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

• Published in: Journal of pharmacological sciences Vol. 134; no. 3; pp. 181 - 189
• Main Authors: Tsutsui-Kimura, Iku, Ohmura, Yu, Yoshida, Takayuki, Yoshioka, Mitsuhiro
• Format: Journal Article
• Language: English
• Published: Japan Elsevier B.V 01.07.2017; Elsevier
• Subjects: Aggression - drug effects; Animals; Behavior, Animal - drug effects; Cyclopropanes - administration & dosage; Cyclopropanes - pharmacology; Cyclopropanes - therapeutic use; Depression; Depressive Disorder, Major - drug therapy; Dopamine - metabolism; Dose-Response Relationship, Drug; Helplessness; Impulsive Behavior - drug effects; Injections, Intraperitoneal; Male; Mice, Inbred C57BL; Prefrontal Cortex - metabolism; Response inhibition; Serotonin - metabolism; Serotonin Uptake Inhibitors - administration & dosage; Serotonin Uptake Inhibitors - pharmacology; Serotonin Uptake Inhibitors - therapeutic use; Serotonin/norepinephrine reuptake inhibitor; Violence; Depression; Response inhibition; Serotonin/norepinephrine reuptake inhibitor; Violence; Helplessness
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1016/j.jphs.2017.06.004

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.