In our first report of DA release modulation by endogenous H202 (Chen et al, 2001), we suggested that H202 might be generated presynaptically at DA synapses to serve as an autoinhibitory signal that would limit DA release after axonal activation. We were wrong. Our subsequent studies showed that generation of modulatory H202 requires AMPA-receptor activation and can be 'fine-tuned' by GABAA-receptor activation. These findings argue against generation in DA axons, since they lack AMPA and GABAa receptors (Bernard and Bolam, 1998; Chen et al, 1998; Fujiyama et al, 2000).
What we found, however, is more exciting: generation of H202 must occur in non-DA cells or processes. Our working hypothesis is that regulation of striatal DA release by glutamate and GABA involves a triad of DA, glutamate, and GABA synapses, separated by a few micrometers on the dendrites of medium spiny neurons (Smith and Bolam, 1990; Bernard and Bolam, 1998; Chen et al, 1998; Fujiyama et al, 2000), and bound together functionally by diffusible H202 (Fig. 4). Although we have not yet confirmed generation of H202 in distal dendrites, we have demonstrated activity dependent H202
generation in the soma and proximal dendrites of medium spiny neurons; the title of this chapter, therefore, refers to 'somatodendritic' rather than 'dendritic' H202.
Regardless of the source, endogenously generated H202 reverses conventional glutamatergic excitation by opening KAtp channels to inhibit striatal DA release. These findings help clarify normal DA-glutamate interactions in striatum. Moreover, because DA-glutamate dysfunction has been implicated as a causal factor in Parkinson's disease (Olanow and Tatton, 1999; Chase and Oh, 2000; Greenamyre, 2001), schizophrenia (Deutsch et al., 2001; Sawa and Snyder, 2002), and addiction (Koob, 2000; Hyman and Malenka, 2001), exploration of this process may also suggest novel pathways through which dysfunction could occur.
One final point is that neuromodulation by H202 is a double-edged sword: an imbalance between H202 generation and regulation could result in oxidative stress, which has been implicated in nigrostriatal degeneration in Parkinson's disease (Cohen, 1994; Sonsalla et al., 1997; Olanow and Tatton, 1999; Xu et al., 2002) and, more recently, as a causal factor in schizophrenia (Do et al., 2000; Yao et al., 2001). Thus, loss of normal H202 regulation might contribute to DA-system pathology. It is relevant to note, therefore, that inhibition of GSH peroxidase by MCS leads to DA neuron hyperpolarization (Avshalumov et al., 2003b) and suppression of somatodendritic DA release in the SNc (Chen et al., 2002); however, MCS does not inhibit DA release in the adjacent ventral tegmental area (VTA) (Chen et al., 2002). This difference between SNc and VTA is potentially important, because DA neurons of the SNc degenerate in Parkinson's whereas those in the VTA are relatively spared (Yamada et al., 1990; Fearnley and Lees 1991).
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