Modulation of central serotonergic neurotransmission by risperidone: underlying mechanism(s) and significance of action.
ABSTRACT 1. The effects of risperidone on brain 5-hydroxytryptamine (5-HT) neuronal activity were investigated using microdialysis in the frontal cortex (FC) or the dorsal raphe nucleus (DRN) as well as single cell recording in the DRN. 2. Systemic administration of risperidone (0.6 and 2.0 mg/kg, s.c.) dose-dependently increased 5-HT output in both the FC and the DRN. 3. Local cortical administration of both risperidone or idazoxan enhanced the 5-HT efflux in the FC, whereas local raphe administration of risperidone but not idazoxan increased the output of 5-HT in the DRN. 4. Systemic administration of risperidone (200 micrograms/kg, i.v.) or the selective alpha 1 adrenoceptor antagonist prazosin (400 micrograms/kg, i.v.) decreased, whereas selective alpha 2 adrenoceptor antagonist idazoxan (20 micrograms/kg, i.v.) increased the 5-HT cell firing in the DRN. 5. Pretreatment with the selective 5-HT1A receptor antagonist WAY 100,635 (5.0 micrograms/kg, i.v.) effectively antagonized the inhibition of 5-HT cells induced by risperidone, but failed to prevent the prazosin-induced decrease in 5-HT cell firing in the DRN. 6. The inhibitory effect of risperidone on 5-HT cell firing in the DRN was significantly attenuated in rats pretreated with the 5-HT depletor PCPA (p-chlorophenylalanine; 300 mg/kg/day i.p. for 3 consecutive days) in comparison with drug naive animals. 7. Consequently, the risperidone-induced increase in 5-HT output in the FC may be related to its alpha 2 adrenoceptor antagonistic action, an effect probably executed at the nerve terminal level, whereas the reduction in 5-HT cell firing by risperidone appears to be associated with increased availability of 5-HT in the somatodendritic region of the neurones leading to an enhanced 5-HT1A autoreceptor activation and, in turn, to inhibition of cell firing.
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ABSTRACT: Previous studies suggest that noradrenaline may regulate serotonergic (5-HT) neurotransmission at the serotonin cell body and noradrenaline nerve terminal. Using microdialysis coupled to HPLC, we investigated the effects of alpha1-adrenoceptor manipulation on extracellular serotonin levels - in the ventral hippocampus, prefrontal cortex, and raphe nuclei - in the presence or absence of the serotonin reuptake inhibitor (SSRI), citalopram. Extracellular 5-HT levels from prefrontal cortex, ventral hippocampus and raphe nuclei were markedly increased following citalopram administration (3.0 mg/kg s.c.). In the prefrontal cortex and ventral hippocampus, local blockade of the alpha1-adrenoceptor (3.0 microM prazosin infusion) significantly decreased this citalopram-induced increase in serotonin, while cirazoline (alpha1-adrenoceptor agonist) and reboxetine (noradrenaline reuptake inhibitor) further increased extracellular serotonin levels when administered systemically (0.02 mg/kg i.p. and 5.0 mg/kg s.c. respectively) or locally infused (10.0 microM and 1.0 microM respectively). Moreover, prazosin pre-infusion into terminal areas prevented the increase in citalopram-induced increase in serotonin levels with systemic cirazoline or reboxetine administration. Prazosin also decreased the citalopram-induced increase in serotonin levels in the raphe nuclei; however no enhancement of the SSRI response was observed with systemic or local administration of cirazoline or reboxetine, suggesting that alpha1-adrenoceptors may already be maximally activated under these conditions. These data provide strong evidence that after acute citalopram administration, the alpha1-adrenoceptor exerts a modulatory role on serotonin levels.Neuropharmacology 06/2010; 58(7):962-71. · 4.11 Impact Factor
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ABSTRACT: To clarify the mechanisms of action of blonanserin, an atypical antipsychotic drug, we studied the effects of systemic administration of blonanserin and risperidone on extracellular levels of norepinephrine, dopamine, serotonin, GABA and glutamate in the medial prefrontal cortex using microdialysis, and neuronal firing in the ventral tegmental area, locus coeruleus, dorsal raphe nucleus and mediodorsal thalamic nucleus using radiotelemetry. The binding affinities of blonanserin to D(2) and 5-HT(2A) receptors in the rat brain were confirmed and found to be similar. Blonanserin transiently increased neuronal firing in locus coeruleus and ventral tegmental area but not in dorsal raphe nucleus or mediodorsal thalamic nucleus, whereas risperidone increased the firing in locus coeruleus, ventral tegmental area and dorsal raphe nucleus but not in mediodorsal thalamic nucleus. Blonanserin persistently increased frontal extracellular levels of norepinephrine and dopamine but not serotonin, GABA or glutamate, whereas risperidone persistently increased those of norepinephrine, dopamine and serotonin but not GABA or glutamate. These results suggest a pharmacological correlation between the stimulatory effects of these antipsychotics on frontal monoamine release and neuronal activity in monoaminergic nuclei. Inhibition of the α(2) adrenoceptor increased extracellular monoamine levels and enhanced blonanserin-induced increase in extracellular serotonin level. These results indicated that the combination of antagonism of D(2) and 5-HT(2A) receptors contribute to the rise in extracellular levels of norepinephrine and dopamine, and that α(2) adrenoceptors play important roles in frontal serotonin release. They also suggest that blonanserin-induced activation of monoaminergic transmission could be, at least partially, involved in atypical antipsychotic properties of blonanserin.European journal of pharmacology 02/2011; 653(1-3):47-57. · 2.59 Impact Factor
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ABSTRACT: In addition to noradrenergic and serotonergic systems, dopaminergic neurotransmission seems to play an important role in the aetiopathogenesis of, and recovery from, depression. Moreover, the incidence of depression is higher in patients affected by diseases where the dopaminergic system is highly impaired, such us Parkinson's disease. Here, we investigated the effects of dopamine degeneration on the activity and response to antidepressants of locus coeruleus (LC) noradrenergic and dorsal raphe nucleus (DRN) serotonergic neurons. To this end, single-unit extracellular recordings were performed in control and 6-hydroxydopamine (6-OHDA)-lesioned animals. In this latter group, LC neurons showed a lower basal firing rate as well as less sensitivity to the administration of the serotonin reuptake inhibitor, fluoxetine. The rest of electrophysiological parameters and the response to the administration of the α2-adrenoceptor agonist, clonidine and the noradrenaline reuptake inhibitor, reboxetine remained unaltered. In the DRN, dopamine depletion did not modify the basal electrophysiological characteristics and the response to clonidine or fluoxetine administration. In contrast, the administration of reboxetine more efficiently induced an inhibitory effect in the lesioned group. In additional analyses it was observed that while in control animals, LC and DRN basal firing rate was significantly correlated, this relationship was lost after the 6-OHDA lesion. In conclusion, dopaminergic degeneration alters LC neuron basal activity, the relationship/synteny between both nuclei, and their response to antidepressants. These findings shed fresh light on our understanding of the role of dopamine in depression and the mechanism action of antidepressants.The International Journal of Neuropsychopharmacology 03/2011; 14(2):187-200. · 5.64 Impact Factor