This review (2016) examines a number of preclinical reports which suggest that serotonergic neurotransmission could play an important role in ketamine’s antidepressant-like activity. The authors hypothesize that ketamine may alleviate depression by increasing serotonin levels in the prefrontal cortex NMDA receptor inhibition and activation of AMPA glutamate receptors. Preclinical animal studies indicate that ketamine may also have an affinity towards serotonergic receptors, including the 5-HT2A receptor, in addition to glutamatergic neurotransmission.
Abstract
“Review: A single i.v. infusion of ketamine, classified as an N-methyl-d-aspartate (NMDA) receptor antagonist, may alleviate depressive symptoms within hours of administration in treatment resistant depressed patients, and the antidepressant effect may last for several weeks. These unique therapeutic properties have prompted researchers to explore the mechanisms mediating the antidepressant effects of ketamine, but despite many efforts, no consensus on its antidepressant mechanism of action has been reached. Recent preclinical reports have associated the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) with the antidepressant-like action of ketamine. Here, we review the current evidence for a serotonergic role in ketamine’s antidepressant effects. The pharmacological profile of ketamine may include equipotent activity on several non-NMDA targets, and the current hypotheses for the mechanisms responsible for ketamine’s antidepressant activity do not appear to preclude the possibility that non-glutamate neurotransmitters are involved in the antidepressant effects. At multiple levels, the serotonergic and glutamatergic systems interact, and such crosstalk could support the notion that changes in serotonergic neurotransmission may impact ketamine’s antidepressant potential. In line with these prospects, ketamine may increase 5-HT levels in the prefrontal cortex of rats, plausibly via hippocampal NMDA receptor inhibition and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. In addition, a number of preclinical studies suggest that the antidepressant-like effects of ketamine may depend on endogenous activation of 5-HT receptors. Recent imaging and behavioral data predominantly support a role for 5-HT1A or 5-HT1B receptors, but the full range of 5-HT receptors has currently not been systematically investigated in this context. Furthermore, the nature of any 5-HT dependent mechanism in ketamine’s antidepressant effect is currently not understood, and therefore, more studies are warranted to confirm this hypothesis and explore the specific pathways that might implicate 5-HT.”
Authors: Kristian Gaarn du Jardin, Heidi Kaastrup Müller, Betina Elfving, Elena Dale, Gregers Wegener & Connie Sanchez
Summary
Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to produce an antidepressant effect within hours of administration and has a high remission rate for patients that are resistant to current first-line treatment. However, ketamine can cause serious psychotomimetic side effects and cognitive impairment. Ketamine’s unique therapeutic properties have prompted researchers to explore the mechanisms mediating its antidepressant effects. However, despite many efforts, no consensus has been reached on its mechanisms, and it may be relevant to consider multiple neurotransmitter systems when exploring mechanisms associated with antidepressant effects. MDD has been associated with decreased central serotonergic tone, and recent preclinical reports suggest that 5-HT is implicated in responsiveness to current first-line antidepressants.
Here, we discuss the antidepressant effects of ketamine and summarize several hypothesized mechanisms of action. We also review the current evidence for serotonergic neurotransmission.
- Pharmacological targets of ketamine and its metabolites
Ketamine is metabolized into a number of metabolites, including (R,S)-norketamine, (R,S)-dehydronorketamine, and a series of hydroxynorketamines. (R,S)-norketamine is an NMDA receptor antagonist with a potency of the same order of magnitude as the parent compound, and is therefore considered an active metabolite. The authors suggest that ketamine’s metabolites inhibit nicotinic acetylcholine receptors, which may contribute to its antidepressant activity. However, this mechanism still needs to be investigated in clinical trials.
Ketamine and its metabolites appear to act on NMDA, dopamine D2,5-HT2,and34- and 7-nicotinic acetylcholine receptors, and their potencies are one order of magnitude relative to NMDA receptor potency.
Ketamine’s 5-HT2A receptor activity may potentially be of interest since 5-HT2A receptor blockade may augment the clinical response to SSRI treatment. However, it remains to be shown whether ketamine acts as an antagonist or an agonist at 5-HT2A receptors, and if these mechanisms then play any role for the overall antidepressant activity of ketamine.
