Milnacipran is a
serotonin/
noradrenaline reuptake inhibitor (
SNRI) which has not yet been systematically studied preclinically or clinically for the treatment of
anxiety disorders. In the four-plate test (FPT) which is known to predict
anxiolytic-like activity in mice,
milnacipran (4, 8, 16 and 32 mg/kg) demonstrated strong anti-punishment effects following acute administration. The
anxiolytic-like effect of
milnacipran was not reversed by the selective
GABA(A) receptor antagonist,
flumazenil (2 and 4 mg/kg), the selective alpha1-adrenoceptor antagonist,
prazosin (0.5 and 2 mg/kg), the selective alpha2-adrenoceptor antagonist,
idazoxan (1 and 4 mg/kg) or the selective
5-HT2B receptor antagonist,
SB 206553 (0.1 and 1 mg/kg). In contrast, the selective
5-HT2A receptor antagonist,
SR 46349B (0.1 and 1 mg/kg), and the non-selective 5-HT2 receptor antagonist,
ketanserin (0.125 and 0.5 mg/kg), completely abolished the
anxiolytic-like effect of
milnacipran in FPT. Neurochemical depletion of NA or
5-HT completely abolished the activity of
milnacipran. These results strongly suggest that activation of 5-HT2A receptors is critically involved in the
anxiolytic activity of
milnacipran. On the other hand the lack of activity of
milnacipran after depletion of NA or
5-HT is consistent with
milnacipran acting on the locus coeruleus to induce
5-HT release. The present data suggest a strong connection between 5-HT2A receptors and NA neurotransmission.