Positive N-Methyl-D-Aspartate Receptor Modulation by Rapastinel Promotes Rapid and Sustained Antidepressant-Like Effects.

BACKGROUND: Modulation of glutamatergic synaptic transmission by N-methyl-D-aspartate receptors can produce rapid and sustained antidepressant effects. Rapastinel (GLYX-13), initially described as a N-methyl-D-aspartate receptor partial glycine site agonist, exhibits rapid antidepressant effect in rodents without the accompanying dissociative effects of N-methyl-D-aspartate receptor antagonists. METHODS: The relationship between rapastinel's in vitro N-methyl-D-aspartate receptor pharmacology and antidepressant efficacy was determined by brain microdialysis and subsequent pharmacological characterization of therapeutic rapastinel concentrations in N-methyl-D-aspartate receptor-specific radioligand displacement, calcium mobilization, and medial prefrontal cortex electrophysiology assays. RESULTS: Brain rapastinel concentrations of 30 to 100 nM were associated with its antidepressant-like efficacy and enhancement of N-methyl-D-aspartate receptor-dependent neuronal intracellular calcium mobilization. Modulation of N-methyl-D-aspartate receptors by rapastinel was independent of D-serine concentrations, and glycine site antagonists did not block rapastinel's effect. In rat medial prefrontal cortex slices, 100 nM rapastinel increased N-methyl-D-aspartate receptor-mediated excitatory postsynaptic currents and enhanced the magnitude of long-term potentiation without any effect on miniature EPSCs or paired-pulse facilitation responses, indicating postsynaptic action of rapastinel. A critical amino acid within the NR2 subunit was identified as necessary for rapastinel's modulatory effect. CONCLUSION: Rapastinel brain concentrations associated with antidepressant-like activity directly enhance medial prefrontal cortex N-methyl-D-aspartate receptor activity and N-methyl-D-aspartate receptor-mediated synaptic plasticity in vitro. At therapeutic concentrations, rapastinel directly enhances N-methyl-D-aspartate receptor activity through a novel site independent of the glycine coagonist site. While both rapastinel and ketamine physically target N-methyl-D-aspartate receptors, the 2 molecules have opposing actions on N-methyl-D-aspartate receptors. Modest positive modulation of N-methyl-D-aspartate receptors by rapastinel represents a novel pharmacological approach to promote well-tolerated, rapid, and sustained improvements in mood disorders.

GLYX-13 Produces Rapid Antidepressant Responses with Key Synaptic and Behavioral Effects Distinct from Ketamine.

GLYX-13 is a putative NMDA receptor modulator with glycine-site partial agonist properties that produces rapid antidepressant effects, but without the psychotomimetic side effects of ketamine. Studies were conducted to examine the molecular, cellular, and behavioral actions of GLYX-13 to further characterize the mechanisms underlying the antidepressant actions of this agent. The results demonstrate that a single dose of GLYX-13 rapidly activates the mTORC1 pathway in the prefrontal cortex (PFC), and that infusion of the selective mTORC1 inhibitor rapamycin into the medial PFC (mPFC) blocks the antidepressant behavioral actions of GLYX-13, indicating a requirement for mTORC1 similar to ketamine. The results also demonstrate that GLYX-13 rapidly increases the number and function of spine synapses in the apical dendritic tuft of layer V pyramidal neurons in the mPFC. Notably, GLYX-13 significantly increased the synaptic responses to hypocretin, a measure of thalamocortical synapses, compared with its effects on 5-HT responses, a measure of cortical-cortical responses mediated by the 5-HT2A receptor. Behavioral studies further demonstrate that GLYX-13 does not influence 5-HT2 receptor induced head twitch response or impulsivity in a serial reaction time task (SRTT), whereas ketamine increased responses in both tests. In contrast, both GLYX-13 and ketamine increased attention in the SRTT task, which is linked to hypocretin-thalamocortical responses. The differences in the 5-HT2 receptor synaptic and behavioral responses may be related to the lack of psychotomimetic side effects of GLYX-13 compared with ketamine, whereas regulation of the hypocretin responses may contribute to the therapeutic benefits of both rapid acting antidepressants.