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


OBJECTIVE
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.
Nordquist
R E
RE
CNS Discovery Research, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, Building 72-148, CH-4070, Basel, Switzerland. r.e.nordquist@uu.nl
Steckler
T
T
Wettstein
J G
JG
Mackie
C
C
Spooren
W
W
D000818:Animals; D001007:Anxiety / Q000188:drug therapy* / Q000523:psychology*; D015415:Biomarkers; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*
D015415:Biomarkers; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate