It looks like Special K may be more special than we first thought.
Ketamine, the psychedelic drug also known as Special K, has gained attention in recent years from the field of biomedical research for its potential use as an antidepressant. Originally designed as an anesthetic, sedative, and pain killer, sub-anesthetic doses produce a dissociative state in the user, leading to its recreational use. Scientists have found that at even lower doses, ketamine has potent antidepressant effects.
One reason ketamine is being investigated as an antidepressant is its fast action. While most antidepressants take weeks to demonstrate effects, ketamine can provide relief in as little as two hours. How is it that ketamine can achieve similar effects as other antidepressants in such a short time frame? Can we use that knowledge to create better drugs? This is what Dr. Mark Rasenick of the University of Illinois at Chicago is setting out to discover.
Dr. Rasenick studies the mechanisms of antidepressants. Most antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), work by altering levels of neurotransmitters, the molecules that send signals from cell to cell in the brain. Below is a diagram demonstrating the action of neurotransmitters between two neurons. Antidepressants increase the concentration of neurotransmitters at the synapse by preventing transporters from taking up the molecules into the cell. They can also slow down degradation of neurotransmitters, leading to more at the synapse.
But what happens next? How do increased levels of neurotransmitters lead to less depression in patients? Does the action of antidepressants have any relationship to increased amounts of neurotransmitter at the synapse? In fact, researchers still don’t know the answer to those questions. They have found pieces of the puzzle, but it is not yet complete. The next diagram shows one piece of the puzzle that scientists have discovered. Cell signaling is a bit like a relay race, passing the signal like a baton from one protein to the next.
- Neurotransmitters bind to their receptors on the surface of a cell.
- G proteins, a complex of proteins that travel along the inside surface of the cell membrane, couple with the receptor.
- G proteins are activated once coupled with the receptor, causing them to travel along the membrane to pass on the signal to another protein, here called the effector.
- The G protein activates the effector, carrying on the message to the rest of the cell.
Because of this relay, the effector protein is able to amplify the signal to the rest of the cell. It’s kind of like calling your mother with some big news. If you tell her you got a new job or met a new guy, the rest of your extended family and friends will know within 24 hours! This mechanism is an efficient way to pass on signals from one neuron to the next.
Dr. Rasenick found that many antidepressants also increase the movement of the G protein along the cell membrane. The easier the G protein is able to shuttle back and forth between the receptor and the Effector (Adenylyl cyclase, the enzyme that makes cAMP), the greater the signal amplification. Could ketamine do this, too?
Dr. Rasenick and his lab measured the mobility of G proteins in neuronal cell culture before and after treatment with ketamine, and compared it with other antidepressants. Interestingly, they found that ketamine was able to increase G protein mobility just like other antidepressants, but much more quickly. However, the effects of ketamine did not last as long as the slower-acting antidepressants. This suggests that future drugs could be designed to increase G protein movement at the membrane leading to antidepressant effects much more rapidly. Perhaps with the right drug formulation, G protein mobility could be extended to last longer, as well.
There is one mystery to this research: The neurons which Dr. Rasenick used to test ketamine, and other antidepressants, were missing the neurotransmitter transporters, and reinserting those transporters had no effect. That suggests that the antidepressants that we have been using, as well as potential new drugs, likely act through multiple pathways that are yet unknown. Only with the dogged pursuit of pharmacologists, biochemists, and clinicians, will we be able to put the puzzle pieces together to solve mental illness.
Scientists and physicians are excited about the potential of ketamine as an antidepressant. However, the risks associated with abuse of the drug are quite serious. By understanding the mechanism that ketamine uses to create its antidepressant effects, perhaps new, safer treatments can be designed for the treatment of depression.
Donati, R.J. and Rasenick, M.M. (2003) G protein signaling and the molecular basis of antidepressant action. Life Sciences 73(1): 1-17.
Czysz, et.al, (2015) Lateral Diffusion of Gαs in the Plasma Membrane Is Decreased after Chronic but not Acute Antidepressant Treatment: Role of Lipid Raft and Non-Raft Membrane Microdomains Neuropsychopharmacology 40, 766–773.