New research suggests a novel approach to treating anxiety and post-traumatic stress disorder (PTSD) may lie in disrupting the way the brain consolidates fear memories. A clinical-stage biopharmaceutical company, Addex Therapeutics, has published data indicating that targeting the metabotropic glutamate receptor 7 (mGlu7) with negative allosteric modulators (NAMs) could offer a transformative therapeutic strategy.
Targeting the Reconsolidation of Fear
The study, conducted by scientists at the Center for Psychiatric Neurosciences (CNP, CHUV/UNIL) in Lausanne, Switzerland, investigated the effects of ADX71743, a highly selective mGlu7 NAM, using established animal models of fear learning and memory. Researchers discovered that modulating mGlu7 selectively interferes with the process of fear memory reconsolidation – the brain’s way of restabilizing a fear memory after it has been recalled. This finding is significant because it suggests a potential “therapeutic intervention point” for anxiety and trauma-related conditions.
“Anxiety- and stress-related disorders remain among the most prevalent neuropsychiatric conditions globally, with many patients experiencing incomplete or transient responses to existing therapies,” explained Tim Dyer, CEO of Addex Therapeutics. He further noted that current anxiety treatments often focus on managing symptoms and frequently require continuous use, such as benzodiazepines, which carry risks of tolerance, dependence, and relapse upon discontinuation. The research on mGlu7 modulation, he believes, offers a different therapeutic avenue to explore.
How Fear Memories are Processed and Disrupted
Fear memories are initially encoded within the lateral amygdala, a key brain region involved in emotional processing. When a fear memory is recalled, it enters a temporary, unstable state, making it susceptible to modification. The study demonstrated that administering ADX71743, both directly into the lateral amygdala and systemically, disrupted this reconsolidation process in rats. This disruption was specific to the conditioned stimulus, required the recall of the memory, occurred within a defined timeframe after recall, and significantly reduced the expression of fear.
Electrophysiological Insights and Human Relevance
Further investigation using electrophysiological analysis provided insights into the mechanism of action. ADX71743 was shown to modulate glutamatergic transmission at synapses connecting the thalamus to the amygdala – connections crucial for fear learning. Under normal conditions, the compound increased spontaneous excitatory signaling. However, during periods of high stimulation, it prevented long-term potentiation, a cellular process fundamental to memory formation. Importantly, similar synaptic effects were observed in human brain tissue, providing early translational support for the findings and addressing a common challenge in central nervous system drug development.
Professor Ron Stoop, a researcher involved in the study from the Center for Psychiatric Neurosciences, stated, “This research shows that fear memories can be weakened by targeting reconsolidation with a drug acting on mGlu7. It offers a realistic path towards a time-limited pharmacological intervention, which combined with memory recall, could reduce pathological fear more durably than continuous symptom-suppressing medication.”
The Potential of mGlu7 as a Therapeutic Target
Addex Therapeutics has been building a substantial library of allosteric modulators targeting metabotropic glutamate receptors. From this library, they identified and optimized several novel chemical series of mGlu7 NAMs, some of which were part of a spin-out transaction called Neurosterix. The company believes these findings will be instrumental in the future development of differentiated therapies for patients suffering from anxiety and PTSD.
The mGlu7 receptor is considered a promising target for a range of disorders beyond anxiety and PTSD, including obsessive-compulsive disorder (OCD), depression, drug abuse, and schizophrenia, due to its multifaceted role in brain function. This research, published in in Molecular Psychiatry, represents a significant step forward in understanding and potentially treating these debilitating conditions.
