Depression: Ketamine reverses deficit in dopamine-dependent synaptic plasticity

[St3ve]

Conclusions This work provides a unique systems perspective on the mechanisms of ketamine on a disrupted limbic system.

Background One of the most novel and exciting findings in major depressive disorder research over the last decade is the discovery of the fast-acting and long-lasting antidepressant effects of ketamine. Indeed, the therapeutic effects of classic antidepressants, such as selective serotonin reuptake inhibitors, require a month or longer to be expressed, with about a third of major depressive disorder patients resistant to treatment. Clinical studies have shown that a low dose of ketamine exhibits fast-acting relatively sustained antidepressant action, even in treatment-resistant patients. However, the mechanisms of ketamine action at a systems level remain unclear.

Methods Wistar-Kyoto rats were exposed to inescapable, uncontrollable footshocks. To evaluate learned helplessness behavior, we used an active avoidance task in a shuttle box equipped with an electrical grid floor. After helplessness assessment, we performed in vivo electrophysiological recordings first from ventral tegmental area dopaminergic (DA) neurons and second from accumbens neurons responsive to fimbria stimulation. Ketamine was injected and tested on helpless behavior and electrophysiological recordings.

Results We show that ketamine is able to restore the integrity of a network by acting on the DA system and restoring synaptic dysfunction observed in stress-induced depression. We show that part of the antidepressant effect of ketamine is via the DA system. Indeed, injection of ketamine restores a decreased dopamine neuron population activity, as well as synaptic plasticity (long-term potentiation) in the hippocampus-accumbens pathway, via, in part, activation of D1 receptors.

For those less familiar with this field. Learned helplessness model is one animal model of depression. Human observations have shown that many depressed people "don't see the point" in things anymore and lack motivation. Learned helplessness is an attempt to recreate this in animals.

Grace and others have previously done a lot of work on D1/D5 receptors and neuronal plasticity (thought to be the neuronal correlate of memory). They (and others) have shown that co-activity of the D1/D5 receptor and NMDA receptor is needed for long lasting long-term potentiation (LTP). NMDA receptor activation by itself with D1/D5 blockade will cause LTP that only lasts for a few hours at most.

Ketamine now seems to be able to somehow restore malfunctioning dopamine dependent plasticity in a model of depression.



Ref: Belujon P and Grace AA. (2014). Restoring mood balance in depression: Ketamine reverses deficit in dopamine-dependent synaptic plasticity. Biological Psychiatry, 76, 927-936.