Salvinorin A modulates the neurotransmitters release from different mouse brain areas through presynaptic metabotropic receptors activation

Salvinorin-A is a component of Salvia divinorum, displaying psychoactive and hallucinogenic properties in humans. Recent literature suggests that this compound can act as a potent and selective opioid receptor agonist, having high affinity towards the K–opioid receptor subtype. The aim of our study was to investigate whether and to what extent this compound can alter the release of neurotransmitters from isolated nerve terminals (synaptosomes) prepared from mouse hippocampus (HC), striatum (STR) and prefrontal cortex (PFC). The experimental approach used, i.e. the up-down superfusion of a synaptosomal monolayer, is considered a method of choice to investigate presynaptic mechanisms of control of neurotransmitter release. We focused on the release of prelabelled [³H]noradrenaline ([³H]NA) and [³H]serotonin ([³H]5HT) from rat HC synaptosomes and of [³H]dopamine ([³H]DA) from PFC and STR synaptosomes. Salvinorin-A failed to affect the spontaneous release of all the three amines, but significantly modified the release of these neurotransmitters induced by transient (90s) exposure to 12 mM K⁺. In particular, Salvinorin-A potentiated in a concentration-dependent manner the K⁺-evoked release of [³H]NA, while it inhibited, always in a concentration-dependent way the release of [³H]5HT and of [³H]DA. Both facilitation and inhibiton of amine exocytosis was prevented by entrapping into synaptosomes the Pertussis toxin, suggesting the primary involvement in these effects of G-protein coupled receptors sensitive to this toxin. These results may be relevant to the comprehension of the molecular mechanisms involved in the central effects induced by this natural product.