- Current mechanistic hypotheses for ketamine’s antidepressant activity
Ketamine’s unique antidepressant effects have been attributed to several signaling pathways and synaptic plasticity, and several hypotheses have been conceptualized based on these findings.
Ketamine’s rapid antidepressant effect is thought to be mediated by activation of the mechanistic target of rapamycin (mTOR) via a transient glutamate surge and brain-derived neurotrophic factor (BDNF) release.
These proposed hypotheses appear compelling, but data that challenge them have also been published. For instance, ketamine’s antidepressant-like effect in mice is independent of NMDA receptor inhibition. The association between ketamine and antidepressant-like effects is ambiguous, and a consensus has not been reached with respect to ketamine’s mechanism of action. It is therefore possible that non-glutamatergic signaling such as serotonergic could be implicated in the mechanisms responsible for ketamine’s antidepressant effect.
4.1. Intracellular level
Immunoreactivity for glutamate and phosphate-activated glutaminase revealed that serotonergic neurons also contain glutamate, and that serotonergic neurons release a neurotransmitter capable of eliciting a fast excitatory postsynaptic potential.
4.2. Synaptic level
There are several reports of direct and functional interactions between the glutamatergic and the serotonergic systems, including interactions between the 5-HT2A and mGluR5 receptors, mGluR4 and 5-HT1A receptors, and NMDA and 5-HT2A receptors.
In the brain, glutamatergic neurotransmission and metabolism are united by the conceptualization of the tripartite synapse, in which astrocytes play a role in modulating kainate receptor function.
4.3. Circuitry level
In patients with MDD, the prefrontal cortex and hippocampus are often affected by serotonergicfibers arising from the raphe nuclei and have a high expression of 5-HT receptors.
In the hippocampus and prefrontal cortex, 5-HT receptors are found on both pyramidal cells and interneurons, and they can either function in a complementary or opposing manner. The effects of 5-HT on glutamate and GABA are region specific and depend on expression patterns of 5-HT receptor subtypes.
Multiple studies suggest that 5-HT inhibits pyramidal cell function and thereby decreases glutamatergic transmission in the hippocampus. Several 5-HT receptor subtypes mediate the inhibitory effects of 5-HT, including 5-HT1A, 5-HT1B, 5-HT2A/C, 5-HT3,5-HT6, and 5-HT7 receptors. 5-HT also exerts some excitatory activities on pyramidal cells in the prefrontal cortex.
The serotonergic system, including local glutamate receptors and glutamatergic projections from distant brain regions, can influence the release of 5-HT in the raphe nuclei.
- Studies relevant for 5-HT signaling and the antidepressant potential of ketamine
5-HT is synthesized from L-tryptophan through a two-step process. The irreversible inhibitor of tryptophan hydroxylase, 4-chloro-DL-phenylalanine ethyl ester HCl, reduced cortical 5-HT content by 70% in male Sprague-Dawley rats, but did not produce any behavioral effects on its own.
In a stress model of depression, ketamine increased immobility in stressed rats on its own, but the combined effects of 5-HT depletion, restraint stress, and ketamine increased immobility to a level similar to naive vehicle-treated controls.
In our laboratory, we found that ketamine’s antidepressant-like effect was 5-HT-dependent at 1 and 48 h prior to the forced swim test in a genetic model of depression, Flinders Sensitive Line (FSL) rats. However, contrary to the findings of Gigliucci et al., ketamine’s acute antidepressant-like effect is also 5-HT-dependent.
Ketamine may elicit some of its antidepressant-like activity via a 5-HT-dependent mechanism, although more studies using different model systems and tests are warranted to confirm this hypothesis.
5.2. Effect of ketamine on 5-HT reuptake and efflux as well as 5-HT related neuronal firing
Ketamine has been found to reduce SERT binding in non-human primates, which may indicate that ketamine may modulate 5-HT reuptake at an antidepressant dose. However, the minimum effective dose (MED) of ketamine for detectable reuptake inhibition is 75 mM in rat cortical synaptosomes and 171 Min in HEK-rSERT cells.
