Group II selective metabotropic glutamate receptor agonists and local cerebral glucose use in the rat.
The novel mGluR agonist LY354740 and a related analogue LY379268 are selective for mGluR2/3 receptors and are centrally active after systemic administration. In this study, rates of local cerebral glucose use were measured using the [14C]2-deoxyglucose autoradiographic technique to examine the functional consequences of their systemic administration in the conscious rat. Both LY354740 (0.3, 3.0, 30 mg/kg) and LY379268 (0.1, 1.0, 10 mg/kg) produced dose-dependent changes in glucose use. After LY354740 (3.0mg/kg), 4 of the 42 regions measured showed statistically significant changes from vehicle-treated controls: red nuclei (-16%), mammillary body (-25%), anterior thalamus (-29%), and the superficial layer of the superior colliculus (+50%). An additional 15 regions displayed significant reductions in function-related glucose use (P < .05) in animals treated with LY354740 (30 mg/ kg). LY379268 (0.1, 1.0, 10 mg/kg) produced changes in glucose metabolism in 20% of the brain regions analyzed. Significant increases (P < .05) in glucose use were evident in the following: the superficial layer of the superior colliculus (+81%), locus coeruleus (+57%), genu of the corpus callosum (+31%), cochlear nucleus (+26%), inferior colliculus (+20%), and the molecular layer of the hippocampus (+14%). Three regions displayed significant decreases: mammillary body (-34%), anteroventral thalamic nucleus (-28%), and the lateral habenular nucleus (-24%). These results show the important functional involvement of the limbic system together with the participation of components of different sensory systems in response to the activation of mGluR2 and mGluR3 with LY354740 and LY379268.
Lam
A G
AG
Wellcome Surgical Institute and Hugh Fraser Neuroscience Laboratories, University of Glasgow, Garscube Estate, United Kingdom.
Monn
J A
JA
Schoepp
D D
DD
Lodge
D
D
McCulloch
J
J
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D020643:Anterior Thalamic Nuclei / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D001345:Autoradiography; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002525:Cerebellar Cortex / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D017626:Cochlear Nucleus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D008297:Male; D008326:Mammillary Bodies / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D013378:Substantia Nigra / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D014793:Visual Cortex / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism
D000596:Amino Acids; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018690:Excitatory Amino Acid Agonists; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D005947:Glucose; C104753:eglumetad