Functional interaction between serotonin and other neuronal systems: focus on in vivo microdialysis studies

In this review, the functional interactions between serotonin (5-HT) and other neuronal systems are discussed with the focus on microdialysis studies in the mammalian brain (mainly rats). 5-HT release is negatively regulated not only by somatodendritic 5-HT1A and terminal 5-HT1B (5-HT1D) autoreceptors but also by alpha 2-adrenergic and mu-opioid heteroreceptors that are located on serotonergic nerve terminals. 5-HT by itself is involved in the inhibitory effects of noradrenaline release and the facilitatory regulation of dopamine release via multiple 5-HT receptors. Acetylcholine release appears to be regulated by inhibitory 5-HT1B heteroreceptors located on cholinergic nerve terminals. Long-term treatment with 5-HT-uptake inhibitors and noradrenaline-uptake inhibitor produces desensitization of 5-HT1A autoreceptors and alpha 2-heteroreceptors, respectively, which may be related therapeutically to the delayed onset of the effects of antidepressants. Some microdialysis studies have predicted that the combination of a 5-HT-uptake inhibitor and 5-HT1A-autoreceptor antagonist might produce much greater availability of 5-HT in the synaptic cleft in terms of much faster induction of subsensitivity of 5-HT1A autoreceptors. Clinical trials based on this hypothesis have revealed that combination therapy with a 5-HT-uptake inhibitor and 5-HT1A-autoreceptor antagonist ameliorated the therapeutic efficacy in depressive patients. Taken together, neurochemical approaches using microdialysis can contribute not only to clarification of the physiological role of the serotonergic neuronal systems but also might be a powerful pharmacological approach for the development of therapeutic strategies.