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Major depression is a devastating mental disorder that affects nearly 20% of the world’s population. Notably, women experience major depression at roughly twice the rate of men and respond differently to different types of antidepressant drugs. However, the neurobiological mechanisms underlying this sex-differentiated responsiveness remain a largely neglected area of experimentation with current treatments based almost exclusively on research conducted in males. Most importantly, currently marketed antidepressant drugs take anywhere from weeks to months in order to elicit their therapeutic effects, thus leading to increased drop-out rates. Ketamine is a unique, rapid-acting antidepressant drug that alleviates depressive symptomatology in both treatment-resistant depressed patients and in animal models of depression. Despite data regarding the antidepressant efficacy of ketamine in the male sex, there is scant evidence of its neurobiological effects on females. Herein, we implemented an in vivo microdialysis approach to investigate the kinetics of glutamate release in the mouse medial prefrontal cortex (mPFC), a brain region implicated in ketamine’s antidepressant mechanism of action. Specifically, male and female mice were administered a single dose of ketamine (10 mg/kg) following stereotactic implantation of a microdialysis probe in the mPFC. Samples were collected every 10 min in a microcentrifuge tube for one hour and glutamate was assayed with high performance liquid chromatography (HPLC) with coulometric detection. Furthermore, we identified the temporal molecular effects of ketamine on the expression of two prominent presynaptic proteins implicated in neurotransmitter release (i.e. Synapsin I and Syntaxin I). Mice were administered a single dose of ketamine (10 mg/kg) and were sacrificed at specific time-points (i.e. 0, 2, and 4h or 1, 3, and 7 days post-administration). Collectively, this study revealed that there is an important time-factor that distinguishes the neurochemical responses of the two sexes to a single dose of ketamine, thereby illustrating that different neurobiological mechanisms underlie its rapid antidepressant actions.

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Pothitos Pitychoutis

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Dissecting the Sex-dependent Neurochemical Effects of the Rapid-acting Antidepressant Drug Ketamine with In Vivo Brain Microdialysis in Mice