Release of cerebral 5-hydroxytryptamine evoked by electrical stimulation of the dorsal and median raphe nuclei: effect of a neurotoxic amphetamine

Abstract

Recent neuroanatomical data suggest that the axons and terminals of serotonergic neurons of the dorsal and median raphe nuclei are morphologically and pharmacologically distinct. Here we attempted to establish a functional in vivo model of serotonergic terminals derived from these nuclei, and then carry out a preliminary comparison of their physiological and pharmacological properties. Brain microdialysis was used to monitor extracellular 5-hydroxytryptamine in the hippocampus (dorsal and median raphe innervation) and frontal cortex (preferential dorsal raphe innervation) of the anaesthetized rat. To distinguish 5-hydroxytryptamine released by terminals of dorsal raphe neurons from that released by median raphe neurons, one or other of these nuclei was stimulated electrically. Electrical stimulation of either the dorsal or median raphe nucleus evoked a release of 5-hydroxytryptamine in the hippocampus. Whereas stimulation of the dorsal raphe nucleus also released 5-hydroxytryptamine in the frontal cortex, stimulation of the median raphe nucleus did not. No release of 5-hydroxytryptamine was evoked when electrodes were located in regions bordering the dorsal raphe nucleus and the median raphe nucleus. The amounts of hippocampal 5-HT released by stimulation of the dorsal or median raphe nucleus were found to be similarly altered by a 5-hydroxytryptamine uptake inhibitor (citalopram) and calcium-free perfusion medium, and also by increasing stimulation frequency (2-10 Hz). Furthermore, the amount of 5-hydroxytryptamine released by electrical stimulation of either the dorsal raphe nucleus or median raphe nucleus was markedly reduced in rats pretreated with p-chloroamphetamine. In summary, our data show that electrical stimulation of the dorsal or median raphe nucleus releases 5-hydroxytryptamine in a regionally specific manner (hippocampus versus frontal cortex), suggesting that serotonergic nerve terminals of the dorsal and median raphe pathways were being activated selectively. Using this model, we found no differences in the responsiveness of dorsal and median raphe pathways to a specific set of physiological and pharmacological manipulations. In particular, our data suggest that the neurotoxic action of p-chloroamphetamine may not be targeted solely on serotonergic axons and terminals of the dorsal raphe nucleus but includes those of the median raphe nucleus.