GABAB/NMDA receptor interaction in the regulation of extracellular dopamine levels in rodent prefrontal cortex and striatum.
Deficits in N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission may underlie dopaminergic hyperactivity in schizophrenia. Dysregulation of the GABAergic system has also been implicated. In this study we investigated a role for GABA(B) receptors as an intermediate step in the pathway leading from NMDAR stimulation to DA regulation. Since glycine (GLY) has been found to ameliorate treatment resistant negative symptoms in schizophrenia, we treated a group of rats with 16% GLY food for 2 weeks. DA levels in prefrontal cortex (PFC) and striatum (STR) were assessed by dual-probe microdialysis and HPLC-EC in freely moving rats. Infusion of the GABA(B) receptor agonists SKF97541 and baclofen into PFC and STR significantly reduced basal DA, an effect that was reversed by the antagonist, CGP52432. In PFC, GABA(B) agonists also reduced AMPH-induced DA release following treatment with either 1 or 5 mg/kg AMPH. Similar effects were seen following subchronic glycine treatment in the absence, but not presence of CGP52432 during 5 mg/kg AMPH treatment. In STR SKF97541 decreased only the 1 mg/kg AMPH-induced DA release. Subchronic GLY treatment in STR leads to a significant reduction in basal DA levels, but did not affect AMPH (5 mg/kg)-induced release. Our findings support a model in which NMDA/glycine-site agonists modulate DA release in part through presynaptic GABA(B) receptors on DA terminals, with both GABA(B) ligands and GLY significantly modulating AMPH-induced DA release. Both sites, therefore, may represent appropriate targets for drug development in schizophrenia and substance abuse disorders.
Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
Andrea
A
Balla
Megan E
ME
Nattini
Henry
H
Sershen
Abel
A
Lajtha
David S
DS
Dunlop
Daniel C
DC
Javitt
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism*; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D008024:Ligands; D008297:Male; D017551:Microdialysis; D009943:Organophosphorus Compounds / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D013882:Thiosemicarbazones / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D008024:Ligands; D009943:Organophosphorus Compounds; D018080:Receptors, GABA-B; D016194:Receptors, N-Methyl-D-Aspartate; D013844:Thiazoles; D013882:Thiosemicarbazones; C068457:3-aminopropyl(methyl)phosphinic acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C092451:CGP 52608; D004298:Dopamine