Hippocampal Bcl-2 expression is selectively increased following chronic but not acute treatment with antidepressants, 5-HT(1A) or 5-HT(2C/2B) receptor antagonists.
Expression of the anti-apoptotic protein Bcl-2 has been shown to increase in the hippocampus and cortex following chronic administration of mood stabilizers such as lithium and valproate, but the effects of long-term antidepressant administration have not been demonstrated. CD1 mice were dosed either acutely or chronically with either antidepressants or 5-HT receptor subtype selective antagonists. Cortex, hippocampus and hypothalamus from these mice were analysed by Western blot for changes in expression of Bcl-2 and Bax protein. Fourteen day but not acute treatment with citalopram (20 mg/kg), imipramine (10 mg/kg) and amitriptyline (10 mg/kg) in mice significantly elevated hippocampal Bcl-2 protein expression as compared to vehicle treated animals (59, 48 and 42% respectively). Similarly, fourteen day but not acute treatment with the 5-HT(1A) and 5-HT(2C/2B) receptor antagonists WAY100635 (0.3 mg/kg) and SB221284 (1 mg/kg) also markedly and significantly increased hippocampal Bcl-2 expression (95 and 52% respectively). Bcl-2 expression was unaffected in cortex by any treatment. There was a smaller increase of hippocampal Bax protein levels following treatment with imipramine after 1 or 14 days, and following citalopram and amitriptyline after 14 but not 1 day. These data present the first substantive evidence that clinically used antidepressants increase the expression of hippocampal Bcl-2 as did chronic blockade of 5-HT(1A) and 5-HT(2C/2B) receptors, which may be involved in the mechanism of action of antidepressants. The induction of hippocampal Bcl-2 expression by long-term antidepressant treatment may contribute to the clinical efficacy of such compounds via its well described neurotrophic and/or anti-apoptotic effects on neuronal function.
Murray
Fraser
F
Merck Sharp and Dohme, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK. Fraser.Murray@astrazeneca.com
Hutson
Peter H
PH
D000639:Amitriptyline / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D015283:Citalopram / Q000494:pharmacology; D005464:Fluorobenzenes / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000096926:Benzenesulfonamides
D000639:Amitriptyline; D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D015283:Citalopram; D005464:Fluorobenzenes; D007099:Imipramine; D007211:Indoles; D010879:Piperazines; D010880:Piperidines; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; C111309:3,N-dimethyl-N-(1-methyl-3-(4-methylpiperidin-1-yl)propyl)benzenesulfonamide; D000096926:Benzenesulfonamides; C494827:Bax protein, mouse; C112099:SB 221284; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C079049:volinanserin