1. The 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). 2. Administration of risperidone (25-400 mu g 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 alpha(1)-adrenoceptor antagonist prazosin (50-400 mu g kg(-1), i.v.). 3. The selective alpha(2)-adrenoceptor antagonist idazoxan (10-80 mu g kg(-1), i.v.), in contrast, increased the firing rate of 5-HT neurones in the DRN, whereas the D-2 and 5-HT2A receptor antagonists raclopride (25-200 mu g kg(-1), i.v.) and MDL 100,907 (50-400 mu g kg(-1), i.v.), respectively, were without effect. Thus, the al-adrenoceptor antagonistic action of the antipsychotic drugs might, at least partly, cause the decrease in DRN 5-HT cell firing. 4. Pretreatment with the selective 5-HT1A receptor antagonist WAY 100,635 (5.0 mu g 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 a,adrenoceptor antagonism is the sole mechanism underlying the inhibitory effect of risperidone on the DRN cells. 5. The inhibitory effect of risperidone on 5-HT cell firing in the DRN was significantly attenuated in rats pretreated with the 5-KT depletor PCPA (p-chlorophenylalanine; 300 mg kg(-1), i.p., day(-1) for 3 consecutive days) in comparison with drug naive animals. 6. Administration of risperidone (2.0 mg kg(-1), s.c.) significantly enhanced 5-HT output in the DRN. 7. Consequently, the reduction in 5-HT cell firing by risperidone appears to be related to increased availability of 5-KT 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 alpha(1)-adrenoceptor antagonistic action.
