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

• 1.1. 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.
• 2.2. 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.
• 3.3. 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.
• 4.4. Systemic administration of risperidone (200 μg/kg i.v.) or the selective α₁ adrenoceptor antagonist prazosin (400 μg/kg i.v.) decreased, whereas selective α₂ adrenoceptor antagonist idazoxan (20 μg/kg i.v.) increased the 5-HT cell firing in the DRN.
• 5.5. Pretreatment with the selective 5-HT_1A receptor antagonist WAY 100,635 (5.0 μg/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.
• 6.6. 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.
• 7.7. Consequently, the risperidone-induced increase in 5-HT output in the FC may be related to its α₂ 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-HT_1A autoreceptor activation and, in turn, to inhibition of cell firing.