Group II mGlu receptor activation suppresses norepinephrine release in the ventral hippocampus and locomotor responses to acute ketamine challenge.
Group II mGlu receptor agonists (eg LY379268 and LY354740) have been shown to reverse many of the behavioral responses to PCP as well as glutamate release elicited by PCP and ketamine. In the present set of experiments, we used in vivo microdialysis to show that, in addition to reversing PCP- and ketamine-evoked glutamate release, group II mGlu receptor stimulation also prevents ketamine-evoked norepinephrine (NE) release. Pretreating animals with the mixed 2/3 metabotropic glutamate (mGlu2/3) receptor agonist LY379268 (0.3-10 mg/kg) dose-dependently inhibited ketamine (25 mg/kg)-evoked NE release in the ventral hippocampus (VHipp). Ketamine hyperactivity was also reduced in a similar dose range. Following our initial observation on NE release, we conducted a series of microinjection experiments to reveal that the inhibitory effects of LY379268 on VHipp NE release may be linked to glutamate transmission within the medial prefrontal cortex. Finally, we were able to mimic the inhibitory effects of LY379268 on ketamine-evoked NE release by using a novel mGlu2 receptor selective positive modulator. (+/-) 2,2,2-Trifluoroethyl [3-(1-methyl-butoxy)-phenyl]-pyridin-3-ylmethyl-sulfonamide (2,2,2-TEMPS, characterized through in vitro GTPgammaS binding) at a dose of 100 mg/kg significantly reduced the NE response. Together, these results demonstrate a novel means to suppress noradrenergic neurotransmission (ie by activating mGlu2 receptors) and may, therefore, have important implications for neuropsychiatric disorders in which aberrant activation of the noradrenergic system is thought to be involved.
Lorrain
Daniel S
DS
Department of Neuropharmacology, Merck Research Laboratories, San Diego, CA 92121, USA. Daniel_lorrain@merck.com
Schaffhauser
Hervé
H
Campbell
Una C
UC
Baccei
Christopher S
CS
Correa
Lucia D
LD
Rowe
Blake
B
Rodriguez
Dana E
DE
Anderson
Jeffery J
JJ
Varney
Mark A
MA
Pinkerton
Anthony B
AB
Vernier
Jean-Michel
JM
Bristow
Linda J
LJ
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000596:Amino Acids / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D006948:Hyperkinesis / Q000188:drug therapy; D066298:In Vitro Techniques; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000145:classification; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy; D012701:Serotonin / Q000378:metabolism; D013460:Sulfur Isotopes / Q000493:pharmacokinetics; D013997:Time Factors; D014270:Trifluoroethanol / Q000494:pharmacology; D014966:Xanthenes / Q000494:pharmacology
D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; D013460:Sulfur Isotopes; D014966:Xanthenes; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D018698:Glutamic Acid; D007649:Ketamine; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D014270:Trifluoroethanol; D009638:Norepinephrine