Glutamate and the Neural Basis of the Subjective Effects of Ketamine: A Pharmaco–Magnetic Resonance Imaging Study

This double-blind, placebo-controlled, randomized, crossover, counterbalanced study (n=33) investigated whether ketamine-induced (20.5mg/70kg) dissociative mental state is blocked via pretreatment with the glutamate release inhibitor lamotrigine (300mg/70kg). Ketamine produced dissociative effects which corresponded to decreased activity in the ventromedial frontal cortex, including the orbitofrontal cortex and subgenual cingulate, and increased activity in mid-posterior cingulate, thalamus, and temporal cortical regions. Most of these effects were mitigated by lamotrigine, thereby indicating that the dissociative effects of ketamine are mediated by glutamate release.

Abstract

“Context: Ketamine evokes psychosis like symptoms, and its primary action is to impair N-methyl-D-aspartate glutamate receptor neurotransmission, but it also induces secondary increases in glutamate release.

Objectives: To identify the sites of action of ketamine in inducing symptoms and to determine the role of increased glutamate release using the glutamate release inhibitor lamotrigine.

Design: Two experiments with different participants were performed using a double-blind, placebo-controlled, randomized, crossover, counterbalanced-order design. In the first experiment, the effect of intravenous ketamine hydrochloride on regional blood oxygenation level– dependent (BOLD) signal and correlated symptoms was compared with intravenous saline placebo. In the second experiment, pretreatment with lamotrigine was compared with placebo to identify which effects of ketamine are mediated by increased glutamate release.

Setting: Wellcome Trust Clinical Research Facility, Manchester, England.

Participants: Thirty-three healthy, right-handed men were recruited by advertisements.

Interventions: In experiment 1, participants were given intravenous ketamine (1-minute bolus of 0.26 mg/kg, followed by a maintenance infusion of 0.25 mg/kg/h for the remainder of the session) or placebo (0.9% saline solution). In experiment 2, participants were pretreated with 300 mg of lamotrigine or placebo and then were given the same doses of ketamine as in experiment 1. Main

Outcome Measures: Regional BOLD signal changes during ketamine or placebo infusion and Brief Psychiatric Rating Scale and Clinician-Administered Dissociative States Scale scores.

Results: Ketamine induced a rapid, focal, and unexpected decrease in ventromedial frontal cortex, including orbitofrontal cortex and subgenual cingulate, which strongly predicted its dissociative effects and increased activity in mid-posterior cingulate, thalamus, and temporal cortical regions (r=0.90). Activations correlated with Brief Psychiatric Rating Scale psychosis scores. Lamotrigine pretreatment prevented many of the BOLD signal changes and the symptoms.

Conclusions: These 2 changes may underpin 2 fundamental processes of psychosis: abnormal perceptual experiences and impaired cognitive-emotional evaluation of their significance. The results are compatible with the theory that the neural and subjective effects of ketamine involve increased glutamate release.”

Authors: J. F. William Deakin, Jane Lees, Shane McKie, Jaime E. C. Hallak, Steve R. Williams & Serdar M. Dursun

Notes

This paper is included in our ‘Top 12 Articles on on Ketamine for Mental Health‘

Summary

Two experiments were performed: one with intravenous ketamine hydrochloride and the other with lamotrigine to identify the effects of ketamine on glutamate release.

In experiment 1, participants were given ketamine and in experiment 2, participants were pretreated with lamotrigine and then were given ketamine.

Ketamine induced activations in the mid-posterior cingulate, thalamus, and temporal cortices that correlated with psychosis. Lamotrigine prevented these activations and symptoms.

Anand et al11 found that lamotrigine attenuated the increase in BPRS psychosis scores after intravenous ketamine administration, but that the mood-elevating effects of ketamine were briefly enhanced by lamotrigine.

Three research groups have used positron emission tomography (PET) to image the effect of ketamine on regional cerebral blood flow or metabolism. All three groups report frontal activation, and 2 report anterior cingulate activation, but Breier et al13 did not.

Pharmaco-MRI has been used to investigate the effects of drugs on the blood oxygenation level-dependent (BOLD) signal and during conventional fMRI studies.

Ketamine has been used to investigate the effect of NMDA antagonism on brain regions engaged by various cognitive fMRI paradigms, but the origins of ketamine’s subjective effects were not the chief concern of these studies.

