Evidence for a selective prefrontal cortical GABA(B) receptor-mediated inhibition of glutamate release in the ventral tegmental area: a dual probe microdialysis study in the awake rat.
Glutamate-containing pyramidal neurons in the medial prefrontal cortex (mPfc) project to the ventral tegmental area (VTA) where they synapse on mesocorticolimbic dopamine containing cell bodies and GABA interneurons. In the present study we employed dual probe microdialysis in intact conscious rat brain to investigate the effects of intra-mPfc perfusion with a depolarising concentration of potassium chloride (KCl) (100 mM, 20 min) alone and in the presence of local GABA(A) and GABA(B) receptor blockade on VTA glutamate release. Intra-mPfc KCl transiently increased VTA glutamate release (+71.48+/-14.29%, 20 min). Intra-mPfc perfusion with a concentration of the GABA(A) receptor antagonist bicuculline (10 microM, 120 min) did not influence the intra-mPfc KCl-induced increase in VTA glutamate release (+102.35+/-33.61%, 20 min). In contrast, intra-mPfc perfusion with a concentration of the GABA(B) receptor antagonist CGP35348 (100 microM, 120 min) which when given alone did not influence basal glutamate levels in the VTA was associated with an enhanced KCl-induced stimulation of VTA glutamate release (+375.19+/-89.69%, 40 min). Furthermore, this enhancement was reversed in the presence of the selective GABA(B) receptor agonist baclofen (10 microM, 120 min). The present findings suggest a key role for the prefrontal cortex in the regulation of glutamate release in the VTA. Furthermore, we demonstrate a selective cortical GABA(B) receptor-mediated inhibition of glutamate transmission in the VTA. These findings may be important in the context of abnormalities in amino acid neurotransmission at the network level in schizophrenia.
Harte
M
M
Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK. m.k.harte@sheffield.ac.uk
O'Connor
W T
WT
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D004347:Drug Interactions; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D017551:Microdialysis / Q000379:methods; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D016571:Neural Networks, Computer; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism* / Q000502:physiology; D017557:Ventral Tegmental Area / Q000166:cytology*; D014851:Wakefulness / Q000502:physiology*
D018755:GABA Agonists; D018756:GABA Antagonists; D009943:Organophosphorus Compounds; D011963:Receptors, GABA-A; D018698:Glutamic Acid; D011189:Potassium Chloride; C066430:CGP 35348; D001418:Baclofen; D001640:Bicuculline