Neuroscientists have made a significant discovery regarding the binding site of low-dose ketamine, shedding light on how this medication, often hailed as a miracle treatment, helps alleviate major depression symptoms within hours, with effects lasting several days.
Researchers at the University at Buffalo have pinpointed the binding site of low-dose ketamine, offering crucial insights into how this medication—frequently referred to as a wonder drug—relieves the symptoms of major depression within just a few hours, with effects lasting for several days.
This finding, published in September in Molecular Psychiatry, will not only help scientists understand how depression begins in the brain but also encourage further research into using ketamine and similar drugs for various brain disorders.
Transformative treatment
Since the 1960s, ketamine has been utilized as an anesthetic, but a study conducted in 2000 demonstrated its rapid effectiveness at much lower doses in treating major depression and suicidal thoughts.
“Thanks to its quick and enduring effects, low-dose ketamine has proven to be a lifesaving medication,” states Gabriela K. Popescu, PhD, the lead researcher and a professor of biochemistry at UB’s Jacobs School of Medicine and Biomedical Sciences.
While traditional antidepressants can take months to work, increasing the risk of suicidal behaviors in patients during that waiting period, ketamine offers near-instant relief from depressive symptoms, maintaining effectiveness for days, sometimes up to a week post-administration. Following the initial findings in the early 2000s, several ketamine clinics have opened across the country to provide intravenous treatment for depression.
However, the exact molecular mechanisms behind ketamine’s swift and potent antidepressant effects have remained unclear. Understanding this information is vital for optimizing the use of ketamine and for creating similar medication.
Targeted impact on NMDA receptors
Ketamine interacts with a category of neurotransmitter receptors known as N-methyl-D-aspartate (NMDA) receptors. Popescu is an authority on how these receptors generate electrical signals that are crucial for cognitive functions like learning and memory; disruptions in these signals can lead to psychiatric conditions.
NMDA receptors are widespread in the brain and essential for sustaining consciousness. Thus, Popescu notes that drugs that indiscriminately target all NMDA receptors can trigger undesirable psychiatric side effects. “We believe that the selectivity we discovered in our research clarifies how low-dose ketamine can effectively treat major depression and help prevent suicides among those affected,” she adds.
This research was initiated after a member of her lab, co-author Sheila Gupta, who was an undergraduate at UB, observed that when ketamine was applied to NMDA receptors that were consistently active, it demonstrated a much stronger inhibitory effect than what the existing literature suggested. “We were intrigued by this finding,” Popescu states.
When ketamine’s antidepressant properties first came to light, researchers attempted to understand its action by applying it to synaptic currents generated by NMDA receptors but found minimal effects.
Based on this lack of response, many experts started exploring receptors outside of synapses that might mediate ketamine’s antidepressant effects. “Sheila’s insight that ketamine has a notably stronger inhibitory impact on receptors that are persistently active led us to explore different mechanisms beyond the presumed direct block of currents,” Popescu details.
Rare lab expertise on NMDA receptors
Popescu’s laboratory is one of the few globally equipped to analyze how NMDA receptors activate, allowing her team to identify and quantify changes occurring during NMDA activations with very low doses of ketamine compared to high doses used for anesthesia.
“By tracking the activity of individual receptor molecules over extended periods, we can document the entire range of behaviors of each receptor and pinpoint what changes when the receptor interacts with a drug or experiences a mutation,” Popescu elaborates.
“Our findings suggest that at low doses, ketamine primarily influences the current from receptors that have been continually active, rather than those located at synapses that activate temporarily,” she continues. “This leads to an immediate boost in excitatory transmission, helping to alleviate depressive symptoms. Additionally, this increase in excitation triggers the formation of new or stronger synapses, enabling elevated excitatory levels to persist even after ketamine is cleared from the body, which explains the prolonged relief experienced by patients.”
The UB study clarifies the effectiveness of low-dose ketamine.
“Our findings reveal that extremely low levels of ketamine, on the nanoscale, are sufficient to occupy two lateral grooves of the NMDA receptors, thereby selectively slowing down extra-synaptic receptors and easing depression. Increasing the dose results in ketamine overflowing into the central pore of the receptor, beginning to block synaptic currents and causing the anesthetic effect,” Popescu explains.
Co-authors from the Department of Physics in the College of Arts and Sciences simulated the three-dimensional structure of the NMDA receptor and predicted the specific residues where ketamine binds in the lateral sites. “These interactions are robust and account for the receptor’s strong attraction to low doses of ketamine,” she notes.
“The simulations indicate that at higher concentrations—used for anesthesia—ketamine indeed embeds itself in the receptor’s central ion-conducting pore where it prevents ionic current from passing,” Popescu explains.
Conversely, at lower concentrations, ketamine operates differently, binding to two symmetrical sites beside the pore, which causes the receptors to slow their opening instead of halting the current entirely. “Identifying the precise binding site on the receptor provides an ideal template for creating ketamine-like drugs that could be taken orally and potentially have less addictive properties,” Popescu states.
Next steps involve screening existing medications capable of fitting into the lateral grooves of NMDA receptors, starting with computer simulations followed by laboratory tests.
Lead authors of this study include Jamie A. Abbott, PhD, from the Department of Biochemistry, and Han Wen from the Department of Physics. Other contributors include Gupta, Wenjun Zheng, Beiying Liu, and Gary J. Iacobucci. The research received funding from the National Institutes of Health.