Ketamine-Placebo Experiment

Ketamine increased all BPRS subscale scores and CADSS score, and the 2 were not highly correlated. The onset of ketamine was rapid, and partial tolerance was rapid, with no frank psychosis occurring at the doses used.

Lamotrigine-Ketamine Experiment

Lamotrigine pretreatment was associated with lower BPRS and CADSS scores after ketamine infusion, but not with withdrawal, anxiety-depression, or hostility-suspicion scores.

Ketamine-Placebo Experiment

Ketamine increased the signal in the precuneus, mid-posterior cingulate gyrus, motor cortex, superior frontal gyrus, inferior temporal gyrus, hippocampus, and superior temporal gyrus bilaterally compared with placebo.

Ketamine-evoked BOLD signal responses were significantly reduced in medial OFC and temporal pole within 2 minutes, and then increased in anterior thalamus and midposterior cingulate cortex within 3 minutes.

Ketamine infusion increased activation in the OFC and temporal pole, which correlated with increased CADSS scores and psychosis ratings. The thalamus did not correlate with symptoms.

Ketamine-Lamotrigine Experiment

Figure 5 compares the placebo-ketamine – lamotrigine-ketamine effects with the ketamine-placebo effects from experiment 1. Lamotrigine diminished most of ketamine’s effects toward saline placebo, and ketamine’s effects were closely reproduced in experiment 2 in the OFC/subgenual cingulate and temporal pole.

ROLE OF GLUTAMATE

Ketamine increased BPRS and CADSS scores in experiment 1, and lamotrigine attenuated these scores in experiment 2. These results suggest that the subjective effects of ketamine are mediated by enhanced glutamate release, and that increased non-NMDA glutamate neurotransmission may underlie aspects of the symptoms of schizophrenia.

The BOLD signal response is principally mediated through the metabolic costs of glutamate synaptic neurotransmission, but other intercellular signaling pathways may also be involved. Nevertheless, the glutamate system is relatively specifically challenged with ketamine and isolated with lamotrigine.

In relation to psychosis, ventral anterior limbic cortex, mid-posterior cingulate, and temporal lobe are activated, and lamotrigine attenuates most of the BOLD signal responses to ketamine.

The correlational evidence suggests that the glutamatergic neural responses to ketamine produce the psychological effects. The OFC deactivation preceded and outlasted all other BOLD signal changes.

VENTRAL FRONTAL AND INFERIOR TEMPORAL CORTICAL DEACTIVATION

Ketamine caused decreased BOLD signal in medial OFC, subgenual cingulate, and bilateral temporal pole, but this was reversed by lamotrigine.

The ventral cingulate cortex is high in serotonin uptake sites and serotonin 1A receptors, and ketamine-evoked increases in serotonin 1A receptor activation may have caused hyperpolarization of pyramidal cells, resulting in the local decrease in BOLD signal.

A study has shown that the medial OFC is activated by rewards and has an important role in the online evaluation of motivational significance of cues in guiding choices. Ketamine-induced deactivation of ventromedial prefrontal cortex may be a plausible substrate for the dissociative state of emotional detachment it produces.

MID-POSTERIOR CINGULATE

The medial OFC, subgenual cingulate, and temporal pole project specifically to the dorsal midcingulate, which was strongly activated after ketamine infusion. This may explain the lack of affective expression seen in this study and in users.

The midcingulate, posterior cingulate, and precuneus were activated after ketamine, and this activity correlated with the dissociative and psychosis ratings.

Experiments in rodents indicate that the posterior cingulate and retrosplenial cortex are focus areas of the effects of systemically applied NMDA channel blockers. However, the authors do not explain why the posterior cingulate is selectively affected and other cortical areas are not.

Ketamine decreased activation of the ventral anterior cingulate and increased activation of the mid-posterior cingulate during retrieval of previously exposed words. This increase in activation was correlated with some aspects of the symptom profile in patients with schizophrenia.

TEMPORAL CORTEX AND HIPPOCAMPAL REGION

The mid-posterior cingulate cortex is connected to the hippocampus and parahippocampal regions, the superior, middle, and inferior temporal cortices, and the hippocampus and parahippocampal gyrus. Ketamine may cause hallucinations.

Ketamine induces abnormal perceptual experiences and dissociation by increasing glutamate release. This results in the splitting of mental functions or schizophrenia and the suppression of ventromedial frontal neuronal function.