Gabaergic interneurons in the dorsal raphe mediate the effects of apomorphine on serotonergic system

Apomorphine (APO) has been shown to elevate the concentrations of serotonin (5-HT) and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the mesostriatal but not the mesolimbic serotonergic systems. We have previously demonstrated that the serotonergic actions of APO were secondary to dopamine (DA) autoreceptor stimulation in the substantia nigra. Using picrotoxin as a pharmacological tool, we have presently found that these effects of APO were also indirectly mediated through gamma-aminobutyric acid (GABA) neurons. In examination of the exact anatomical locus of GABA neurons responsible for the observed effects of APO, the results indicate that bilateral lateral habenular lesions did not block the effects of APO on 5-HT neurons, while direct picrotoxin infusion to the dorsal raphe, at a dose having no significant influence by itself, antagonized APO's actions. Together with the anatomical, biochemical and histofluorescent findings, it is suggested that APO influences dorsal raphe 5-HT by stimulation of DA autoreceptors in the substantia nigra; therefore, inhibition of DA neuron activity and the nigro-raphe pathway. Normally, DA probably exerts an excitatory influence on gabaergic interneurons in the dorsal raphe, and these inhibitory interneurons then synapse on 5-HT neurons in the same area. Activation of 5-HT neurons were explained by a disinhibitory effect as a result of reduced release of GABA due to feedback inhibition of DA neuron firing following APO activation of DA autoreceptors in the substantia nigra. The striatal presynaptic and postsynaptic DA receptors, however, do not appear to mediate the above effects of APO.