AUTORADIOGRAPHIC CHARACTERIZATION OF BINDING-SITES FOR [H-3] MILNACIPRAN, A NEW ANTIDEPRESSANT DRUG, AND THEIR RELATIONSHIP TO THE SEROTONIN TRANSPORTER IN RAT-BRAIN

Milnacipran is a new antidepressant drug and an equipotent inhibitor of the uptake of serotonin and noradrenaline, Quantitative autoradiography and radioligand binding studies were used to characterize recognition sites of [H-3]milnacipran in rat brain. [H-3]Milnacipran demonstrated saturable, reversible and nanomolar affinity binding. The binding was Na+-dependent, potently displaced by serotonin uptake inhibitors in all structures and moderately or weakly displaced by catecholamine uptake inhibitors (order of potency: paroxetine > fluoxetine > mazindol > desipramine > nomifensine > maprotiline). High density of recognition sites were found in structures dense in serotonergic innervation (raphe, basal ganglia, colliculi, cortex). The autoradiographic pattern of [H-3]milnacipran recognition sites resembled that of [H-3]paroxetine, but their distribution did not correlate well in some structures. Selective lesioning of serotonergic neurons by intracerebral injection of 5,7-dihydroxytryptamine caused a large decrease of [H-3]milnacipran binding in various regions (septum, caudate, hippocampus, thalamus, ventral and dorsal hypothalamus), but in other structures, the [H-3]milnacipran binding was partially affected (putamen) or even unchanged (amygdala, lateral hypothalamus). In contrast, lesion of noradrenergic neurons by intraperitoneal administration of [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] did not affect the binding of [H-3]milnacipran in any region. These results show that [H-3]mxilnacipran mainly binds to the serotonin transporter and does not recognize the catecholamine transporters under the conditions used, In addition, [H-3]milnacipran might also bind to other sites, serotonin transporter localized on non-serotonergic neurons or serotonergic neurons insensitive to 5,7-DHT neurotoxicity.