DIFFERENTIAL-EFFECTS OF IPSAPIRONE ON 5-HYDROXYTRYPTAMINE RELEASE IN THE DORSAL AND MEDIAN RAPHE NEURONAL PATHWAYS

Serotonergic neurons of the dorsal and median raphe nuclei are morphol ogically dissimilar. Recent results challenge previous evidence indica ting a greater inhibition of dorsal raphe neurons after 5-hydroxytrypt amine(1A) (5-HT1A) autoreceptor activation. As both nuclei innervate d ifferent forebrain territories, this issue is critical to understandin g the changes in brain function induced by anxiolytic and antidepressa nt drugs. Using microdialysis, we examined the modifications of 5-HT r elease induced by the selective 5-HT1A agonist ipsapirone in both neur onal pathways. Maximal and minimal basal 5-HT values (in the presence of 1 mu M citalopram) were 45.0+/-4.8 fmol/fraction in the median raph e nucleus and 8.4+/-0.4 fmol/fraction in the dorsal hippocampus. Ipsap irone (0.3, 3, and 10 mg/kg s.c.) reduced dose-dependently 5-HT in the two raphe nuclei and four forebrain areas. Maximal reductions (to sim ilar to 25% of predrug values) were observed in cortex and striatum an d in median raphe nucleus. The effects were more moderate in dorsal an d ventral hippocampus (to 66 and 50% of baseline, respectively). These results are consistent with a higher sensitivity of dorsal raphe neur ons to 5-HT1A autoreceptor activation. Yet the differential reduction of 5-HT release in the median raphe nucleus and hippocampus suggests t he presence of complex mechanisms of control of 5-HT release in these neurons.