Modulation of the firing activity of rat serotonin and noradrenaline neurons by (±)pindolol
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Keywords:
Pindolol
Autoreceptor
Dorsal raphe nucleus
5-HT1A receptor
Locus coeruleus
Raphe nuclei
Dorsal raphe nucleus
Autoreceptor
Raphe nuclei
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Summary— Somatodendritic 5‐HT 1A autoreceptors play a key role in the control of the electrical and metabolic activity of serotoninergic neurons in the dorsal raphe nucleus. These neurons also possess intracellular glucocorticoid receptors which may be involved in the well established modulation of serotonin (5‐hydroxytryptamine, 5‐HT) metabolism by corticosterone in stressed animals. The possible mediation by somatodendritic 5‐HT 1A autoreceptors of such corticosterone‐dependent changes in serotoninergic neuron activity was investigated using an in vitro electrophysiological approach. 5‐HT 1A autoreceptor‐mediated inhibition of the firing of serotoninergic neurons was examined in brain stem slices from rats whose serum corticosterone concentrations had been markedly increased (+ 100–200%) by two different stressful conditions. Immobilization for 30 or 90 min (restraint stress) did not modify the concentration‐dependent inhibition of the firing of serotoninergic neurons by the 5‐HT 1A receptor agonist ipsapirone. In contrast, placing the rats in novel uncontrolled environmental conditions for 16 h significantly reduced the cell response to ipsapirone, indicating a decreased sensitivity of somatodendritic 5‐HT 1A autoreceptors. Such a change was not observed in adrenalectomized rats subjected to the same stressful conditions. These data show that some forms of stress can reduce the 5‐HT 1A autoreceptor‐dependent inhibitory control of the electrophysiological activity of serotoninergic neurons in the dorsal raphe nucleus. Both the nature and duration of stress seem to be critical factors for triggering the (corticosterone‐dependent) mechanism(s) responsible for the functional desensitization of 5‐HT 1A autoreceptors in stressed rats.
Autoreceptor
Dorsal raphe nucleus
Ipsapirone
Raphe nuclei
Corticosterone
Raphe
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It has been hypothesized that 5‐HT 1A autoreceptor antagonists may enhance the therapeutic efficacy of SSRIs and other antidepressants. Although early clinical trials with the β‐adrenoceptor/5‐HT 1 ligand, pindolol, were promising, the results of recent more extensive trials have been contradictory. Here we investigated the actions of pindolol at the 5‐HT 1A autoreceptor by measuring its effect on 5‐HT neuronal activity and release in the anaesthetized rat. Pindolol inhibited the electrical activity of 5‐HT neurones in the dorsal raphe nucleus (DRN). This effect was observed in the majority of neurones tested (10/16), was dose‐related (0.2–1.0 mg kg −1 , i.v.), and was reversed by the 5‐HT 1A receptor antagonist, WAY 100635 (0.1 mg kg −1 , i.v.), in 6/7 cases tested. Pindolol also inhibited 5‐HT neuronal activity when applied microiontophoretically into the DRN in 9/10 neurones tested. This effect of pindolol was current‐dependent and blocked by co‐application of WAY 100635 (3/3 neurones tested). In microdialysis experiments, pindolol caused a dose‐related (0.8 and 4 mg kg −1 , i.v.) fall in 5‐HT levels in dialysates from the frontal cortex (under conditions where the perfusion medium contained 1 μ M citalopram). In rats pretreated with WAY 100635 (0.1 mg kg −1 , i.v.), pindolol (4 mg kg −1 , i.v.) did not decrease, but rather increased 5‐HT levels. We conclude that, under the experimental conditions used in this study, pindolol displays agonist effects at the 5‐HT 1A autoreceptor. These data are relevant to previous and ongoing clinical trials of pindolol in depression which are based on the rationale that the drug is an effective 5‐HT 1A autoreceptor antagonist.
Pindolol
Autoreceptor
Dorsal raphe nucleus
Microdialysis
5-HT1A receptor
Raphe nuclei
Neurochemical
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Autoreceptor
Dorsal raphe nucleus
Paroxetine
Raphe nuclei
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Dorsal raphe nucleus
Autoreceptor
Raphe nuclei
5-HT1A receptor
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Median raphe nucleus
Hypoactivity
Dorsal raphe nucleus
8-OH-DPAT
5-HT1A receptor
Raphe nuclei
Raphe
Forebrain
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Dorsal raphe nucleus
Autoreceptor
Raphe nuclei
Median raphe nucleus
Microdialysis
Forebrain
Raphe
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Pindolol
Autoreceptor
Dorsal raphe nucleus
5-HT1A receptor
Locus coeruleus
Raphe nuclei
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The effects of corticosterone (10 mg/kg, s.c., 6 h) on dorsal raphe 5-HT1A autoreceptors have been studied in adrenalectomized rats with or without porcine galanin modulation. Adrenalectomy diminishes 5-HT1A autoreceptors affinity. Corticosterone increases 5-HT1A autoreceptor agonist affinity (+90%, p<0.001) in adrenalectomized rats. Galanin (10 nM) increases dorsal raphe 5-HT1A autoreceptor density (+65%, p<0.05) and its Kd value (+248%, p<0.05) only in adrenalectomized rats treated with corticosterone. Dorsal raphe glucocorticoid receptors activation by corticosterone may therefore lead to an increased signalling of 5-HT1A autoreceptors that may become counteracted by galanin receptor activation. Glucocorticoids, by enhancing dorsal raphe 5-HT1A autoreceptor function, may therefore cause reduced 5-HT neuronal activity and thus lead to a depressive state.
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Dorsal raphe nucleus
Corticosterone
Raphe
Raphe nuclei
5-HT1A receptor
TPH2
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