotrophic Factor; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D013876:Thiophenes; C092069:activity regulated cytoskeletal-associated protein; C097216:serotonin 6 receptor; C117443:SB 271046