Elsevier

Biological Psychiatry

Volume 76, Issue 12, 15 December 2014, Pages 927-936
Biological Psychiatry

Archival Report
Restoring Mood Balance in Depression: Ketamine Reverses Deficit in Dopamine-Dependent Synaptic Plasticity

https://doi.org/10.1016/j.biopsych.2014.04.014Get rights and content

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.

Conclusions

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

Section snippets

Animals

Adult male Wistar-Kyoto rats (300–350 g; Charles River Laboratories, Wilmington, Massachusetts) were used for their susceptibility to LH (15). Rats were housed singly on a reversed 12-hour dark/light cycle (lights on: 7:00 p.m.) with food and water ad libitum. All experiments were performed in accordance with the guidelines outlined in the National Institutes of Health Guide for Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee of the University

Repeated Injections of Ketamine Restore Escape Behavior in Helpless Rats

Rats received inescapable shocks on day 1 and were tested for escape behavior on 3 consecutive days before electrophysiological recordings (Figure 1A, B). As previously reported (17, 27), inescapable shocks induce helpless behavior in ≈ 50% of the rats (nonhelpless rats: 87 of 172 rats or 50.6%; helpless rats: 85 of 172 rats or 49.4%). Between no-shock (n = 28) and nonhelpless rats (n = 40), there was no difference in the number of failures to escape (F1,27 = .645, p = .429) as well as the

Discussion

In this study, we examined the effect of repeated and acute ketamine injections in a behavioral model of depression. We find that ketamine reverses helpless behavior, restores normal DA neuron population activity, and restores LTP in the vSub-NAc pathway. Our findings indicate that a normal LTP in the NAc shell correlates with a failure to induce helplessness. Moreover, this study shows that the effect of ketamine on synaptic plasticity is, at least in part, due to activation of D1 receptors in

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