Rats whose serotonin-producing neurons were destroyed by the chemical 5,7-DHT developed muscle twitching (myoclonus) after receiving L-5-HTP or a serotonin-like drug. The twitching was dose-dependent and blocked by serotonin antagonists. Even large serotonin increases in intact rats did not cause twitching unless an enzyme was first inhibited. Repeated drug doses reduced the response, and this reduction was blocked by a serotonin antagonist, while repeated antagonist pretreatment increased the response. The findings suggest that after serotonin nerve damage, changes in postsynaptic receptors underlie behavioral supersensitivity, and restoring serotonin or stimulating its receptors may suppress the development of supersensitivity at the receiving membranes.
Ketamine, originally developed as a dissociative anesthetic and a tool for modeling psychosis, has been repositioned as a rapidly acting antidepressant for treatment-resistant depression. This narrative review traces its trajectory over six decades, drawing on historical sources, clinical trials, and regulatory documents. By the early 2000s, trials showed rapid and robust antidepressant effects, challenging older monoamine-based theories and spurring new models involving glutamate and neuroplasticity. Its dissociative effects, once seen as drawbacks, are now debated but evidence suggests they are not necessary for efficacy.