Biochemical profile of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug

Modulation of the Extracellular 5-Hydroxytryptamine Brain Concentrations by the Serotonin and Noradrenaline Reuptake Inhibitor, Milnacipran Microdialysis Studies in Rats

“…) This suggests that milnacipran blocks the 5-HT reuptake in vivo in rat brain with a potency in the range of that of imipramine or clomipramine. This is in agreement with the similar in vivo potency of imipramine and milnacipran to prevent the hypothermic and hyperthermic action of H75/12 and H77/77, respectively, which are related to the availability of brain monoamines (Moret et al 1985).However, 10 to 20 mg/kg clomipramine and imipramine increased 3-to 4-fold the 5-HT output in the midbrain raphe nuclei; whereas, 60 mg/kg milnacipran scarcely doubled the 5-HT output (Figure 3). Moreover, 10 mg/kg of the SSRI fluoxetine (with an EC 50 of about 30 mol/l) increased the 5-HT output 3-fold in the dorsal and the median raphe nucleus (Hervás and Artigas 1998).…”

“…The experimental conditions used in vivo (low flow rate, continuous removal of applied drugs by the CSF and systemic circulation, tortuosity of brain tissue, etc.) make these values much higher than their corresponding in vitro counterparts (the in vitro value for the 5-HT uptake is 203 nM; Moret et al 1985).The maximal increments affected by milnacipran were very large (7-and 10-fold in frontal cortex and midbrain raphe, respectively) and comparable to those induced by the local application of SSRIs Hervás and Artigas 1998. ) This suggests that milnacipran blocks the 5-HT reuptake in vivo in rat brain with a potency in the range of that of imipramine or clomipramine.…”

“…6 drugs, mainly derived from their affinity for ␣ -adrenergic, cholinergic, and histamine receptors (Richelson 1978;Richelson and Nelson 1984). Milnacipran is one such drug that blocks in vitro and in vivo the reuptake of 5-HT and noradrenaline, although it displays a slightly higher affinity for the latter (Moret et al 1985;Stenger et al 1987).…”

“…6 drugs, mainly derived from their affinity for ␣ -adrenergic, cholinergic, and histamine receptors (Richelson 1978;Richelson and Nelson 1984). Milnacipran is one such drug that blocks in vitro and in vivo the reuptake of 5-HT and noradrenaline, although it displays a slightly higher affinity for the latter (Moret et al 1985;Stenger et al 1987).Despite the potential advantages of SNRIs, the information on their in vivo effects on serotonergic transmission is scarce (e.g., Engleman et al 1995;. In particular, a comparison of their effects in the somatodendritic region in the raphe nuclei and in forebrain has not been performed.…”

“…Moreover, the SNRI duloxetine increased the 5-HT output in hypothalamus more markedly than in frontal cortex (Engleman et al 1996;Kihara and Ikeda 1995). These observations suggest that hypothalamic 5-HT is particularly sensitive to the actions of SNRIs.In addition, because milnacipran inhibits the noradrenaline uptake with a potency slightly greater than that of serotonin uptake (IC 50 values of 100 and 203 nM, respectively; Moret et al 1985) an interaction between the noradrenergic and serotonergic systems cannot be disregarded as a potential source of these differences. Thus, the activation of ␣ 2 -heteroceptors reduces termi- NEUROPSYCHOPHARMACOLOGY 1999-VOL.…”