title: Captodiamine, a putative antidepressant, enhances hypothalamic BDNF expression in vivo by synergistic 5-HT2c receptor antagonism and sigma-1 receptor agonism.
abstract: The putative antidepressant captodiamine is a 5-HT2c receptor antagonist and agonist at sigma-1 and D3 dopamine receptors, exerts an anti-immobility action in the forced swim paradigm, and enhances dopamine turnover in the frontal cortex. Captodiamine has also been found to ameliorate stress-induced anhedonia, reduce the associated elevations of hypothalamic corticotrophin-releasing factor (CRF) and restore the reductions in hypothalamic BDNF expression. Here we demonstrate chronic administration of captodiamine to have no significant effect on hypothalamic CRF expression through sigma-1 receptor agonism; however, both sigma-1 receptor agonism or 5-HT2c receptor antagonism were necessary to enhance BDNF expression. Regulation of BDNF expression by captodiamine was associated with increased phosphorylation of transcription factor CREB and mediated through sigma-1 receptor agonism but blocked by 5-HT2c receptor antagonism. The existence of two separate signalling pathways was confirmed by immunolocalisation of each receptor to distinct cell populations in the paraventricular nucleus of the hypothalamus. Increased BDNF induced by captodiamine was also associated with enhanced expression of synapsin, but not PSD-95, suggesting induction of long-term structural plasticity between hypothalamic synapses. These unique features of captodiamine may contribute to its ability to ameliorate stress-induced anhedonia as the hypothalamus plays a prominent role in regulating HPA axis activity.
authors.affiliation: School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Ring
authors.forename: Ciaran M
authors.initials: CM
authors.lastname: Regan
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D050882:CREB-Binding Protein / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000096:biosynthesis; D000076122:Disks Large Homolog 4 Protein; D004347:Drug Interactions; D005021:Ethylamines / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D051528:Guanylate Kinases / Q000096:biosynthesis; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D017480:Receptors, sigma / Q000819:agonists*; D016713:Ritanserin / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013440:Sulfides / Q000494:pharmacology*; D016704:Synapsins / Q000096:biosynthesis; D000097605:Sigma-1 Receptor
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D050882:CREB-Binding Protein; D002227:Carbazoles; D003346:Corticotropin-Releasing Hormone; D000076122:Disks Large Homolog 4 Protein; D005021:Ethylamines; D051528:Guanylate Kinases; D008565:Membrane Proteins; D044405:Receptor, Serotonin, 5-HT2C; D017480:Receptors, sigma; D016713:Ritanserin; D058830:Serotonin 5-HT2 Receptor Antagonists; D013440:Sulfides; D016704:Synapsins; D000097605:Sigma-1 Receptor; C501447:Dlg4 protein, mouse; C034931:rimcazole; C494364:Crebbp protein, mouse; C495502:captodiamine
keywords: 5-HT2c receptor; BDNF; hypothalamus; plasticity; sigma-1 receptor; synapsin