Aromatic L-amino acid decarboxylase (AAAD) is the second enzyme in the sequence leading to the formation of catecholamines. It is not considered to be rate-limiting and Until now' there is no evidence for enzyme modulation in vivo. In a model system of CNS dopaminergic neurons (rat retinal dopaminergic neurons) it was observed that AAAD is apparently modulated in vivo by neuronal activity and by drugs that 'interact with neurotransmitter receptors. When rats were placed in a lighted environment from the dark there was a slow rise of AAAD activity over about 3 hours. Activity plateau at about 2 to 3 times the activity found in the dark. Kinetic analysis of AAAD activity revealed an increase of Vmax in light. In addition, the rise was blocked by pretreatment with cycloheximide. These observations suggest that there is induction of AAAD or of a factor(s) needed for enzyme activity. When the lights were turned off, AAAD activity fell rapidly at first and then slowly. Mixing homogenates from animals killed in the light and dark resulted in AAAD activity values similar to dark activity, suggesting that an endogenous inhibitor(s) plays a role in enzyme modulation. Furthermore, administering D-1 dopamine (DA) or alpha-2 adrenergic receptor antagonists to rats in the dark resulted in enhancement of AAAD activity. Conversely, D-1 or alpha-2 receptor agonist administration suppressed AAAD activity in the light. We now seek support to investigate these findings in more detail and to use the information gained in the retinal model system to investigate the enzyme of brain. These studies will change our concepts about neuronal AAAD and provide insight into the mechanism of action of psychoactive drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH043374-04
Application #
2245744
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1989-09-01
Project End
1994-08-31
Budget Start
1992-09-30
Budget End
1994-08-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Ohio State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Hadjiconstantinou, M; Rossetti, Z L; Wemlinger, T A et al. (1995) Dizocilpine enhances striatal tyrosine hydroxylase and aromatic L-amino acid decarboxylase activity. Eur J Pharmacol 289:97-101
Eaton, M J; Gudehithlu, K P; Quach, T et al. (1993) Distribution of aromatic L-amino acid decarboxylase mRNA in mouse brain by in situ hybridization histology. J Comp Neurol 337:640-54
Hadjiconstantinou, M; Wemlinger, T A; Sylvia, C P et al. (1993) Aromatic L-amino acid decarboxylase activity of mouse striatum is modulated via dopamine receptors. J Neurochem 60:2175-80
Young, E A; Neff, N H; Hadjiconstantinou, M (1993) Evidence for cyclic AMP-mediated increase of aromatic L-amino acid decarboxylase activity in the striatum and midbrain. J Neurochem 60:2331-3