Mechanisms of adenosine 5'-triphosphate-induced dopamine release in the rat nucleus accumbens in vivo.
The endogenous mechanisms modulating ATP-induced dopamine release in the nucleus accumbens (NAc) were studied by microdialysis in freely moving rats. The ATP analog 2-Methylthio ATP (2-MeSATP) facilitated the release of dopamine in a manner sensitive to pertussis toxin and tetrodotoxin. It is suggested that G-protein-coupled P2Y receptors and voltage-gated sodium channels are involved in this process. N-methyl-D-aspartate (NMDA) applied in a concentration of 100 microM decreased the extracellular dopamine level, whereas 1 and 10 mM NMDA enhanced it. The endogenous agonist glutamate (10 microM) inhibited the basal and facilitated release of dopamine. Infusion with a combination of the ionotropic glutamate receptor antagonists (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), as well as with the metabotropic glutamate receptor antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG) increased the basal level of dopamine and potentiated the 2-MeSATP-facilitated dopamine release, suggesting an ATP-mediated glutamate release. The GABA(A) receptor antagonist bicuculline infused into the NAc also enhanced the basal level of dopamine; however, the application of 2-MeSATP in the presence of bicuculline caused an early decrease and a subsequent increase of dopamine release. The facilitatory phase of the 2-MeSATP effect was comparable with that measured in the absence of bicuculline. By contrast, when bicuculline was infused into the ventral tegmental area (VTA) it elevated the accumbal basal dopamine level and in addition facilitated the 2-MeSATP- and the glutamate-induced dopamine release above that measured in the absence of bicuculline. These results suggest that ATP in the NAc has a physiologically relevant function in modulating dopaminergic transmission depending on the mesolimbic neuronal activity. The first component of the ATP effect involves a direct stimulation of the terminals of VTA neurons, while the second inhibitory component involves a sequential activation of glutamate and, finally, via ionotropic and metabotropic glutamate receptors, of GABA neurons projecting to the VTA.
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Rudolf Boehm Department of Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany. krueu@medizin.uni-leipzig.de
Kittner
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Illes
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D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000502:physiology; D017551:Microdialysis; D008845:Microinjections; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D037342:Pertussis Toxin; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D018756:GABA Antagonists; D018048:Receptors, Purinergic P2; D013873:Thionucleotides; D010566:Virulence Factors, Bordetella; D018698:Glutamic Acid; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D000255:Adenosine Triphosphate; D037342:Pertussis Toxin; D004298:Dopamine; C008501:2-methylthio-ATP; D001640:Bicuculline