Effects of glutamate antagonists on the activity of aromatic L-amino acid decarboxylase

Abstract

This study examines the hypothesis that glutamate tonically suppresses the activity of the enzyme aromatic L-amino acid decarboxylase (AADC), and hence the biosynthesis of dopamine, to explain how antagonists of glutamate receptors might potentiale the motor actions of L-DOPA in animal models of Parkinson's disease. A variety of glutamate antagonists were therefore administered acutely to normal rats, which were sacrificed 30-60 min later and AADC activity assayed in the substantia nigra pars reticulata (SNr) and corpus striatum (CS). The NMDA receptor-ion channel antagonists MK 801, budipine, amantadine, memantine and dextromethorphan all caused a pronounced in creased in AADC activity, more especially in the SNr than CS. The NMDA glycine site antagonist (R)-HA 966 produced a modest increase in AADC activity in the CS but not SNr, whilst the NMDA polyamine site antagonist eliprodil, the NMDA competitive antagonist CGP 40116 and the AMPA antagonist NBQX were without effect. The results suggest that an increase in dopamine synthesis might contribute to the L-DOPA-facilitating actions of some glutamate antagonists.

Amantadine attenuates levodopa‐induced dyskinesia in mice and rats preventing the accompanying rise in nigral GABA levels

“…It inhibits DA reuptake (Heikkila and Cohen 1972; Mizoguchi et al. 1994) and increases DOPA decarboxyalase activity (Fisher et al. 1998; Deep et al.…”

“…The mechanisms underlying the dual effect of amantadine, used both as anti-parkinsonian and anti-dyskinetic in combination with L-DOPA are not completely understood, also because amantadine has a complex pharmacodynamic profile. It inhibits DA reuptake (Heikkila and Cohen 1972;Mizoguchi et al 1994) and increases DOPA decarboxyalase activity (Fisher et al 1998;Deep et al 1999). Amantadine also behaves as an antagonist at NMDA receptors (Kornhuber et al 1991;Parsons et al 1996), where it acts by stabilizing the 'close' state of the channel (Blanpied et al 2005).…”

Enhancing Aromatic L‐amino Acid Decarboxylase Activity: Implications for L‐DOPA Treatment in Parkinson's Disease

“…AAAD is regulated in vivo and in vitro, and regulation involves both enzyme activation and induction. Activation in vivo occurs in response to the acute action of physiological stimuli, drugs that act at neurotransmitter receptors, or modulation of the activity of endogenous kinases/phosphatases [6–16]. In striatum and retina, kinetic activation of AAAD is rapid, short‐lasting, and characterized by changes in the apparent Vmax for both the substrate and the cofactor pyridoxal‐5′‐phosphate, suggesting partial phosphorylation of the enzyme [6,7].…”

“…For example, the 5‐HT 2A /5‐HT 2C antagonist ketanserin, the 5‐HT 1A /5‐HT 2A antagonist metergoline, and the 5‐HT 1A selective antagonist Way 100635 all increase AAAD activity in striatum after acute administration, while selective antagonists of 5‐HT 2C and 5‐HT 3 receptors do not influence enzyme activity [19]. Acute blockade of the glutamate NMDA ionotropic receptors by the noncompetitive antagonist MK‐801 enhances the activity of AAAD in striatum [30], and similar observations have been made for other NMDA channel blockers, phencyclidine, budipine, amantadine, memantine, and dextromethorphan [14–16]. Unlike NMDA competitive antagonists, antagonists acting at the glycine or polyamine site, and AMPA noncompetitive antagonists have little effect [14,15].…”

Amantadine increases aromatic 1L-amino acid decarboxylase mRNA in PC12 cells

“…More recently, it has been shown that amantadine increases DA turnover in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice (Rojas et al, 1993) and that it increases rat striatal AADC activity (Fisher et al, 1998). In addition, amantadine produces a uncompetitive blockade of the NMDA receptor (Danysz et al, 1994(Danysz et al, , 1997) that correlated well with the increases in striatal AADC activity (Hadjiconstantinou et al, 1995;Fisher et al, 1998). It may be postulated that the effect of amantadine may occur by at least two different mechanisms: increasing availability of DA, and low affinity uncompetitive blocking of NMDA-type glutamate receptors.…”