Ketamine, a drug that blocks NMDA receptors, rapidly activates the mTOR pathway in the prefrontal cortex of rats, increasing synaptic signaling proteins and the number and function of new spine synapses. Blocking mTOR signaling prevented ketamine from inducing synaptogenesis and behavioral antidepressant-like responses in depression models. These effects reverse the synaptic deficits caused by stress and may explain ketamine's fast antidepressant action in treatment-resistant depressed patients, which contrasts with the weeks or months needed for standard medications.
A single dose of LY 341495, an mGluR₂/₃ antagonist, rapidly activates the mTOR pathway and increases synaptic proteins in the prefrontal cortex, similar to the fast-acting antidepressant ketamine. Within one hour, LY 341495 activates mTOR, p70S6K, and 4E-BP1, and 24 hours later elevates levels of PSD-95, GluR1, and Synapsin I. The antidepressant effects of LY 341495 in the rat forced swim test are completely blocked by the mTOR inhibitor rapamycin, indicating that these actions are mediated by mTOR activation. This suggests mGluR₂/₃ antagonists could produce rapid antidepressant effects in depressed patients.
The antidepressant effects of ketamine require vascular endothelial growth factor (VEGF) signaling through its receptor Flk-1 in excitatory neurons of the medial prefrontal cortex (mPFC). Deleting VEGF or Flk-1 from forebrain excitatory neurons, or blocking VEGF in the mPFC, prevented ketamine's behavioral effects in mice. Infusing VEGF directly into the mPFC produced rapid antidepressant-like actions similar to ketamine, but these were blocked by Flk-1 deletion. Local knockdown of Flk-1 in adult mPFC excitatory neurons also blocked ketamine's effects. Additionally, blocking neuronal VEGF signaling prevented the neurotrophic and synaptogenic actions of ketamine. Neuronal VEGF-Flk-1 signaling in the mPFC is essential for ketamine's rapid antidepressant actions.
A single injection of the experimental compound LY341495, which blocks mGluR2/3 receptors, rapidly and lastingly reversed anhedonia—a core symptom of depression—in rats subjected to chronic unpredictable stress. The effect appeared within one to two days and persisted for at least ten days, a timeline comparable to the rapid antidepressant action of ketamine but without ketamine's side effects and abuse potential. Typical antidepressants require weeks to produce a response. The findings suggest that mGluR2/3 antagonists may offer a safer alternative for fast-acting depression treatment.