The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant.

BACKGROUND: Rapastinel (GLYX-13) is a NMDA receptor modulator with glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid and long-lasting antidepressant properties in both animal models and in humans. METHODS: Rapastinel was derived from a monoclonal antibody, B6B21, is a tetrapeptide (threonine-proline-proline-threonine-amide) obtained from amino acid sequence information obtained from sequencing one of the hypervariable regions of the light chain of B6B21. The in-vivo and in-vitro pharmacology of rapastinel was examined. RESULTS: Rapastinel was found to be a robust cognitive enhancer in a variety of learning and memory paradigms and shows marked antidepressant-like properties in multiple models including the forced swim (Porsolt), learned helplessness and chronic unpredictable stress. Rapastinel's rapid-acting antidepressant properties appear to be mediated by its ability to activate NMDA receptors leading to enhancement in synaptic plasticity processes associated with learning and memory. This is further substantiated by the increase in mature dendritic spines found 24 hrs after rapastinel treatment in both the rat dentate gyrus and layer five of the medial prefrontal cortex. Moreover, ex vivo LTP studies showed that the effects of rapastinel persisted at least two weeks post-dosing. CONCLUSION: These data suggest that rapastinel has significant effects on metaplasticity processes that may help explain the long lasting antidepressant effects of rapastinel seen in the human clinical trial results.

GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects.

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.

Regional brain cholecystokinin changes as a function of rough-and-tumble play behavior in adolescent rats.

Brain cholecystokinin (CCK) levels have been shown to be elevated in animals defeated during adult social aggression. The present experiment evaluated whether similar effects are evident in prolonged bouts of juvenile social-play fighting, which tend to switch from largely positive to some negative affect after approximately 15 min into a half-hour play session, as indexed by a gradual shift from positively valenced 50 kHz ultrasonic vocalizations (USVs) to negatively valenced 20 kHz USVs. Given the role of CCK in both positive and negative emotional events, we examined levels of CCK-8 in tissue homogenates from 14 brain areas in animals 6h after a 30 min play bout compared to no-play control animals tested similarly in isolation for 30 min. As with patterns observed following adult defeat, significantly higher CCK levels were evident after play in the posterior neo-cortex compared to no-play control animals (+26%). Levels of CCK were also elevated in the midbrain (+35%). However, unlike in adult aggression, CCK levels were reduced in the hypothalamus (-40%) and basal forebrain (-24%) as compared to no-play animals. Posterior cortex CCK levels were positively correlated to the duration that each animal was pinned (r = +.50) which suggests that elevated CCK in the posterior cortex may be related to the negative aspects of play. Hypothalamic CCK levels were negatively related to dorsal contacts and pins (r's = -.57), and suggest that the lower CCK levels may reflect the more positive valenced aspects of play. The data indicate that CCK utilization in the brain is dynamically responsive to rough-and-tumble play.