Ketamine’s binding to SERT at antidepressant doses has negligible, if any, effects on 5-HT reuptake, as suggested by the finding that fenfluramine produced a comparable 5-HT1B receptor binding reduction for saline and ketamine in primates subjected to PET scans.
Ketamine administration in the prefrontal cortex of rats and primates increases extracellular 5-HT levels, suggesting that regional neuronal pathways mediate this enhancement rather than local effects. Ketamine’s effect on 5-HT release in the prefrontal cortex may be secondary to a primary release of glutamate in the prefrontal cortex, which is a critical part of the theory proposed by Duman and colleagues for the mechanism responsible for ketamine’s antidepressant effect. Ketamine increases c-fos protein expression in serotonergic neurons of the dorsal raphe nuclei, which is blocked by NBQX microinjection into the prefrontal cortex.
One recent study did not find any effect of systemic ketamine at antidepressant doses on neuronal firing in the dorsal raphe nuclei of rats. However, the study was conducted using chloral hydrate for anesthesia, which may have biased the results. Although the effect on 5-HT release may be temporary, one study reported that ketamine increased excitatory postsynaptic potentials in response to 5-HT, and that this effect was prevented by inhibition of mTOR via rapamycin pretreatment.
A subanesthetic dose of ketamine may acutely enhance 5-HT release in the prefrontal cortex, and a sustained enhancement of 5-HT responses in the prefrontal cortex at 24 h after dosing has also been reported.
Ketamine, given before inescapable tail shock stress, abolishes a stress-induced increase in 5-HT levels in the basolateral amygdala and deficits in a social investigation test. Ketamine likely mediates its beneficial effect on social investigation via activation of afferent neurons projecting from the prelimbic medial prefrontal cortex.
Ketamine modulates serotonergic signaling in a complex and highly region specific manner. Using the data presented thus far, it is not possible to single out or disregard specific modifications as potential mediators of ketamine’s antidepressant effect.
5.3.1. 5-HT1 receptors
Ketamine treatment, fluoxetine treatment, and vortioxetine treatment exhibited antidepressant-like effects in 5-HT depleted FSL rats. Vortioxetine is hypothesized to exert its therapeutic activity through 5-HT1A and 5-HT1B receptor antagonism, 5-HT1B receptor partial agonism, and inhibition of SERT.
Ketamine’s acute antidepressant-like effect in the novelty suppressed feeding test requires 5-HT1A receptor agonism, and 5-HT1A receptor agonist 8-OH-DPAT did not have any effect as a single treatment.
Ketamine’s antidepressant effects are likely due to its increased 5-HT1B receptor binding, which is suppressed by the AMPA receptor antagonist NBQX. A single dose of the selective 5-HT1B receptor agonist CP94253 rescued ketamine’s acute and sustained antidepressant-like effect in 5-HT depleted FSL rats.
5.3.2. 5-HT2A receptors
Ketamine may have serotonergic implication in the antidepressant effect of ketamine, but Ritanserin did not affect ketamine’s antidepressant-like activity in the novelty suppressed feeding test.
5.3.3. 5-HT3 receptors
A combination of ketamine and the 5-HT3 receptor antagonist MDL-72222 decreased immobility in the mouse tail suspension test, suggesting a synergistic antidepressant-like effect of ketamine and 5-HT3 receptor antagonism, but did not provide evidence for direct involvement of 5-HT3 receptors in the antidepressant-like activity of ketamine.
- Conclusion
Ketamine’s affinity for multiple targets opens the possibility that ketamine mediates its antidepressant response via direct modulation of non-glutamatergic neurotransmission, including serotonergic. Additionally, ketamine may regulate serotonergic neurotransmission via NMDA receptor inhibition, or ketamine may mediate its antidepressant effect via modulation of glutamatergic neurotransmission.
Ketamine’s antidepressant effect may depend on certain aspects of serotonergic neurotransmission, with 5-HT1 receptor agonism being potentially important. However, more studies are clearly warranted to evaluate this hypothesis.