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

Abstract

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 antidepressant such as SSRIs require a month or longer to be expressed, with about a third of MDD patients resistant to treatment. Clinical studies have shown that 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 restores synaptic plasticity (long-term potentiation) in the hippocampus-accumbens pathway, via in part, activation of D1 receptors. Conclusions This work provides for a unique systems perspective on the mechanisms of ketamine on a disrupted limbic system.

Withdrawal from Acute Amphetamine Induces an Amygdala-Driven Attenuation of Dopamine Neuron Activity: Reversal by Ketamine

“…In animal models of MDDs, in which anhedonia is a core symptom, a decrease in DA neuron activity in the VTA has been described by our group (Belujon and Grace, 2014;Chang and Grace, 2014) and others (Tye et al, 2013). Indeed, we have shown previously in the CMS model (Chang and Grace, 2014) a decrease in DA activity in the VTA, as well as an increase in immobility time, in the FST.…”

“…Indeed, we have shown previously in the CMS model (Chang and Grace, 2014) a decrease in DA activity in the VTA, as well as an increase in immobility time, in the FST. Moreover, in the learned helplessness model, a decrease in DA activity, as well as failure to escape, has been described (Belujon and Grace, 2014). Using optogenetic techniques, Tye et al (2013) have observed in CMS rats a robust increase in kick frequency in the FST following activation of DA neurons in the VTA, which was not time locked to the light pulses, suggesting a role for dopaminergic tone, rather than bursting activity, in this behavior.…”

“…Electrodes were lowered through nine tracks in the VTA, separated by 200 μm (AP 5.5-5.9 mm, ML 0.6-1.0 mm from bregma and DV 6.5-9.0 mm from dura). Electrophysiological characterization of DA neurons was used to ensure correct identification, based on action potential waveform, firing pattern and frequency, and location, as previously described (Belujon and Grace, 2014;Grace and Bunney, 1983;Ungless and Grace, 2012). Three parameters of activity were measured: (1) population activity, ie, the number of active DA neurons per track; (2) basal firing rate; and (3) the proportion of action potentials occurring in bursts (Grace and Bunney, 1984).…”

“…In animal models of depression, such as the chronic mild stress (CMS) and the learned helplessness model, we have shown previously that there is a decrease in DA activity that could be reversed by inactivation of the basolateral amygdala (BLA) (Chang and Grace, 2014) and injection of the N-methyl-D-aspartate (NMDA) antagonist and novel antidepressant ketamine (Belujon and Grace, 2014). In drug addiction, many studies have focused on the negative affective state after repeated drug administration in humans (Leventhal et al, 2008) and animal models (Der-Avakian and Markou, 2010); however, this condition appears even after a drug is taken for the first time (Koob and Le Moal, 2001).…”

Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial

“…Mechanistic studies in animals show that ketamine rapidly enhances synaptic plasticity at the level of prefrontal cortical neurons (Li et al, 2010(Li et al, , 2011, and is able to rapidly reverse stress-induced dendritic atrophy and behavioral depression in a brain-derived neurotrophic factor (BDNF)-dependent manner (Li et al, 2011;Liu et al, 2012). A recent study found that ketamine reversed deficit dopamine signaling in a learned helplessness model of depression and normalized synaptic plasticity within the nucleus accumbens (indexed by long-term potentiation) via activation of dopamine D1 receptors (Belujon and Grace, 2014). Chronic and/or uncontrollable forms of stress are known to reduce dopamine signaling at the level of the ventral tegmental area (VTA) and striatum (Cabib and Puglisi-Allegra, 2012), and these data suggest that ketamine may alleviate depressive symptoms, at least in part, via modulation of dopamine signaling.…”