Aaad Activity in pd Models

AAAD activity in nigrostriatal neurons appears to be up-regulated soon after a MPTP lesion [96] implying the involvement of compensatory or altered regulatory mechanisms. In MPTP-treated mice, AAAD in the denervated striatum responds more robustly to D1- and D2-like antagonists [52], and the same appears to be true for clozapine [66]. We have termed this exaggerated responsiveness of AAAD after a lesion of the nigrostriatal neurons "presynaptic supersensitivity", and it is manifested by a shift of the time- and dose-response curves to the left and upward; i.e. AAAD activity is more pronounced and observed earlier and with lower antagonist doses. Altered post-translational modification of AAAD after MPTP and/or altered receptor/second messenger signaling cascades secondary to the dopaminergic lesion might underlie this phenomenon (Figure 2). Indeed, the magnitude of exogenous PKA-induced AAAD phosphorylation is greater in homogenates prepared from striatum and midbrain of MPTP-lesioned mice, with the response increasing with time following the lesion (Figure 2A), and icv administration of forskolin in MPTP-mice amplifies the activation of the enzyme (Figure 2B), and causes an earlier induction of AAAD mRNA [57,59].

Imaging studies using 18F-DOPA [97,98] have shown that the PD process differentially affects AAAD in various brain regions and within the striatum over time [24,99-102] and have estimated a relative upregulation of striatal AAAD by comparison to other neurochemical, neuroanatomical and imaging dopaminergic markers [103-106]. Although this has been attributed to a compensatory increase of AAAD activity in the remaining dopaminergic neurons, serotonergic, noradrenergic and intrinsic striatal neurons contribute to the AAAD measurements and enzyme activity in striatum [100,102] and might add to the calculated AAAD "upregulation" [106] as well. Regardless, radiotracer imaging studies have strengthened our original proposal that AAAD is a regulated enzyme [53,54] and provided clues supporting the idea that AAAD can be subjected to pharmacological manipulation in PD. For example, therapeutic infusion of L-DOPA or apomorphine caused a small decrease in L-[nC]DOPA influx in the striatum with early but not advanced PD [107,108], and decreases in putamen AAAD activity following a 2 year treatment with L-DOPA, -20.3%, or a D2 agonist, -13.4% have been reported [109].

Figure 2. Exogenous PKA-induced phosphorylation of AAAD in the striatum and midbrain is enhanced in MPTP-treaded mice over time (Figure 2.A). AAAD activity in the striatum of MPTP-treated mice is enhanced following icv administration of forskolin (Figure 2.B). *P<0.05 compared with Control.
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