One major theory helping to explain ketamine’s mental health effects focuses on its interactions with the receptors on neurons and its ability to increase receptor health and number. Under this model, which we will refer to as the Ketamine Receptor Theory, ketamine produces its antidepressant effects through directly acting upon NMDA receptor activity as well as through non-NMDA receptor-dependent activity (meaning that ketamine and its metabolites activate other receptors, proteins, and chemicals) to produce its effects.
NMDA Receptor-Dependent Ketamine Activity:
Ketamine acts directly on:
(A) NMDA receptors on GABA interneurons
(B) NMDA receptors in the synaptic cleft
(C) Extra-synaptic NMDA receptors
(D) Lateral Habenula NMDA receptors
The direct action of ketamine on NMDA receptors in different areas of the synapse and brain ultimately leads to increased brain-derived neurotrophic factor (BDNF) synthesis and release. BDNF is essential for neuronal development early in life as well as for its survival and function, including activity-dependent synaptic plasticity in the adult brain.
(A) NMDA Receptors on GABA Interneurons
Ketamine inhibits GABA interneurons, which, in turn, leads to increased surges of glutamate release during normal neuron firing. The glutamate surges activate mechanisms that increase BDNF synthesis and release, maintaining and improving the health of the postsynaptic neuron dendrites.
(B) NMDA Receptors in the Synaptic Cleft
Glutamate can "leak" out of the presynaptic neuron even when that neuron is not actively transmitting. These glutamate neurotransmitters can float to the postsynaptic dendrites and bind to NMDA receptors, chronically activating them, and leading to neuron toxicity (*glutamate excitotoxicity). Ketamine binding and suppression of "at rest" NMDA receptors in the synaptic cleft prevent ambient levels of glutamate from binding to the NMDA receptors. By binding to these postsynaptic NMDA receptors, ketamine inhibits their activation, preventing (1) glutamate excitotoxicity and (2) causing an increase in certain proteins that ultimately lead to BDNF synthesis and release.
*Glutamate excitotoxicity is a cell death mechanism initiated by chronically excessive glutamate release into the synaptic space. When there are chronic periods of high exposure to glutamate, this leads to a persistent activation of the NMDA and AMPA receptors. In turn, this leads to chronic activation of calcium channels, leading to an eventual lethal influx of extracellular calcium into the cell.
(C) Extra-Synaptic NMDA Receptors
Ketamine binds to NMDA receptors outside of the synaptic space (different from NMDA receptors that are in the synaptic space). Extra-synaptic cleft NMDA receptor blockade by ketamine prevents the binding of glutamate released by glial cells (cells that provide physical and chemical support to neurons) and protects against glutamate excitotoxicity. This further prevents the suppression of key pathways that lead to neuron health.
(D) Lateral Habenula NMDA Receptors Ketamine blocks NMDA receptors on the Lateral Habenula (LHb). Decreased activation of the LHb neurons leads to decreased activation of GABA interneurons that decrease activity in the midbrain (similar to the pathway described in [A]). Ketamine’s effects on the LHb indirectly lead to increased activity in the midbrain neurons (increased neuron signaling) and improve communication between midbrain and forebrain neurons.
NMDA Receptor-Independent Ketamine Activity:
Before we talk about ketamine’s effects, it is important to understand that IV ketamine is a racemic mixture. Basically, this means that ketamine is made up of two different types of molecules: S-ketamine & R-ketamine.
S-ketamine and R-ketamine, when metabolized, break down to metabolites that are believed to have antidepressant effects as well. The metabolites of S- and R-ketamine that are pertinent to this next section are the following:
Metabolites of S-ketamine:
2S,6S-HNK
S-DHNK
Metabolites of R-ketamine:
2R,6R-HNK
R-DHNK
Ketamine’s metabolites have NMDA receptor-independent activity. Said another way, the metabolites do not need to bind to the NMDA receptor to have antidepressant effects.
Their action is through:
(A) Direct AMPA receptor activation
(B) Activation of eEF2
(C) Inhibition of 𝝰7-nicotinic acetylcholine receptors and decreasing production of D-serine
(A) Direct AMPA Receptor Activation
Literature suggests that R-ketamine metabolite 2R,6R-HNK induces and increases AMPA receptor-mediated excitatory postsynaptic activation. The activation of AMPA receptors, on the postsynaptic neuron, by 2R,6R-HNK leads to increases in the synthesis and release of BDNF. This, in turn, leads to improved health and stability of the postsynaptic neuron.
(B) Activation of eEF2
R-ketamine metabolite 2R,6R-HNK increases the activation of a protein called Eukaryotic elongation factor 2 (eEF2). This leads to an increase in the translation and synthesis of proteins, including BDNF, which, in turn, improves the health of the postsynaptic neuron dendrites.
(C) Inhibition of 𝝰7-Nicotinic Acetylcholine Receptors and D-serine Production
Ketamine metabolites 2R,6R-HNK, 2S,6S-HNK, R-DHNK, and S-DHNK bind to and inhibit 𝝰7-nACh receptors on glial cells. The inhibition of these receptors leads to decreased transient glutamate release, which decreases the likelihood of glutamate neurotoxicity. Furthermore, the binding of ketamine metabolites to the 𝝰7-nACh receptors decreases the production of D-serine, which further decreases the likelihood of glutamate neurotoxicity.
Putting It All Together:
All of the above processes ultimately aid in the synthesis and release of BDNF in the synaptic cleft and lead to improved health and density of the receptors on the postsynaptic neurons. The improved health of the neuron is due to the proliferation of new dendritic spines (which house the receptors), enhancing the neuron dendrite density, and improving neuron cell signaling. Although the way in which ketamine successfully treats depression symptoms is not fully understood, these pathways give us insight into the possible mechanisms (working together) that lead to chemical and structural changes in the brain associated with improved mental health.
Sources:
Aleksandrova, L. R., Wang, Y. T., & Phillips, A. G. (2017). Hydroxynorketamine: Implications for the NMDA receptor hypothesis of ketamine’s antidepressant action. Chronic Stress, 1, 1-12. https://doi.org/10.1177/2470547017743511 Duman, R. S. & Aghajanian, G. K. (2012). Synaptic dysfunction in depression: Potential therapeutic targets. Science, 338(6103), 68-72. doi:10.1126/science.1222939
Zanos, P. & Gould, T.D. (2018). Mechanisms of ketamine action as an antidepressant. Molecular Psychiatry, 23(4), 801-811. DOI:10.1038/mp.2017.255.
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