Risperidone inhibits 5-hydroxytryptaminergic neuronal activity in the dorsal raphe nucleus by local release of 5-hydroxytryptamine
Version of Record online: 10 FEB 2009
1997 British Pharmacological Society
British Journal of Pharmacology
Volume 122, Issue 8, pages 1639–1646, December 1997
How to Cite
Hertel, P., Nomikos, G. G. and Svensson, T. H. (1997), Risperidone inhibits 5-hydroxytryptaminergic neuronal activity in the dorsal raphe nucleus by local release of 5-hydroxytryptamine. British Journal of Pharmacology, 122: 1639–1646. doi: 10.1038/sj.bjp.0701561
- Issue online: 10 FEB 2009
- Version of Record online: 10 FEB 2009
- (Received September 15, 1997, Accepted September 19, 1997)
- Neuroleptic drugs;
- spontaneous firing;
- dorsal raphe nucleus;
- 1The effects of risperidone on brain 5-hydroxytryptamine (5-HT) neuronal functions were investigated and compared with other antipsychotic drugs and selective receptor antagonists by use of single cell recording and microdialysis in the dorsal raphe nucleus (DRN).
- 2Administration of risperidone (25–400 μg kg−1, i.v.) dose-dependently decreased 5-HT cell firing in the DRN, similar to the antipsychotic drug clozapine (0.25–4.0 mg kg−1, i.v.), the putative antipsychotic drug amperozide (0.5–8.0 mg kg−1, i.v.) and the selective α1-adrenoceptor antagonist prazosin (50–400 μg kg−1, i.v.).
- 3The selective α2-adrenoceptor antagonist idazoxan (10–80 μg kg−1, i.v.), in contrast, increased the firing rate of 5-HT neurones in the DRN, whereas the D2 and 5-HT2A receptor antagonists raclopride (25–200 μg kg−1, i.v.) and MDL 100,907 (50–400 μg kg−1, i.v.), respectively, were without effect. Thus, the α1-adrenoceptor antagonistic action of the antipsychotic drugs might, at least partly, cause the decrease in DRN 5-HT cell firing.
- 4Pretreatment with the selective 5-HT1A receptor antagonist WAY 100,635 (5.0 μg kg−1, i.v.), a drug previously shown to antagonize effectively the inhibition of 5-HT cells induced by risperidone, failed to prevent the prazosin-induced decrease in 5-HT cell firing. This finding argues against the notion that α1-adrenoceptor antagonism is the sole mechanism underlying the inhibitory effect of risperidone on the DRN cells.
- 5The 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−1, i.p., day−1 for 3 consecutive days) in comparison with drug naive animals.
- 6Administration of risperidone (2.0 mg kg−1, s.c.) significantly enhanced 5-HT output in the DRN.
- 7Consequently, the reduction in 5-HT cell firing by risperidone appears to be related to 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 firing, and is probably only to a minor extent caused by its α1-adrenoceptor antagonistic action.