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1.
PLoS One ; 4(8): e6797, 2009 Aug 27.
Article in English | MEDLINE | ID: mdl-19710918

ABSTRACT

BACKGROUND: Serotonin (5-HT) is a neurotransmitter with important roles in the regulation of neurobehavioral processes, particularly those regulating affect in humans. Drugs that potentiate serotonergic neurotransmission by selectively inhibiting the reuptake of serotonin (SSRIs) are widely used for the treatment of psychiatric disorders. Although the regulation of serotonin synthesis may be an factor in SSRI efficacy, the effect of chronic SSRI administration on 5-HT synthesis is not well understood. Here, we describe effects of chronic administration of the SSRI citalopram (CIT) on 5-HT synthesis and content in the mouse forebrain. METHODOLOGY/PRINCIPAL FINDINGS: Citalopram was administered continuously to adult male C57BL/6J mice via osmotic minipump for 2 days, 14 days or 28 days. Plasma citalopram levels were found to be within the clinical range. 5-HT synthesis was assessed using the decarboxylase inhibition method. Citalopram administration caused a suppression of 5-HT synthesis at all time points. CIT treatment also caused a reduction in forebrain 5-HIAA content. Following chronic CIT treatment, forebrain 5-HT stores were more sensitive to the depleting effects of acute decarboxylase inhibition. CONCLUSIONS/SIGNIFICANCE: Taken together, these results demonstrate that chronic citalopram administration causes a sustained suppression of serotonin synthesis in the mouse forebrain. Furthermore, our results indicate that chronic 5-HT reuptake inhibition renders 5-HT brain stores more sensitive to alterations in serotonin synthesis. These results suggest that the regulation of 5-HT synthesis warrants consideration in efforts to develop novel antidepressant strategies.


Subject(s)
Antidepressive Agents, Second-Generation/pharmacology , Citalopram/pharmacology , Prosencephalon/drug effects , Serotonin/biosynthesis , Animals , Antidepressive Agents, Second-Generation/blood , Citalopram/blood , Male , Mice , Mice, Inbred C57BL , Prosencephalon/metabolism
2.
J Neurochem ; 108(5): 1126-35, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19166502

ABSTRACT

Both microdialysis and electrophysiology were used to investigate whether another serotonin (5-HT) receptor subtype next to the 5-HT(1A) autoreceptor is involved in the acute effects of a selective serotonin reuptake inhibitor on 5-HT neuronal activity. On the basis of a previous study, we decided to investigate the involvement of the 5-HT(7) receptors. Experiments were performed with the specific 5-HT(7) antagonist SB 258741 and the putative 5-HT(7) agonist AS19. In this study WAY 100.635 was used to block 5-HT(1A) receptors. Systemic administration of SB 258741 significantly reduced the effect of combined selective serotonin reuptake inhibitor and WAY 100.635 administration on extracellular 5-HT in the ventral hippocampus as well as 5-HT neuronal firing in the dorsal raphe nucleus. In the microdialysis study, co-administration of AS19 and WAY 100.635 showed a biphasic effect on extracellular 5-HT in ventral hippocampus, hinting at opposed 5-HT(7) receptor mediated effects. In the electrophysiological experiments, systemic administration of AS19 alone displayed a bell-shaped dose-effect curve: moderately increasing 5-HT neuronal firing at lower doses while decreasing it at higher doses. SB 258741 was capable of blocking the effect of AS19 at a low dose. This is consistent with the pharmacological profile of AS19, displaying high affinity for 5-HT(7) receptors and moderate affinity for 5-HT(1A) receptors. The data are in support of an excitatory effect of selective serotonin reuptake inhibitors on 5-HT neuronal activity mediated by 5-HT(7) receptors. It can be speculated, that the restoration of 5-HT neuronal firing upon chronic antidepressant treatment, which is generally attributed to desensitization of 5-HT(1A) receptors alone, in fact results from a shift in balance between 5-HT(1A) and 5-HT(7) receptor function.


Subject(s)
Action Potentials/drug effects , Neurons/drug effects , Receptors, Serotonin/physiology , Serotonin Agents/pharmacology , Serotonin/metabolism , Action Potentials/physiology , Analysis of Variance , Animals , Brain/cytology , Chromatography, High Pressure Liquid/methods , Citalopram/pharmacology , Drug Interactions , Electrochemistry/methods , Male , Microdialysis/methods , Neurons/physiology , Piperazines/pharmacology , Piperidines/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Pyrrolidines/pharmacology , Rats , Rats, Wistar , Receptor, Serotonin, 5-HT1A/physiology , Serotonin 5-HT1 Receptor Antagonists , Selective Serotonin Reuptake Inhibitors/pharmacology , Tetrahydronaphthalenes/pharmacology , Tosyl Compounds/pharmacology , Wakefulness
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