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 nu cleus accumbens (NAc) were studied by microdialysis in freely moving rats. The ATP analog 2-Methylthio ATP (2-MeSATP) facilitated the release of dopam ine in a manner sensitive to pertussis toxin and tetrodotoxin. It is sugges ted that G-protein-coupled P2Y receptors and voltage-gated sodium channels are involved in this process. N-methyl-D-aspartate (NMDA) applied in a conc entration of 100 muM decreased the extracellular dopamine level, whereas I and 10 mM NMDA enhanced it. The endogenous agonist glutamate (10 muM) inhib ited the basal and facilitated release of dopamine. Infusion with a combina tion of the ionotropic glutamate receptor antagonists (+/-)-3-(2-carboxypip erazin-4-yl)-propyl-1-phosphonic acid (CPP) and 6-cyano-7-nitroquinoxaline- 2,3-dione (CNQX), as well as with the metabotropic glutamate receptor antag onist (+/-)-alpha -methyl-4-carboxyphenylglycine (MCPG) increased the basal level of dopamine and potentiated the 2-MeSATP-facilitated dopamine releas e, suggesting an ATP-mediated glutamate release. The GABA(A) receptor antag onist bicuculline infused into the NAc also enhanced the basal level of dop amine; 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 measure d in the absence of bicuculline. By contrast, when bicuculline was infused into the ventral tegmental area (VTA) it elevated the accumbal basal dopami ne level and in addition facilitated the 2-MeSATP- and the glutamate-induce d dopamine release above that measured in the absence of bicuculline. These results suggest that ATP in the NAc has a physiologically relevant functio n in modulating dopaminergic transmission depending on the mesolimbic neuro nal activity. The first component of the ATP effect involves a direct stimu lation of the terminals of VTA neurons, while the second inhibitory compone nt involves a sequential activation of glutamate and, finally, via ionotrop ic and metabotropic glutamate receptors, of GABA neurons projecting to the VTA. (C) 2001 Wiley-Liss Inc.