Risperidone dose-dependently increases extracellular concentrations of serotonin in the rat frontal cortex: role of alpha 2-adrenoceptor antagonism.
We have previously shown that risperidone, an antipsychotic drug with high affinity for 5-hydroxytryptamine (5-HT)2A and dopamine (DA)2 receptors, as well as for alpha 2- and alpha 2-adrenoceptors, enhances 5-HT metabolism selectively in the rat frontal cortex (FC). To further study the influence of risperidone on central 5-HT systems, we compared its effects on dialysate 5-HT in the FC, as assessed by microdialysis, with those obtained with other antipsychotic drugs, i.e., clozapine, haloperidol, and amperozide, as well as with the selective alpha 2- or 5-HT2A receptor antagonists idazoxan or MDL 100,907, respectively. The underlying mechanism for risperidone's effect on 5-HT output in the FC was also investigated using single-cell recording in the dorsal raphe nucleus (DRN). Administration of risperidone (0.2, 0.6, and 2.0 mg/kg, SC) dose-dependently increased 5-HT levels in the FC. This stimulatory action was mimicked by amperozide (10 mg/kg, SC) and, to some extent, by idazoxan (0.25 mg/kg, SC). In contrast, clozapine (10 mg/kg, SC), haloperidol (2.0 mg/kg, SC), and MDL 100,907 (1.0 mg/kg, SC) exerted only minor effects on 5-HT output in brain. Local administration of risperidone or idazoxan (1.0-1000 mumol/L) in the FC dose-dependently increased dialysate levels of 5-HT in this region. On the other hand, risperidone 25-800 micrograms/kg, IV) dose-dependently decreased the firing rate of 5-HT cells in the DRN, an effect that was largely antagonized by pretreatment with the selective 5-HT1A receptor antagonist WAY 100,635 (5.0 micrograms/kg, IV). These results indicate that the risperidone-increased 5-HT output in the FC may be related to its alpha 2-adrenoceptor antagonistic action, a property shared with both amperozide and idazoxan, and that this action probably is executed at the nerve terminal level. The inhibition of 5-HT cell firing by risperidone is probably secondary to increased 5-HT availability, e.g., in the DRN, since it could be antagonized by a 5-HT1A receptor antagonist. The enhanced 5-HT output in the FC by risperidone may be of particular relevance for the treatment of schizophrenia when associated with depression and in schizoaffective disorder.
Hertel
P
P
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Nomikos
G G
GG
Schilström
B
B
Arborelius
L
L
Svensson
T H
TH
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019329:Idazoxan / Q000494:pharmacology*; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology; D051381:Rats; D018967:Risperidone / Q000494:pharmacology*; D012701:Serotonin / Q000032:analysis*
D000317:Adrenergic alpha-Antagonists; D014150:Antipsychotic Agents; D010879:Piperazines; D011725:Pyridines; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D018967:Risperidone; D004298:Dopamine; D019329:Idazoxan