Electrical stimulation of the dorsal and median raphe nuclei increases extracellular noradrenaline in rat hippocampus: Evidence for a 5-HT-independent mechanism.

Recent studies have used raphe stimulation combined with in vivo measurements of extracellular dopamine to investigate interactions between the 5-hydroxytryptamine (5-HT) and dopamine systems. Here we have tested whether the same approach can be used to investigate interactions between the 5-HT and noradrenaline systems. Electrical stimulation of the dorsal raphe nucleus (DRN) or median raphe nucleus (MRN) was performed in anaesthetised rats implanted with microdialysis probes in the hippocampus and locus coeruleus (LC). DRN stimulation (3, 5 and 10 Hz) evoked a frequency-dependent increase in extracellular noradrenaline in the hippocampus. MRN stimulation had a similar effect. Both DRN and MRN stimulations enhanced extracellular 5-HT levels in the LC and previous studies have demonstrated that extracellular 5-HT also increases in the hippocampus. However, the increase in hippocampal noradrenaline evoked by DRN stimulation was not altered by 5-HT neuronal lesions, which reduced 5-HT metabolite levels by 90%. In conclusion, electrical stimulation of the midbrain raphe increases extracellular noradrenaline in the hippocampus, however, experiments in 5-HT-lesioned animals suggest that this response is not mediated by 5-HT. Although raphe stimulation may be useful to investigate interactions between 5-HT and dopamine, our data indicate that the same approach may not be feasible for 5-HT and noradrenaline

Effect of a selective 5-hydroxytryptamine reuptake inhibitor on brain extracellular noradrenaline: microdialysis studies using paroxetine.

The clinical efficacy of selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs) is normally attributed to their ability to increase brain 5-HT function although recent preclinical findings indicate that their selectivity for 5-HT over noradrenaline may be less evident in vivo. The present study investigated the effects of the SSRI, paroxetine, on extracellular levels of noradrenaline. Microdialysis was carried out in the hippocampus of the awake rat. In rats treated twice daily for 14 days with paroxetine (5 mg/kg s.c.), dialysate levels of noradrenaline showed a maintained two-fold increase compared to saline-injected controls. Paroxetine (5 mg/kg s.c.) administered once daily for 14 days did not cause a sustained increase in noradrenaline but levels showed a moderate (+58%) increase in response to a paroxetine challenge. Acute injection of paroxetine (5 mg/kg s.c.) did not elevate noradrenaline levels. Paroxetine (5 mg/kg s.c.) elevated dialysate 5-HT after both acute and repeated (twice daily for 14 days) treatment. The paroxetine-induced increase in noradrenaline (and 5-HT) was positively correlated with plasma concentrations of the drug, which were around the therapeutic range. In comparison to paroxetine, desipramine (10 mg/kg s.c.) caused a four-fold increase in dialysate noradrenaline (but did not change 5-HT) following repeated (once daily for 14 days) treatment and a two-fold increase at for acute treatment. In summary, despite its selectivity as a 5-HT reuptake inhibitor, paroxetine increased extracellular levels of noradrenaline in rat hippocampus following repeated administration. We discuss the possibility that a facilitation of noradrenaline function might be involved in the antidepressant effect of paroxetine, and possibly other SSRIs

Neurochemical and electrophysiological studies on the functional significance of burst firing in serotonergic neurons.

We have previously described a population of 5-hydroxytryptamine neurons which repetitively fires bursts of usually two (but occasionally three or four) action potentials, with a short (<20 ms) interspike interval within a regular low-frequency firing pattern. Here we used a paradigm of electrical stimulation comprising twin pulses (with 7- or 10-ms inter-pulse intervals) to mimic this burst firing pattern, and compared the effects of single- and twin-pulse electrical stimulations in models of pre- and postsynaptic 5-hydroxytryptamine function. Firstly, we measured the effect of direct electrical stimulation (2 Hz for 2 min) of rat brain slices on efflux of preloaded [3H]5-hydroxytryptamine. In this in vitro model, twin-pulse stimulation increased the efflux of tritium by about twice as much as did single-pulse stimulation. This effect was evident in the medial prefrontal cortex (area under the curve: 2. 59+/-0.34 vs 1.28+/-0.22% relative fractional release), as well as in the caudate-putamen (3.93+/-0.65 vs 2.17+/-0.51%) and midbrain raphe nuclei (5.42+/-1.05 vs 2.51+/-0.75%). Secondly, we used in vivo microdialysis to monitor changes in endogenous extracellular 5-hydroxytryptamine in rat medial prefrontal cortex in response to electrical stimulation (3 Hz for 10 min) of the dorsal raphe nucleus. In this model, twin-pulse stimulation of the dorsal raphe nucleus increased 5-hydroxytryptamine by approximately twice as much as did single-pulse stimulation at the same frequency (area under the curve: 50.4+/-9.0 vs 24.2+/-4.4 fmol). Finally, we used in vivo extracellular recording to follow the response of postsynaptic neurons in the rat medial prefrontal cortex to 5-hydroxytryptamine released by dorsal raphe stimulation. Electrical stimulation of the dorsal raphe nucleus (1 Hz) induced a clear-cut poststimulus inhibition in the majority of cortical neurons tested. In these experiments, the duration of poststimulus inhibition following twin-pulse stimulation was markedly longer than that induced by single-pulse stimulation (200+/-21 vs 77+/-18.5 ms). Taken together, the present in vitro and in vivo data suggest that in 5-hydroxytryptamine neurons, short bursts of action potentials will propagate along the axon to the nerve terminal and will enhance both the release of 5-hydroxytryptamine and its postsynaptic effect