AMN082, an allosteric mGluR7 agonist that inhibits afferent glutamatergic transmission in rat basolateral amygdala.
Glutamatergic neurotransmission has been implicated in the pathophysiology of psychiatric disorders, such as anxiety and depression. The possible contribution of group III metabotropic glutamate receptors has been poorly investigated, due to the lack of selective pharmacological tools. However, a selective agonist of mGLUR7, AMN082 has been identified recently, and shown to act through an allosteric mechanism in recombinant cells expressing the receptor. Thus, using AMN082, we examined the role of mGLUR7 in modulating synaptic transmission in the rat basolateral amygdala (BLA), a brain region known to be important for the genesis of anxious states. We found that bath application of AMN082 (1-10microM) produced a concentration-dependent inhibition of synaptic transmission evoked at 2Hz, but had no effect on transmission evoked at 0.05Hz. However, at this lower frequency, AMN082 (10microM) significantly increased the synaptic inhibition produced by a group III mGLUR agonist, L-AP4 (100microM). This effect was blocked by pre-application of CPPG (500microM), a group III mGLUR-preferring antagonist, consistent with the involvement of mGLUR7. Thus, we have shown that AMN082 can modulate high frequency synaptic transmission in the BLA, in vitro, and appears to act on the receptor via an allosteric mechanism. These results suggest that mGLUR7 has a unique role in regulating neuronal activity in the BLA and may be a target for novel drugs for the treatment of anxiety.
Department of Biology, Neuroscience Centre of Excellence for Drug Discovery, Psychiatry CEDD, GlaxoSmithKline Medicines Research Centre S.p.A., Via Fleming 4, 37135 Verona, Italy. annarosa.2.ugolini@gsk.com
Annarosa
A
Ugolini
Charles H
CH
Large
Mauro
M
Corsi
D000344:Afferent Pathways / Q000166:cytology; D000679:Amygdala / Q000166:cytology / Q000187:drug effects*; D000818:Animals; D000831:Animals, Newborn; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D018698:Glutamic Acid / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects* / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000528:radiation effects
C114785:2-amino-4-phosphono-propinate; C110733:3,4-dicarboxyphenylglycine; D001559:Benzhydryl Compounds; D001565:Benzoates; D018690:Excitatory Amino Acid Agonists; C507346:N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride; D011422:Propionates; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7; D018698:Glutamic Acid; D005998:Glycine