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: The actions of diverse antipsychotics at cloned h5-HT1B and h5-HT1D receptors were examined employing [3H]-GR125,743 and [35S]-GTPγS for determination of affinities and efficacies, respectively. Compared with hD2 receptors, haloperidol, chlorpromazine and olanzapine showed markedly (>100-fold) lower affinity for h5-HT1D and h5-HT1B receptors at which they expressed inverse agonist properties. Clozapine, risperidone and ocaperidone likewise behaved as inverse agonists at h5-HT1B and h5-HT1D receptors but their affinities were only ~10-fold lower than at hD2 receptors. Moreover, ziprasidone, S16924 and ORG5222 interacted at h5-HT1B and h5-HT1D receptors with affinities similar to hD2 sites. While S16924 and ORG5222 were inverse agonists at h5-HT1B and h5-HT1D sites, ziprasidone was an inverse agonist at h5-HT1D receptors yet a partial agonist at h5-HT1B receptors. These actions of antipsychotics were abolished by the selective, neutral antagonist, S18127. In conclusion, with the exception of ziprasidone, all antipsychotics were inverse agonists at h5-HT1B and h5-HT1D receptors, although they differed markedly in their potency at these sites as compared to hD2 receptors.Neuropsychopharmacology 02/2001; 25(3):410-422. DOI:10.1016/S0893-133X(01)00237-8 · 7.83 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; DOI:10.1016/j.bbr.2014.07.025 · 3.39 Impact Factor
European Journal of Integrative Medicine 12/2010; 2(4):233-233. DOI:10.1016/j.eujim.2010.09.127 · 0.65 Impact Factor