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Risperidone inhibits 5‐hydroxytryptaminergic neuronal activity in the dorsal raphe nucleus by local release of 5‐hydroxytryptamine
Author(s) -
Hertel Peter,
Nomikos George G.,
Svensson Torgny H.
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701561
Subject(s) - dorsal raphe nucleus , prazosin , chemistry , idazoxan , raclopride , pharmacology , ritanserin , antagonist , ketanserin , receptor antagonist , 5 ht receptor , endocrinology , medicine , serotonin , receptor , serotonergic
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 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 α 1 ‐adrenoceptor antagonist prazosin (50–400 μg kg −1 , i.v.). 3 The selective α 2 ‐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 D 2 and 5‐HT 2A 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 α 1 ‐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‐HT 1A 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 α 1 ‐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‐HT 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‐HT in the somatodendritic region of the neurones leading to an enhanced 5‐HT 1A autoreceptor activation and, in turn, to inhibition of firing, and is probably only to a minor extent caused by its α 1 ‐adrenoceptor antagonistic action.