Acute pharmacological modulation of mGluR8 reduces measures of anxiety.
Metabotropic glutamate receptors (mGluRs), which are coupled to second messenger pathways via G proteins, modulate glutamatergic and GABAergic neurotransmission. Because of their role in modulating neurotransmission, mGluRs are attractive therapeutic targets for anxiety disorders. Previously we showed that mGluR8(-/-) male mice showed higher measures of anxiety in the open field and elevated plus maze than age-matched wild-type mice. In this study, we assessed the potential effects of acute pharmacological modulation of mGluR8 on measures of avoidable and unavoidable anxiety. In addition to wild-type mice, we also tested apolipoprotein E-deficient (Apoe(-/-)) mice, as these mice show increased levels of anxiety-like behaviors and therefore might show an altered sensitivity to mGluR8 stimulation. mGluR8 stimulation with the specific agonist DCPG, or modulation with AZ12216052, a new, positive allosteric modulator of mGluR8 reduced measures of anxiety in both wild-type mice. The effects of mGluR8 positive allosteric modulators, which only affect neurotransmission in the presence of extracellular glutamate, seem particularly promising for patients with anxiety disorders showing benzodiazepine insensitivity.
Duvoisin
Robert M
RM
Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR, USA.
Pfankuch
Tim
T
Wilson
Julie M
JM
Grabell
Julie
J
Chhajlani
Vijay
V
Brown
Dean G
DG
Johnson
Edwin
E
Raber
Jacob
J
D000083:Acetanilides / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001307:Auditory Perception / Q000187:drug effects / Q000502:physiology; D001565:Benzoates / Q000494:pharmacology; D002491:Central Nervous System Agents / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009483:Neuropsychological Tests; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D013864:Thioglycolates / Q000494:pharmacology; D013997:Time Factors
C110733:3,4-dicarboxyphenylglycine; C552361:AZ 12216052; D000083:Acetanilides; D001057:Apolipoproteins E; D001565:Benzoates; D002491:Central Nervous System Agents; D018094:Receptors, Metabotropic Glutamate; D013864:Thioglycolates; C111435:metabotropic glutamate receptor 8; D005998:Glycine
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