RISPERIDONE INHIBITS 5-HYDROXYTRYPTAMINERGIC NEURONAL-ACTIVITY IN THEDORSAL RAPHE NUCLEUS BY LOCAL RELEASE OF 5-HYDROXYTRYPTAMINE

1. The effects of risperidone on brain 5-hydroxytryptamine (5-HT) neur onal functions were investigated and compared with other antipsychotic drugs and selective receptor antagonists by use of single cell record ing and microdialysis in the dorsal raphe nucleus (DRN). 2. Administra tion of risperidone (25-400 mu g kg(-1), i.v.) dose-dependently decrea sed 5-HT cell firing in the DRN, similar to the antipsychotic drug clo zapine (0.25-4.0 mg kg(-1), i.v.), the putative antipsychotic drug amp erozide (0.5-8.0 mg kg(-1), i.v.) and the selective alpha(1)-adrenocep tor antagonist prazosin (50-400 mu g kg(-1), i.v.). 3. The selective a lpha(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, wher eas 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 recept or antagonist WAY 100,635 (5.0 mu g kg(-1), i.v.), a drug previously s hown 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,adrenocepto r 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 p retreated with the 5-KT depletor PCPA (p-chlorophenylalanine; 300 mg k g(-1), i.p., day(-1) for 3 consecutive days) in comparison with drug n aive animals. 6. Administration of risperidone (2.0 mg kg(-1), s.c.) s ignificantly enhanced 5-HT output in the DRN. 7. Consequently, the red uction in 5-HT cell firing by risperidone appears to be related to inc reased availability of 5-KT in the somatodendritic region of the neuro nes leading to an enhanced 5-HT1A autoreceptor activation and, in turn , to inhibition of firing, and is probably only to a minor extent caus ed by its alpha(1)-adrenoceptor antagonistic action.