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Journal: (2R,6R)-hydroxynorketamine exerts mGlu receptor-dependent antidepressant actions. (Pubmed Central) - May 22, 2019
These findings highlight that (2R,6R)-HNK exerts antidepressant-relevant actions via a mechanism converging with mGlu receptor signaling and suggest enhanced cortical gamma oscillations as a marker of target engagement relevant to antidepressant efficacy. Moreover, these results support the use of (2R,6R)-HNK and inhibitors of mGlu receptor function in clinical trials for treatment-resistant depression either alone or in combination.
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Targeting NMDAR Hypofunction During Early Development for the Prevention of Schizophrenia Phenotypes in Adulthood in the MAM Model (Regency R) - Apr 3, 2019 - Abstract #SIRS2019SIRS_739;
• Drugs and behavioral tests: Juvenile treatment with mGluR2 agonist/mGluR3 antagonist LY395756 (subchronic, 0.3 mg/kg, i.p., once daily for 5 days; Cross-maze); mGluR2/3 agonist LY379268 (0.1, 0.3, 1mg/kg, i.p., once daily for 5 days; Morris water maze, T maze, and locomotor activity) from P21 to P25; GSK3b inhibitor SB216763 (2 mg/kg/day or vehicle, once daily for 8 days; T maze) from P21 to P28 8 y Results We found that the levels of synaptic NR2B protein are significantly decreased in juvenile MAM animals, and the function of NMDARs is substantially compromised as reflected in decreased NMDA-EPSCs...The selective loss of NR2B protein and subsequent synaptic dysfunction weakens the PFC function during development and may underlie early cognitive impairments in SCZ models and patients. The latter is supported by the efficacy of glutamatergic modulators to prevent both prefrontal NMDAR hypofunction and cognitive deficits, highlighting the importance of targeting glutamatergic dysfunction as a potential early intervention for SCZ.
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Preclinical, Journal: Schizophrenia-related cognitive dysfunction in the Cyclin-D2 knockout mouse model of ventral hippocampal hyperactivity. (Pubmed Central) - Apr 3, 2019
...Conducting a comprehensive phenotyping of CD2-KO mice, we found that they displayed novelty-induced hyperlocomotion (a rodent correlate of positive symptoms of schizophrenia), that was largely resistant against D1- and D2-dopamine-receptor antagonism, but responsive to the mGluR2/3-agonist LY379268...In contrast, sustained attention and forms of spatial and object-related memory that are mediated by short-term habituation of stimulus-specific attention were intact. Our results suggest that CD2-KO mice are a valuable model in translational research targeted at the pharmacoresistant cognitive symptom domain in causal relation to hippocampal over-activity in the prodrome-to-psychosis transition.
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