Purinergic modulation of extracellular glutamate levels in the nucleus accumbens in vivo.
In the present study, the P2 receptor-mediated modulation of the extracellular glutamate concentration was investigated by microdialysis in the nucleus accumbens (NAc) of freely moving rats. Because of the known interference of dopaminergic and glutamatergic mechanisms in this area the experiments were performed with animals intra-accumbally treated with 6-hydroxydopamine (6-OHDA) to deplete dopamine pools. Perfusion of the NAc with the prototypic P2 receptor agonist 2-methylthioadenosine 5'-triphosphate (2-MeSATP, 0.1, 1 and 10mM) concentration-dependently increased the extracellular level of glutamate in this area. Pretreatment with the P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 0.1mM) decreased the basal extracellular glutamate concentration and inhibited the 2-MeSATP-induced outflow of glutamate. In rats treated with 6-OHDA, 2-MeSATP increased the total extracellular glutamate to an extent about fivefold larger than in sham-lesioned rats. The perfusion of the dopamine-depleted NAc with the D(2)/D(3) dopamine receptor agonist quinpirole (0.1mM) diminished the basal concentration of glutamate and reduced the effect of 2-MeSATP on the extracellular glutamate. These results provide evidence that the stimulation of P2 receptors is involved in the increase of accumbal extracellular glutamate in vivo. This behaviourally relevant mechanism depends on a dopamine D(2) receptor-mediated tone in the nucleus accumbens. Furthermore, the inhibition of P2 receptors may prevent, at least partly, glutamate-mediated neurodegeneration.
Krügel
Ute
U
Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Haertelstrasse 16-18, D-04107 Leipzig, Germany. krueu@medizin.uni-leipzig.de
Schraft
Thomas
T
Regenthal
Ralph
R
Illes
Peter
P
Kittner
Holger
H
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism*; D005971:Glutamates / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D008297:Male; D018696:Neuroprotective Agents / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D016627:Oxidopamine / Q000494:pharmacology*; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D013873:Thionucleotides / Q000494:pharmacology
D005971:Glutamates; D018696:Neuroprotective Agents; D018048:Receptors, Purinergic P2; D013873:Thionucleotides; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D011732:Pyridoxal Phosphate; D016627:Oxidopamine; D000255:Adenosine Triphosphate; C008501:2-methylthio-ATP