Differential effects of clomipramine given locally or systemically on extracellular 5-hydroxytryptamine in raphe nuclei and frontal cortex
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The antidepressant drug clomipramine (CIM) blocks 5-hydroxytryptamine (5-HT) uptake in vitro. Electrophysiological studies have shown that CIM also reduces the firing of serotonergic neurons in the dorsal raphe nucleus. In order to assess the effects of CIM on serotonergic transmission in vivo, the technique of intracerebral microdialysis was used. CIM was administered either through the dialysis probe or i. p., and dialysate 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were determined in frontal cortex and/or raphe nuclei. In addition, the action of extracellular 5-HT in raphe nuclei on the release of 5-HT in frontal cortex was studied.
The administration of CIM through the dialysis probe increased dialysate 5-HT in frontal cortex in a dose-dependent fashion. An actual ED50 of 3.15 μM CIM for the in vivo inhibition of 5-HT uptake can be calculated in this brain area. When given systemically (10 or 20 mg/kg i. p.), CIM did not increase dialysate 5-HT in the frontal cortex. The occurrence of extracellular 5-HT in the raphe area was demonstrated. This pool of 5-HT increased markedly after local (10 or 40 μM) or systemic (20 mg/kg i. p.) administration of CIM. We also examined the effect of CIM applied locally in the raphe nuclei on extracellular 5-HT in the frontal cortex. The increased dialysate 5-HT in raphe after 10 or 40 μM CIM paralleled a decrease of dialysate 5-HT in the frontal cortex. Values of dialysate 5-HT in the two areas correlated negatively. The administration of CIM through the dialysis probe slightly decreased dialysate 5-HIAA in the frontal cortex. When given systemically, CIM also decreased dialysate 5-HIAA in the frontal cortex, but significantly only after the highest dose tested (20 mg/kg i.p.). Furthermore, the local application of CIM into the raphe nuclei produced a decrease of dialysate 5-HIAA in the frontal cortex.
These results prove the in vivo inhibitory activity of CIM on 5-HT uptake. This effect is much more pronounced in the raphe nuclei than in the frontal cortex when CIM is given systemically. However, both areas are equally sensitive to the local application of the drug. The effect of CIM on raphe nuclei partly antagonizes that on the frontal cortex, providing evidence for a functional link between these two brain regions.
Key words5-Hydroxytryptamine Clomipramine Microdialysis Dorsal and median raphe nuclei Frontal cortex In vivo uptake inhibition
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