Effect of repeated treatment with milnacipran on the central dopaminergic system

Milnacipran (MIL) is a representative of a new class of antidepressants (SNRIs) which inhibit the reuptake of serotonin and noradrenaline, but, in contrast to tricyclics, show no affinity for neurotransmitters receptors. The present study was aimed at determining whether repeated MIL administration (given at doses of 10 or 30 mg/kg, twice daily for 14 days) induced the adaptive changes in the dopaminergic system similar to those reported by us earlier for tricyclic antidepressants. The obtained results showed that MIL administered repeatedly did not change the responsiveness of dopamine D1 receptors since it did not change the SKF 38393-induced grooming. Repeated MIL treatment increased the hyperlocomotion induced by D-amphetamine and 7-OH-DPAT, but did not affect the D-amphetamine and apomorphine stereotypies. The binding parameters (Bmax and Kd) to dopamine D1 and D2 receptors in the limbic forebrain were not affected by repeated MIL treatment when [3H]SCH 23390 and [3H]spiperone, respectively, were used as ligands. On the other hand, the increased density of dopamine D2 receptors (Bmax) was observed in the striatum after repeated treatment with MIL. MIL administered acutely or repeatedly did not change the binding of [3H]7-OH-DPAT to dopamine D3 receptors in the islands of Calleja and the shell region of the nucleus accumbens septi. The above results indicate that repeated MIL administration induces the adaptive changes in the dopaminergic system, especially it enhances the functional responsiveness of dopamine D2 and D3 receptors. However, the question whether this increased functional responsiveness is important for the clinical antidepressant efficacy, remains open.