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J Pharmacol Sci. 2017 Jul;134(3):181-189. doi: 10.1016/j.jphs.2017.06.004. Epub 2017 Jun 27.

Milnacipran affects mouse impulsive, aggressive, and depressive-like behaviors in a distinct dose-dependent manner.

Author information

1
Department of Neuropsychiatry, Keio University, School of Medicine, Tokyo 160-8582, Japan; Japan Society for the Promotion of Science, Japan; Department of Neuropharmacology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan. Electronic address: firstmolars@yahoo.co.jp.
2
Department of Neuropharmacology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan. Electronic address: gwd0701@yahoo.co.jp.
3
Department of Neuropharmacology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.

Abstract

Serotonin/noradrenaline reuptake inhibitors (SNRIs) are widely used for the treatment for major depressive disorder, but these drugs induce several side effects including increased aggression and impulsivity, which are risk factors for substance abuse, criminal involvement, and suicide. To address this issue, milnacipran (0, 3, 10, or 30 mg/kg), an SNRI and antidepressant, was intraperitoneally administered to mice prior to the 3-choice serial reaction time task, resident-intruder test, and forced swimming test to measure impulsive, aggressive, and depressive-like behaviors, respectively. A milnacipran dose of 10 mg/kg suppressed all behaviors, which was accompanied by increased dopamine and serotonin levels in the medial prefrontal cortex (mPFC) but not in the nucleus accumbens (NAc). Although the most effective dose for depressive-like behavior was 30 mg/kg, the highest dose increased aggressive behavior and unaffected impulsive behavior. Increased dopamine levels in the NAc could be responsible for the effects. In addition, the mice basal impulsivity was negatively correlated with the latency to the first agonistic behavior. Thus, the optimal dose range of milnacipran is narrower than previously thought. Finding drugs that increase serotonin and dopamine levels in the mPFC without affecting dopamine levels in the NAc is a potential strategy for developing novel antidepressants.

KEYWORDS:

Depression; Helplessness; Response inhibition; Serotonin/norepinephrine reuptake inhibitor; Violence

PMID:
28694090
DOI:
10.1016/j.jphs.2017.06.004
[Indexed for MEDLINE]
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