Rats (Rattus norvegicus) emit a variety of ultrasonic vocalizations throughout their lifespan that reflect different forms of emotional arousal and accompanying affective states. In this study, high frequency recordings of ultrasonic vocalizations were made during mating, aggression, and both conspecific and heterospecific (dubbed "tickling") rough-and-tumble play behavior. We found that frequency modulated 50-kHz calls (trills and step calls) were positively correlated with positively valenced appetitive behavior during mating, play, and aggression. These calls were also positively correlated with the reward value of these social encounters. However, constant frequency (i.e., flat) 50-kHz calls were not related to appetitive behaviors or reward. In contrast, 22-kHz calls were positively related to aversive/withdrawal behaviors during mating, play, and aggression. Finally, we found that rats self-administered playback of frequency modulated 50-kHz trill calls and avoided playback of 22-kHz calls. Playback of flat 50-kHz calls or tape hiss was neutral. These results suggest that frequency modulated 50-kHz calls index a positively valenced, appetitive, social-emotional state in rats.

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Recent human clinical studies with the NMDA receptor (NMDAR) antagonist ketamine have revealed profound and long-lasting antidepressant effects with rapid onset in several clinical trials, but antidepressant effects were preceded by dissociative side effects. Here we show that GLYX-13, a novel NMDAR glycine-site functional partial agonist, produces an antidepressant-like effect in the Porsolt, novelty induced hypophagia, and learned helplessness tests in rats without exhibiting substance abuse-related, gating, and sedative side effects of ketamine in the drug discrimination, conditioned place preference, pre-pulse inhibition and open-field tests. Like ketamine, the GLYX-13-induced antidepressant-like effects required AMPA/kainate receptor activation, as evidenced by the ability of NBQX to abolish the antidepressant-like effect. Both GLYX-13 and ketamine persistently (24 h) enhanced the induction of long-term potentiation of synaptic transmission and the magnitude of NMDAR-NR2B conductance at rat Schaffer collateral-CA1 synapses in vitro. Cell surface biotinylation studies showed that both GLYX-13 and ketamine led to increases in both NR2B and GluR1 protein levels, as measured by Western analysis, whereas no changes were seen in mRNA expression (microarray and qRT-PCR). GLYX-13, unlike ketamine, produced its antidepressant-like effect when injected directly into the medial prefrontal cortex (MPFC). These results suggest that GLYX-13 produces an antidepressant-like effect without the side effects seen with ketamine at least in part by directly modulating NR2B-containing NMDARs in the MPFC. Furthermore, the enhancement of 'metaplasticity' by both GLYX-13 and ketamine may help explain the long-lasting antidepressant effects of these NMDAR modulators. GLYX-13 is currently in a Phase II clinical development program for treatment-resistant depression.

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In this early POC study, GLYX-13 reduced depressive symptoms within 2 hours and this effect was maintained for 7 days on average in subjects with MDD who had not responded to another antidepressant agent during the current depressive episode. The findings of this study support the hypothesis that modulation of the NMDA receptor is a valid target for the development of antidepressant drugs and the need for additional studies to further evaluate the effects of GLYX-13. POC studies such as the one described here play a pivotal role in allowing drug researchers to decide whether to move forward with larger and more expensive studies, and they enable them to focus available resources on those molecules that appear to have the most therapeutic promise. Based on the POC study described here, a multiple dose study has been completed which showed sustained therapeutic benefit with repeated dosing of GLYX-13 for more than 6 weeks. Phase 3 studies are now being planned.

Persistent neuronal plasticity, including that observed at some hippocampal synapses, requires N-methyl-D-aspartate (NMDA)-mediated transmission. NMDA receptor activation may be necessary for hippocampus-dependent learning as antagonists block acquisition in many such tasks. The behavioural effects of NMDA agonists are less well defined. We have shown that a monoclonal antibody (B6B21) displaced [3H]-glycine that was bound specifically to the NMDA receptor, and enhanced the opening of its integral cation channel in a glycine-like fashion, effects that were competitively antagonized by 7-chlorokynurenic acid. B6B21 also enhanced long-term potentiation in hippocampal slices. We report here that intraventricular infusions of B6B21 significantly enhances acquisition rates in hippocampus-dependent trace eye blink conditioning in rabbits, halving the number of trials required to reach a criterion of 80% conditioned responses. Peripheral injections of D-cycloserine, a partial agonist of the glycine site on the NMDA receptor which crosses the blood-brain barrier, also doubles rabbits' learning rates. Pseudoconditioning control experiments indicated a lack of nonspecific behavioural sensitization effects. Our data suggest that enhanced activation of the glycine coagonist site on the NMDA receptor/channel complex facilitates one form of associative learning and may be used in other learning tasks.

Introduction The N-methyl-d-aspartate receptor-ionophore complex plays a key role in learning and memory and has efficacy in animals and humans with affective disorders. GLYX-13 is an N-methyl-d-aspartate receptor (NMDAR) glycine-site functional partial agonist and cognitive enhancer that also shows rapid antidepressant activity without psychotomimetic side effects. Areas covered The authors review the mechanism of action of GLYX-13 that was investigated in preclinical studies and evaluated in clinical studies. Specifically, the authors review its pharmacology, pharmacokinetics, and drug safety that were demonstrated in clinical studies. Expert opinion NMDAR full antagonists can produce rapid antidepressant effects in treatment-resistant subjects; however, they are often accompanied by psychotomimetic effects that make chronic use outside of a clinical trial inpatient setting problematic. GLYX-13 appears to exert its antidepressant effects in the frontal cortex via NMDAR-triggered synaptic plasticity. Understanding the mechanistic underpinning of GLYX-13’s antidepressant action should provide both novel insights into the role of the glutamatergic system in depression and identify new targets for therapeutic development.

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