Nya rön om hur ketamin får sin antidepressiva effekt

The experiments confirmed that the rapid antidepressant-like effects require activation of AMPA receptors, not inhibition of NMDA receptors.

This paper predicts that it would have a similar, very rapid onset of action and efficacy against treatment resistant depression to ketamine, but that it would lack some of the undesirable side effects such as percetual [sic] distortion and addiction potential

Glutamate is the main excitatory neurotransmitter in the mammalian brain. Roughly one-third of central nervous system (CNS) neurons use glutamate and, in combination with other excitatory neurotransmitters, it plays a key role in memory, learning, and neuroplasticity (Machado-Vieira et al., 2009b and Machado-Vieira et al., 2012); broadly, the term neuroplasticity includes changes in gene regulation and intracellular signaling cascade, variations in neurotransmitter release, modifications of synaptic number and strength, modeling of dendritic and axonal architecture and, in some areas of the CNS, the generation of new neurons (Machado-Vieira et al., 2008). Glutamate is also crucial to dendritic spine formation remodeling, influencing the density and morphology of dendritic spines. Indeed, changes in glutamate levels could contribute to abnormalities in dendritic spines and may represent a therapeutic target for rapid-acting glutamate modulators.

[...]Glutamate is subsequently released pre-synaptically into the synaptic cleft and activates both ionotropic and metabotropic glutamate receptors on astrocytes and in pre- and postsynaptic neurons. Glutamate receptor subtypes involve ligand-gated ion channels (N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptors) as well as the eight G-protein coupled metabotropic receptors (mGluRs). Glutamate is not metabolized by any process; its concentrations are tightly regulated by glutamate reuptake transporters localized on neurons and glia (Danbolt, 2001).
The NMDA receptor is activated by glutamate in the presence of a co-agonist d-serine or glycine and blocked by extracellular magnesium. Only depolarization induced by AMPA receptor activation releases magnesium-induced blockade from the NMDA receptor pore, thus allowing the flow of other electrolytes (e.g., calcium) (Lai et al., 2014 and Machado-Vieira et al., 2009b).

[...] The AMPA channel is composed of the glutamate receptor GluA1, GluA2, GluA3, and GluA4 subunits, which have lower affinity for glutamate than NMDA receptors. Within the tripartite glutamate synapse and its circuitry (Machado-Vieira et al., 2009b), a complex and intricate dynamic interaction exists between ionotropic glutamate receptors and mGluRs with regard to the reuptake and transport of glutamate as well as the glutamate/glutamine recycling mechanism (Machado-Vieira et al., 2009b). Indeed, the glutamate system is far more complex than the monoaminergic system. Both ionotropic glutamate receptors and mGluRs have a wide range of effects, enzymes, downstream targets, and proposed biological models. This complexity is one of the main reasons why some glutamate modulators are so effective in treating mood disorders (e.g., ketamine, lamotrigine), while others appear not to work (e.g., memantine, riluzole).

[...]In preclinical studies, the rapid antidepressant effects of ketamine appeared to involve the activation of AMPA receptors. Increased glutamatergic activity seems key to this effect, given that AMPA receptor antagonists blocked ketamine's antidepressant effects in preclinical studies (Autry et al., 2011, Duman and Aghajanian, 2012, Koike et al., 2011 and Maeng et al., 2008). Specifically, pre-treatment with NBQX, an AMPA receptor antagonist, blocked ketamine's molecular and behavioral effects (Maeng et al., 2008 and Zhou et al., 2014). In support of this model, increased hippocampal AMPA/NMDA receptor density ratio was observed after ketamine treatment in rodents (Tizabi et al., 2012). In the same context, low-dose ketamine enhanced glutamate activity in the PFC, activating synaptic function. This, in turn, was proposed to activate AMPA signaling (Autry et al., 2011 and Maeng et al., 2008). These data support the notion that ketamine exerts rapid antidepressant-like effects by enhancing AMPA relative to NMDA throughput in critical neuronal circuits and molecular pathways and targets. Given the supported key role for AMPA in the rapid efficacy of ketamine, several new pharmacological approaches were developed and tested that target AMPA receptor function and levels. These AMPAkines, also known as AMPA positive allosteric modulators, are described in Section 8.1.

Other agents currently under development that target different receptors include AMPAkines, also known as AMPA receptor positive allosteric modulators. Notably, the activation of AMPA receptor signaling plays a key role in inducing neuroplasticity and activity-dependent BDNF release (Jourdi et al., 2009). For instance, the AMPA receptor potentiator LY392098 increased BDNF expression in neuronal cultures (Legutko et al., 2001). However, at the same time, direct stimulation of AMPA receptors can be neurotoxic (O’Neill et al., 2004). To overcome this potential issue, drug development in this field has focused on the use of AMPAkines, which potentiate currents mediated by AMPA receptors. Nevertheless, success in this area has been limited by low bioavailability and potential toxicity (Menniti et al., 2013). Preclinical studies found that these agents exhibit antidepressant-like efficacy (Bleakman et al., 2007 and O’Neill and Witkin, 2007), and several AMPA modulators are being developed to treat MDD, including the AMPA agonist farmampator (CX-691/ORG 2448). While older AMPAkines (e.g., levetiracetam) have shown no evidence of efficacy (Saricicek et al., 2011), several more potent compounds have been developed; these include coluracetam (BCI-540), which is in clinical trials (Dutta et al., 2015). ORG-26576, an AMPA receptor positive allosteric modulator, has also been studied. A phase Ib safety and efficacy trial found that the maximum tolerated dose (400 mg po bid) of ORG-26576 demonstrated preliminary antidepressant efficacy in a small cohort (n = 30) (Nations et al., 2012). Among the three doses assessed (100 mg/bid, 400 mg/bid, and placebo), however, none of the arms statistically separated over the 28-day testing period. Nevertheless, the higher dose was associated with improved speed of information processing, improved executive functioning, increased growth hormone, and decreased cortisol; no effect was seen on prolactin or BDNF levels. As is true for other glutamate modulators, replication in larger cohorts will be critical to assess the overall safety, tolerability, and antidepressant efficacy of AMPAkines.