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: A mechanism for interdependent changes in the concentrations of neuromodulators during paradoxical sleep is proposed. According to this mechanism, the release of dopamine in the striatum and modulation of corticostriatal inputs promote disinhibitions via the basal ganglia of cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei, thus initiating paradoxical sleep. Simultaneously, dopamine activates postsynaptic Gi/0-protein-coupled D3 receptors on serotonergic and noradrenergic neurons, thereby promoting depression of their excitation and suppression of their activity. An increase in the concentration of acetylcholine, in turn, leads to an increase in the level of dopamine, serotonin, and noradrenaline, due to activation of nicotinic α-receptors and depolarization of neurons that release these neuromodulators. Serotonergic and noradrenergic neurons enable reciprocal excitation due to activation of Gq/11-protein-coupled 5-HT2 and α1 adrenergic receptors. However, an increase in the activity of serotonergic and noradrenergic cells suppresses paradoxical sleep, first, due to depression of excitation of cholinergic neurons via Gi/0-protein-coupled 5-HT1 and α2 adrenergic receptors. Second, serotonin and noradrenaline suppress the activity of dopaminergic cells by affecting 5-HT2 and α1 adrenergic receptors and by potentiating excitation of GABAergic interneurons projecting onto dopaminergic cells. Owing to the specified changes in the efficiency of inputs to neuromodulatory neurons, opposite changes in concentrations of acetylcholine and dopamine, on the one hand, and serotonin and noradrenaline, on the other hand, lead to alternation of various phases of sleep and wakefulness.Neurochemical Journal 02/2007; 1(23):1819-7124. · 0.24 Impact Factor
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ABSTRACT: Antipsychotic drugs are the treatment of choice in schizophrenia. Since the discovery of chlorpromazine, several generations of antipsychotic drugs have been developed with disparate mechanism of action and complex binding profile. Although the modifications of their mechanisms have translated into decreased side effects, their superior therapeutic efficacy is often debated. Furthermore, the lack of clear criteria to define antipsychotic drugs as typical or atypical is delaying the development of new compounds with innovative mechanisms of actions. There is general agreement that we are abusing dopaminergic based criteria to evaluate the newly available compounds although they are targeting several other neurotransmitter systems. The present work will overview the antipsychotic drugs effects on serotonin levels as measured with microdialysis in the rat brain. A functional association among therapeutic mechanisms of antipsychotic drugs, their serotonin receptors affinities and serotonin level changes will be attempted. The primary ambition of this investigation is to provide an exhaustive reference for who is interested, at any levels, in antipsychotic drugs effects on cortical and subcortical serotonin output.Behavioural brain research. 07/2014;
- European Journal of Integrative Medicine 01/2010; 2(4):233-233. · 0.56 Impact Factor