RESUMO
(1) Using in vivo intracerebral microdialysis in conscious, freely moving rats, we examined the effect of flibanserin, a potential antidepressant drug with high affinity for human 5-HT(1A) receptors and four-50-fold lower affinity for 5-HT(2A) and D(4) receptors, on basal extracellular concentrations of serotonin (5-hydroxytryptamine, 5-HT), dopamine (DA) and noradrenaline (NA) in selected regions of the rat brain. (2) Flibanserin at 3 and 10 mg kg(-1) significantly reduced extracellular 5-HT in the prefrontal cortex (by 30 and 45%) and dorsal raphe (35 and 44%), but had no effect on extracellular 5-HT in the ventral hippocampus. The 3 and 10 mg kg(-1) doses raised extracellular NA to a similar extent in the prefrontal cortex (47 and 50%). In all, 10 mg kg(-1) raised extracellular DA in the prefrontal cortex (63%) whereas 3 mg kg(-1) had no significant effect. (3) Pretreatment with the selective 5-HT(1A) receptor antagonist WAY100,635 (0.3 mg kg(-1)) 30 min before 10 mg kg(-1) flibanserin completely antagonized the latter's effects on extracellular 5-HT, DA and NA in the prefrontal cortex. WAY100,635 by itself had no effect on cortical extracellular monoamines. (4) The results show that the stimulation of 5-HT(1A) receptors plays a major role in the effect of flibanserin on brain extracellular 5-HT, DA and NA.
Assuntos
Antidepressivos/farmacocinética , Benzimidazóis/farmacologia , Benzimidazóis/farmacocinética , Dopamina/química , Previsões , Norepinefrina/química , Córtex Pré-Frontal/química , Serotonina/química , Animais , Antidepressivos/administração & dosagem , Benzimidazóis/administração & dosagem , Benzimidazóis/antagonistas & inibidores , Dopamina/metabolismo , Líquido Extracelular/química , Hipocampo/química , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Injeções Subcutâneas , Masculino , Microdiálise/métodos , Norepinefrina/metabolismo , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Piridinas/administração & dosagem , Piridinas/farmacocinética , Núcleos da Rafe/química , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/fisiologia , Serotonina/metabolismoRESUMO
The present study investigated whether 5-HT(2C) receptors in the ventrotegmental area and prefrontal cortex regulate basal and stimulus-evoked dopamine release in the prefrontal cortex. Using the in vivo microdialysis technique in conscious rats, we studied the effect of a selective 5-HT(2C) receptor agonist, Ro60-0175, on basal and immobilization stress-induced dopamine release in the prefrontal cortex. Ro60-0175 intraperitoneally (2.5 mg/kg) and into the ventrotegmental area (10 microg/0.5 microL) completely antagonized the effect of stress on extracellular dopamine without altering basal levels. Infusion of 10 microm Ro60-0175 through the cortical probe had no significant effect on basal and stress-induced dopamine release. SB242084 (10 mg/kg), a selective antagonist of 5-HT(2C) receptors, significantly increased basal extracellular dopamine and completely prevented the effect of intraperitoneal and intraventrotegmental Ro60-0175 on the stress-induced rise of extracellular dopamine, but had no effect itself in stressed rats. The results show that Ro60-0175 suppresses cortical dopamine release induced by immobilization stress through the stimulation of 5-HT(2C) receptors in the ventrotegmental area. While confirming that endogenous 5-HT acting on 5-HT(2C) receptors tonically inhibit basal dopamine release in the prefrontal cortex, the present findings suggest that the stimulation of 5-HT(2C) receptors with an exogenous agonist preferentially inhibit stimulated release.