Differential effects of NMDA and non-NMDA antagonists on the activity of aromatic L-amino acid decarboxylase activity in the nigrostriatal dopamine pathway of the rat.
This study examined the acute effects of a variety of NMDA and non-NMDA antagonists on the activity of aromatic l-amino acid decarboxylase (AADC) in the corpus striatum (CS) and substantia nigra (SN) of the rat. Sixty min pretreatment with the high affinity NMDA receptor-channel blockers MK 801 (0.01, 0.1 and 1 mg/kg) and phencyclidine (4 mg/kg) elevated AADC activity in both the CS and SN (2- to 3-fold). Even more striking increases in AADC were noted with 40 mg/kg amantadine (3.8-fold for CS, 9.0-fold for SN), 40 mg/kg memantine (3.4-fold for CS, 3.1-fold for SN; 20 mg/kg no effect) and 40 mg/kg dextromethorphan (3.4-fold for CS, 6.2-fold for SN, in 6/10 'responders'). Similarly pronounced increases in AADC activity in CS (1.9-fold) and SN (2.8-fold) were detected after administering clonidine (2 mg/kg). R-HA 966 (5 mg/kg, not 1 mg/kg) modestly raised AADC activity in CS (0.45-fold) and not SN. Other drugs had no effect on the activity of the decarboxylase enzyme, including CGP 40116 (1 and 5 mg/g), eliprodil (10 mg/kg), NBQX (10 mg/kg, 30 min pretreatment) and atropine (1 mg/kg). These experiments indicate that blocking the NMDA receptor-channel (and to a lesser extent the glycine site) or stimulating alpha2-adrenoceptors, profoundly increases AADC activity, more especially in the SN than CS. By contrast, inhibiting the NMDA glutamate recognition or polyamine sites, AMPA or muscarinic receptors is without effect on AADC in either brain region. The ability of amantadine and memantine to potentiate the antiparkinsonian actions of l-DOPA in the clinic, may be due to facilitated decarboxylation of l-DOPA by the brain.
Fisher
A
A
Department of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
Biggs
C S
CS
Starr
M S
MS
D058647:Adrenergic alpha-2 Receptor Agonists; D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D004298:Dopamine / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology*; D009434:Neural Pathways / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology*
D058647:Adrenergic alpha-2 Receptor Agonists; D018691:Excitatory Amino Acid Antagonists; D018727:Muscarinic Antagonists; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D001142:Aromatic-L-Amino-Acid Decarboxylases; D004298:Dopamine