AsianScientist (Jan. 14, 2014) – Japanese researchers have discovered the mechanism of how ketamine acts as an antidepressant: by boosting “feel-good” hormones in the brain region involved in motivation.
Ketamine, an anesthetic drug used in human and veterinary medicine, is a promising candidate for the fast treatment of depression in patients who do not respond to other medications.
The drug has previously been shown to have an antidepressant action with short onset and long-term duration in patients suffering from treatment-resistant major depressive disorder, and who do not respond to standard medications. However, the mechanisms underlying ketamine’s action on the depressive brain have remained unclear.
In the study published in the journal Translational Psychiatry, Dr. Hajime Yamanaka and Dr. Hirotaka Onoe from the RIKEN Center for Life Science Technologies in Japan used positron emission tomography (PET) imaging on rhesus monkeys to show that ketamine increases the activity of serotoninergic neurons in the brain region regulating motivation. The subsequent boost in serotonin production may explain its antidepressant action in humans.
The team performed PET imaging studies on four rhesus monkeys with two tracer molecules related to serotonin (5-HT) that bind highly selectively to serotonin 1B receptor 5-HT1B and serotonin transporter SERT.
From the PET scan images, the researchers inferred that ketamine induces an increase in the binding of serotonin to its receptor 5-HT1B in the nucleus accumbens and the ventral pallidum, but induces a decrease in binding to its transporter SERT in these brain regions. These two brain regions are associated with motivation and both have been shown to be involved in depression.
In addition, the researchers demonstrated that treatment with NBQX, a drug known to block the anti-depressive effect of ketamine in rodents, 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.
The article can be found at: Yamanaka H et al. (2014) A possible mechanism of the nucleus accumbens and ventral pallidum 5-HT1B receptors underlying the antidepressant action of ketamine: a PET study with macaques.
Source: RIKEN; Photo: _DJ_/Flickr/CC.
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