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Naunyn Schmiedebergs Arch Pharmacol. 2003 Mar;367(3):297-305. Epub 2003 Feb 4.

Effects of selective serotonin and serotonin/noradrenaline reuptake inhibitors on extracellular serotonin in rat diencephalon and frontal cortex.

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  • 1Department of Cell Biology and Neuroscience, Nelson Biological Laboratories, Rutgers University, 604 Allison Road, Piscataway, NJ 08854, USA.


Some clinical reports suggest that tricyclic antidepressants which block both noradrenaline and serotonin (5-HT) reuptake (SNRIs) are more effective than selective 5-HT reuptake inhibitors (SSRIs) in treating severe depression. Moreover, one neurochemical study reported larger increases in extracellular 5-HT in rat frontal cortex in response to the tricyclic antidepressant imipramine compared to the SSRI fluoxetine. However, imipramine, which blocks both 5-HT and noradrenaline reuptake, also binds with relatively high affinity to receptors for noradrenaline, histamine and acetylcholine. Thus, to test the hypothesis that compounds that inhibit both 5-HT and noradrenaline reuptake produce larger increases in 5-HT efflux, we compared the effects of acute systemic administration of several SNRIs and SSRIs. Extracellular 5-HT was measured using microdialysis probes implanted in the diencephalon and frontal cortex of unanesthetized rats. We tested the SSRIs paroxetine (0.3-10 mg/kg), citalopram (10-20 mg/kg) and fluoxetine (10 mg/kg), the nonselective tricyclic antidepressant imipramine (20 mg/kg) and the more selective SNRIs duloxetine (3-30 mg/kg) and venlafaxine (30-50 mg/kg). During the lights-off period, paroxetine and duloxetine increased 5-HT in the diencephalon approximately 300 and approximately 200%, respectively. During the lights-on period, paroxetine and duloxetine each increased 5-HT approximately 400% in the diencephalon. In the frontal cortex, both paroxetine and duloxetine increased 5-HT approximately 200%. Citalopram and venlafaxine each increased 5-HT in the diencephalon approximately 300%. Fluoxetine and imipramine increased 5-HT in the diencephalon by approximately 125 and approximately 80%, respectively. Thus, these results do not support the hypothesis that compared to SSRIs, compounds which inhibit both 5-HT and noradrenaline reuptake have a larger acute effect on extracellular 5-HT.

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