MODULATION OF CENTRAL SEROTONERGIC NEUROTRANSMISSION BY RISPERIDONE -UNDERLYING MECHANISM[S] AND SIGNIFICANCE OF ACTION

1. The effects of risperidone on brain 5-hydroxytryptamine (5-HT) neur onal activity were investigated using microdialysis in the frontal cor tex (FC) or the dorsal raphe nucleus (DRN) as well as single cell reco rding 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 i dazoxan enhanced the 5-HT efflux in the FC, whereas local raphe admini stration of risperidone but not idazoxan increased the output of 5-HT in the DRN. 4. Systemic administration of risperidone (200 mu g/kg, i. v.) or the selective a, adrenoceptor antagonist prazosin (400 mu g/kg, i.v.) decreased, whereas selective cl, adrenoceptor antagonist idazox an (20 mu g/kg, i.v.) increased the 5-HT cell firing in the DRN. 5. Pr etreatment with the selective 5-HT1A receptor antagonist WAY 100,635 ( 5.0 mu g/kg, i.v.) effectively antagonized the inhibition of 5-HT cell s induced by risperidone, but failed to prevent the prazosin-induced d ecrease in 5-HT cell firing in the DRN. 6. The inhibitory effect of ri speridone 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 na ive animals. 7. Consequently, the risperidone-induced increase in 5-HT output in the FC may be related to its a, adrenoceptor antagonistic a ction, an effect probably executed at the nerve terminal level, wherea s the reduction in 5-HT cell firing by risperidone appears to be assoc iated with increased availability of 5-HT in the somatodendritic regio n of the neurones leading to an enhanced 5-HT1A autoreceptor activatio n and, in turn, to inhibition of cell firing.