AROMATIC L-AMINO ACID DECARBOXYLASE MODULATION

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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.