Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety

Abstract

Rationale The increasing awareness of the need to align clinical and preclinical research to facilitate rapid development of new drug therapies is reflected in the recent introduction of the term "translational medicine". This review examines the implications of translational medicine for psychiatric disorders, focusing on metabotropic glutamate (mGlu) receptor biology in anxiety disorders and on anxiety-related biomarkers. Objectives This review aims to (1) examine recent progress in translational medicine, emphasizing the role that translational research has played in understanding of the potential of mGlu receptor agonists and antagonists as anxiolytics, (2) identify lacunas where animal and human research have yet to be connected, and (3) suggest areas where translational research can be further developed.Results Current data show that animal and human mGlu 5 binding can be directly compared in experiments using the PET ligand 11 C-ABP688. Testing of the mGlu 2/3 receptor agonist LY354740 in the fear-potentiated startle paradigm allows direct functional comparisons between animals and humans. LY354740 has been tested in panic models, but in different models in rats and humans, hindering efforts at translation. Other potentially translatable methods, such as stress-induced hyperthermia and HPA-axis measures, either have been underexploited or are associated with technical difficulties. New techniques such as quantitative trait loci (QTL) analysis may be useful for generating novel biomarkers of anxiety. Conclusions Translational medicine approaches can be valuable to the development of anxiolytics, but the amount of cross-fertilization between clinical and pre-clinical departments will need to be expanded to realize the full potential of these approaches.

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

“…Great efforts are focused on the development of novel mGluRs, including mGluR5, PET radioligands for 'proof-of-concept' studies in sub-human and human primates (Nordquist et al 2008;Mu et al 2010;Li et al 2012;Pillai and Tipre 2016). Interestingly, a recent study with ligand [ 18 F]-FPEB, showed a correlation between increased mGluR5 availability and novelty-seeking temperament in non-smokers healthy volunteers in limbic brain areas and primary sensory areas.…”

Genetic Approaches to Modeling Anxiety in Animals

“…Currently, no biochemical or electrophysiological criteria are used in the diagnostic procedure, although such findings may be used in support of diagnoses. A number of experimental models of human anxiety are utilized with readouts based on alterations in body temperature, HPA axis, and startle in addition to self report (Graeff et al 2003;Grillon 2008;Nordquist et al 2008;Vinkers et al 2008), which is advancing the translational aspects of animal models of anxiety. These coupled with continuous progress in neuroimaging, are sure to provide an informative platform for advancing the understanding of the physiological basis and nosology of anxiety disorders (Bremner 2004;Brown and Hariri 2006;Rauch et al 2006;Etkin and Wager 2007;Damsa et al 2009).…”

Challenges for translational psychopharmacology research—some basic principles

“…Both are critical in the development of an effective therapy. A similar strategy guides the fear-potentiated startle procedure where treatments with anxiolytic potential attenuate the classically conditioned potentiation effect but leave the non-potentiated startle reflex intact (Davis et al 1993;Grillon 2008;Nordquist et al 2008). The same logic is also the basis for comparing potentially anxiolytic treatments in rodents that promote exploration of open and brightly lit spaces relative to dark and safe spaces (e.g., elevated plus or zero maze, light/dark transitions, open-field tests).…”

“…The benzodiazepine anxiolytics provided good validation for the procedure, but the procedure was less sensitive with purported anxiolytic compounds targeting serotonergic or glutamatergic receptor subtypes and transporter molecules. To use the procedure with these agents require careful adjustments to the experimental protocols (Barrett et al 1986;Griebel 1995;Millan 2003;Nordquist et al 2008;Sanger 1992;Spooren et al 2001). The procedures for assessing anxiolytic compounds typically assess two objectively defined behavioral changes, the punishment-attenuating effects which are predictive of potentially anxiolytic effects, and the sedativelike and other behaviorally disruptive effects.…”

“…In contrast, there is little information on experimental models for treatment of posttraumatic stress or obsessive-compulsive or phobic disorders. A potentially valuable test for studying other forms of anxiety may be procedures using startle responses that are exaggerated either by discrete, sudden fear-provoking stimuli or uncertain, distal anxiety-inducing contexts (Grillon 2008;Nordquist et al 2008). These procedures may reveal a core symptom of phobias, post-traumatic stress, or panic disorders related to the phasic startle potentiation that are distinct from the sustained form of aversive conditioning typically used to model generalized anxiety disorder.…”