Metabotropic Glutamate Receptors – Regulation of Acute and Chronic Stress-Related Behavior and Physiology
Year: 2017
Type: dissertation
Abstract: Etiology and pharmacotherapy of stress-related psychiatric conditions and comorbid somatic pathologies are nowadays areas of high unmet medical need and intense research. It is widely accepted that stressors holding a chronic and psychosocial component represent the most acknowledged risk factor. The L-glutamatergic system represents the primary excitatory neurotransmitter system of the mammalian brain and mGlu receptors acting as important pre- and postsynaptic regulators of neurotransmission provide a mechanism by which fast synaptic responses through iGlu receptors can be fine-tuned. During the last decades, research on mGlu receptors advanced remarkably and much attention was given to the mGlu5 and mGlu7 subtypes in acute stress, fear and depression-related behavior and physiology (see Introduction). As the most widely distributed throughout the mammalian brain, the presynaptic mGlu7 receptor is an important regulator of glutamatergic function and postulated to be critical for both normal CNS functioning and a range of stress-related disorders. Although genetic and pharmacological approaches have helped to understand mGlu7’s function in a host of behavioral and physiological processes, available allosteric ligands have often yielded disparate results despite displaying similar pharmacological properties in vitro. The recent discovery of XAP044 raised great hope to resolve this discrepancy. XAP044 was characterized as the first mGlu7-selective full antagonist that blocks the receptor’s signaling pathways by binding to its large VFTD, but not to allosteric sites within the transmembrane domain. Thus, XAP044 presumably binds via a novel mechanism compared to that from known selective ligands. It was part of the present PhD thesis to characterize this novel compound XAP044 in vivo in a broad battery of acute stress tests for depression, fear and anxiety in mice. It was shown that XAP044 is systemically active and demonstrates a wide spectrum of anti-stress, antidepressant and anxiolytic-like efficacy, strongly supporting pharmacological blockade of mGlu7 as a promising mode of action for future treatment of stress-related disorders of emotion in man. Also the mGlu5 subtype has become a recent focus for drug discovery efforts (see Introduction). Due to its physical and functional association with the postsynaptic NMDA receptor the mGlu5 subtype is considered as a good target to modulate NMDA receptor function. This is an important consideration as, for instance, the NMDA receptor antagonist ketamine – despite showing rapid and sustained efficacy in clinical depression trials – is also associated with severe cognition-altering and dissociative effects. To date, several mGlu5 NAMs have been reported to have therapeutic potential for numerous conditions including clinical depression and anxiety disorders. A recent study revealed the mGlu5 NAM basimglurant as a promising antidepressant drug with the potential to also alleviate comorbidities such as anxiety and pain. Despite the overall well-established link between mGlu5 and mGlu7 and acute stress-related behavior and physiology, the roles these receptors play in chronic stress-related conditions is only little explored. The CSC paradigm represents a powerful animal model as it displays harmful behavioral, physiological and immunological changes induced by chronic psychosocial stress. Those consequences are relevant for the development of psychiatric, somatic and/or gastrointestinal disorders in humans and the question whether mGlu5 and mGlu7 have the potential to exert control on these pathological consequences is of great interest, and it may suggest future therapeutic strategies for the treatment of chronic stress-related disorders in humans, i.e. a wide clinical application spectrum. In a first step of the present PhD thesis, the molecular changes were assessed that occur within the mGlu receptor system in response to CSC exposure. Here, an increase by trend of mGlu5 mRNA was found in the hypothalamus. Additional saturation binding analysis revealed increased mGlu5 protein binding specifically in the hippocampus. Furthermore, robust downregulation of mGlu7 mRNA was found specifically in the PFC. In contrast, mGlu2 and mGlu3 were not dysregulated upon CSC exposure. Taken together, the present results indicate specific CSC-induced alterations of mGlu5 and mGlu7 expression in stress-sensitive brain regions involved in the regulation of behavior and HPA axis functionality, and thus provide early evidence towards a role of specific mGlu receptor subtypes in chronic psychosocial stress-induced pathophysiology. In a next step, the influence of genetic ablation of mGlu7 on behavioral, physiological and immunological consequences of CSC was analyzed to reveal the potential role of the endogenous mGlu7 receptor during chronic psychosocial stress. Indeed, genetic ablation of mGlu7 relieved multiple CSC induced alterations; mGlu7 deficient mice were protected against the CSC-induced anxiety-prone phenotype as well as against several CSC-induced physiological and immunological consequences such as HPA axis dysfunction and colonic inflammation, respectively. These findings point to a distinct role of mGlu7 in modulating a wide range of affective and somatic alteration that occur upon CSC exposure. Moreover, the stress-protective phenotype of genetic mGlu7 ablation suggests mGlu7 pharmacological blockade to be a possible treatment strategy for chronic stress-related emotional and somatic conditions in man. In the last part of the present thesis, the potentially beneficial role of genetic and pharmacological mGlu5 inhibition on CSC-induced alterations (the same broad range as presented above) was analyzed. Interestingly, also mGlu5 deficient mice were protected against a variety of CSC-induced physiological and behavioral changes, including the newly established CSC-induced increase in SIH response. Moreover, the effects of the mGlu5 NAM CTEP, a close analogue to the clinically active drug basimglurant with long half-life in rodents, were studied on a wider range of CSC-affected parameters. Here, CTEP relieved in a dose-dependent manner various CSC-induced consequences such as HPA axis dysfunction, immunological alterations and colonic inflammation, suggesting that mGlu5 is a relevant mediator for a wide range of alterations induced by chronic psychosocial stress and a potentially valuable drug target for the treatment of stress-related somatic pathologies. In conclusion, the present PhD thesis provides clear evidence for the importance of especially the mGlu5 and mGlu7 subtypes in the regulation of acute and chronic stress-related behavior and physiology, lending further support towards future development of mGlu5- and mGlu7-selective antagonists and their administration as therapy for stress-related psychiatric and somatic disorders in humans.
Author: Daniel Peterlik
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2612297687