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Ketamine Acts As Antidepressant By Boosting Serotonin

Using PET imaging studies on macaque monkeys, new research found that ketamine increases the activity of serotoninergic neurons in the brain areas regulating motivation. The finding, the RIKEN Center for Life Science Technologies suggests Ketamine’s action on serotonin may explain its antidepressant action in humans.

The work demonstrates that Positron Emission Tomography (PET) molecular imaging studies may be useful in the diagnosis of major depressive disorder in humans, as well as the development of new antidepressants.

Ketamine has recently been shown[2] to have an antidepressant action with short onset and long-term duration in patients suffering from treatment-resistant major depressive disorder, who do not respond to standard medications such as serotonin reuptake inhibitors, monoamine oxidase inhibitors and tricyclic antidepressants. However, the mechanisms underlying ketamine’s action on the depressive brain have remained unclear.

Serotonin Receptors

To understand the effects of ketamine on the serotonergic system in the brain, Dr Hajime Yamanaka and Dr Hirotaka Onoe, who has pioneered PET imaging on conscious non-human primates, together with an international team, performed a PET study on rhesus monkeys.

The team performed PET imaging studies on four rhesus monkeys with two tracer molecules related to serotonin (5-HT) that bind highly selectively to the serotonin 1B receptor 5-HT1B and the serotonin transporter SERT.

From the analysis of the 3 dimensional images generated by the PET scans, the researchers infer that ketamine induces an increase in the binding of serotonin to its receptor 5-HT1B in the nucleus accumbens and the ventral pallidum, but a decrease in binding to its transporter SERT in these brain regions. The nucleus accumbens and the ventral pallidum are brain regions associated with motivation and both have been shown to be involved in depression.

In addition, the researchers demonstrate that treatment with NBQX, a drug known to block the anti-depressive effect of ketamine in rodents by selectively blocking the glutamate AMPA receptor, cancels the action of ketamine on 5-HT1B but not on SERT binding.

Taken together, these findings indicate that ketamine may act as an antidepressant by increasing the expression of postsynaptic 5-HT1B receptors, and that this process is mediated by the glutamate AMPA receptor.

[1] H Yamanaka, C Yokoyama, H Mizuma, S Kurai, S J Finnema, C Halldin, H Doi & H Onoe. A possible mechanism of the nucleus accumbens and ventral pallidum 5-HT1B receptors underlying the antidepressant action of ketamine: a PET study with macaques. Translational Psychiatryvolume 4, pagee342 (2014)

[2] Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000; 47: 351–354.