Modulation of central serotonergic neurotransmission by risperidone: Underlying mechanism(s) and significance of action

Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Progress in Neuro-Psychopharmacology and Biological Psychiatry (Impact Factor: 3.69). 08/1998; 22(5):815-34. DOI: 10.1016/S0278-5846(98)00042-6
Source: PubMed


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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    • "Interestingly, the inhibition of FCX release of 5-HT by α 2A - ARs may, nevertheless, be distinguished from the control of NAD release therein inasmuch as it is not expressed tonically. That is α 2A -AR antagonists do not elevate levels of 5-HT in FCX (Gobert et al., 1998), although it remains controversial as to whether α 2 - ARs tonically inhibit 5-HT levels in other cerebral structures (Tao and Hjorth, 1992; Mongeau et al., 1993; Hertel et al., 1998). This finding parallels the lack of tonic control of serotonergic transmission by 5-HT 1A/1B autoreceptors as compared to the tonic modulation of noradrenergic transmission by α 2A -ARs (vide supra). "
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