title: Effects of ketamine and N-methyl-D-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268.
abstract: Previous studies have shown that the metabotropic glutamate receptor (mGluR)2/3 agonist LY354740 attenuated glutamate release in medial prefrontal cortex (mPFC) induced by the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine. In the present study we examined the effects of the more potent mGluR2/3 selective agonist LY379268 on ketamine-evoked glutamate and dopamine (DA) release in mPFC of male rats. Subjects were implanted with a unilateral microdialysis probe in the mPFC and were tested 12-24 h after implantation. Ketamine (18 mg/kg, s.c.) evoked a significant release of glutamate and DA, although the glutamate response was slower in onset compared with DA. Pretreatment with either systemic (3 mg/kg s.c.) or local (1 microM, in the probe) LY379268 blocked ketamine-evoked glutamate, but not DA, release. When applied directly to the mPFC via the dialysis probe, ketamine (1 mM in the probe) had no effect on glutamate release but did significantly enhance the release of DA. Application of NMDA (500 microM in the probe), on the other hand, decreased DA while increasing glutamate release. The effect of NMDA on evoking glutamate release was blocked by systemic but not local administration of LY379268. These findings indicate that systemic ketamine increases both glutamate and DA release in mPFC and that the effect on glutamate can be blocked by stimulating mPFC group II mGluR receptors. Local ketamine, on the other hand, does not increase glutamate but does increase DA release. This suggests that ketamine acts outside of the mPFC to enhance glutamate, but within the mPFC to enhance DA release. The origin of the ketamine effect on mPFC glutamate is currently not known.
authors.affiliation: Department of Neuropharmacology, Merck Research Laboratories, Avera Pharmaceuticals MRLSDB1, 3535 General Atomics Court, San Diego, CA 92121, USA. daniel_lorrain@merck.com
authors.forename: D S
authors.initials: DS
authors.lastname: Lorrain
authors.forename: C S
authors.initials: CS
authors.lastname: Baccei
authors.forename: L J
authors.initials: LJ
authors.lastname: Bristow
authors.forename: J J
authors.initials: JJ
authors.lastname: Anderson
authors.forename: M A
authors.initials: MA
authors.lastname: Varney
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004333:Drug Administration Routes; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis / Q000379:methods; D016202:N-Methylaspartate / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000596:Amino Acids; D000779:Anesthetics, Local; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; D013779:Tetrodotoxin; D016202:N-Methylaspartate; D007649:Ketamine; D004298:Dopamine