The results support the hypothesis that A(2A) receptor mechanisms contribute to symptom production in PD and that drugs able to selectively block these receptors may help palliate symptoms in levodopa-treated patients with this disorder.

Poly(ADP-ribose) polymerase (PARP) transfers ADP ribose groups from NAD ؉ to nuclear proteins after activation by DNA strand breaks. PARP overactivation by massive DNA damage causes cell death via NAD ؉ and ATP depletion. Heretofore, PARP has been thought to be inactive under basal physiologic conditions. We now report high basal levels of PARP activity and DNA strand breaks in discrete neuronal populations of the brain, in ventricular ependymal and subependymal cells and in peripheral tissues. In some peripheral tissues, such as skeletal muscle, spleen, heart, and kidney, PARP activity is reduced only partially in mice with PARP-1 gene deletion (PARP-1 ؊͞؊ ), implicating activity of alternative forms of PARP. Glutamate neurotransmission involving N-methyl-D-aspartate (NMDA) receptors and neuronal nitric oxide synthase (nNOS) activity in part mediates neuronal DNA strand breaks and PARP activity, which are diminished by NMDA antagonists and NOS inhibitors and also diminished in mice with targeted deletion of nNOS gene (nNOS ؊͞؊ ). An increase in NAD ؉ levels after treatment with NMDA antagonists or NOS inhibitors, as well as in nNOS ؊͞؊ mice, indicates that basal glutamate-PARP activity regulates neuronal energy dynamics. P oly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.4.30) participates in DNA repair as DNA damage activates PARP-1 to catalyze extensive polymerization of ADP-ribose from its substrate NAD ϩ to nuclear proteins, most notably PARP-1 itself (1). Through PARP activation, massive DNA damage substantially reduces NAD ϩ levels and kills cells by critically depleting ATP (2). This cell death mechanism is important in septic shock (3), retinal ischemia (4), and head trauma (5, 6). Streptozotocin damage to pancreatic ␤ cells, a model of insulin-dependent diabetes, is abolished in PARP-1 Ϫ͞Ϫ mice (7-9), and ischemic myocardial damage is substantially reduced in PARP-1 Ϫ͞Ϫ hearts and by PARP inhibitors in wild-type (WT) hearts (10-13).Poly(ADP-ribosyl)ation is implicated in glutamate neurotoxicity and vascular stroke. Glutamate toxicity involving N-methyl-D-aspartate receptors (NMDA-R) is mediated by activation of neuronal nitric oxide synthase (nNOS; ref. 1). NO stimulates neuronal PARP (14), and PARP inhibitors block cortical neuron NMDA toxicity (14) and cerebellar granule cell glutamate toxicity (15). NMDA toxicity is abolished in PARP-1 Ϫ͞Ϫ cortical cultures (16). Neural damage after middle cerebral artery occlusion elicits poly(ADP-ribose) (PAR) synthesis (16-18), which is attenuated in nNOS Ϫ͞Ϫ mice after cerebral ischemia͞ reperfusion (I͞R; ref. 19). The PARP inhibitor 3,4-dihydro-5-[4-1(1-piperidinyl) butoxy]-1 (2H)-isoquinolinone (DPQ) inhibits ischemia-elicited PAR synthesis and markedly reduces infarct volume in rodent middle cerebral artery occlusion (20)(21)(22), and PARP-1 Ϫ͞Ϫ mice show 65% (17) to 80% (16) reduction in infarct volume after middle cerebral artery occlusion.DNA damage and poly(ADP-ribosyl)ation have classically been considered negligible under basal conditions. We now report sub...