Abstract
The rapid antidepressant action of a subanesthetic dose of ketamine in treatment-resistant patients represents the most striking recent breakthrough in the understanding of the antidepressant response. Evidence demonstrates tight interactions between the glutamatergic and monoaminergic systems. It is thus hypothesized that monoamine systems may play a role in the immediate/rapid effects of ketamine. In vivo electrophysiological recordings were carried in male rats following ketamine administration (10 and 25 mg/kg, i.p.) to first assess its effects on monoaminergic neuron firing. In a second series of experiments, the effects of ketamine administration on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)- and N-methyl-D-aspartate receptor (NMDA)-evoked responses in hippocampus CA3 pyramidal neurons were also investigated using micro-iontophoretic applications. Although acute (~2 hours) ketamine administration did not affect the mean firing activity of dorsal raphe serotonin and ventral tegmental area dopamine neurons, it did increase that of locus coeruleus norepinephrine neurons. In the latter brain region, while ketamine also enhanced bursting activity, it did increase population activity of dopamine neurons in the ventral tegmental area. These effects of ketamine were prevented by the prior administration of the AMPA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide. An increase in AMPA-evoked response of CA3 pyramidal neurons was also observed 30 minutes following acute ketamine administration. The present findings suggest that acute ketamine administration produces a rapid enhancement of catecholaminergic neurons firing activity through an amplification of AMPA transmission. These effects may play a crucial role in the antidepressant effects of ketamine observed shortly following its infusion in depressed patients.
Highlights
Several clinical studies have demonstrated the rapid but transient antidepressant effects of subanesthetic doses of the noncompetitive N-methylD-aspartate receptor (NMDA) receptor antagonist ketamine (Ki = 0.5 μM; Kapur and Seeman, 2002) in patients with treatment-resistant major depressive disorder (MDD)
The lack of effect on the firing activity of 5-HT neurons after both acute and two-day administration cannot be attributed to using an inadequate dose of ketamine, since a higher dose (25 mg/kg) was without effect, whereas significant change were obtained on the firing activity of NE, DA and pyramidal neurons when using the low dose
The modulation exerted on 5-HT neuronal firing was previously shown to be through amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA receptors, since iontophoretic applications of AMPA and NMDA increased their firing activity that was blocked by glutamate receptor antagonists (Gartside et al, 2007)
Summary
Significant improvement in depressive symptoms occurred within 72 hours following infusion of ketamine in seven subjects in the first placebo-controlled double-blind study (Berman et al, 2000). This was replicated in a larger double-blind study (Zarate et al, 2006). A larger twosite trial using the benzodiazepine midazolam to control for the psychotropic effects of ketamine confirmed a rapid onset of antidepressant effects (Murrough et al, 2013a). Repeated infusions of ketamine produced a more durable antidepressant response when compared to a single infusion (Murrough et al, 2013b). Understanding the mechanism behind these effects should bring the field a step closer to understanding and developing rapid, highly effective and mechanistically novel antidepressant treatments, leading to improved patient outcomes
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