Regulation of tyrosine hydroxylase and aromatic l-amino acid decarboxylase by dopaminergic drugs

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Abstract

We provide evidence that dopamine receptors differentially modulate tyrosine hydroxylase and aromatic l-amino acid decarboxylase in the mouse striatum. The dopamine D1 receptor family (D1-like) antagonist, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benazepine (SCH 23390), elevated aromatic l-amino acid decarboxylase activity and protein content in striatum, as well as the mRNA for the enzyme in midbrain. The dopamine D1-like receptor agonist, (±)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF 38393), had no effect on aromatic l-amino acid decarboxylase. The dopamine D1-like drugs had no effect on tyrosine hydroxylase. In contrast, the dopamine D2 receptor family (D2-like) antagonists haloperidol and spiperone elevated both tyrosine hydroxylase and aromatic l-amino acid decarboxylase activities. The increase in aromatic l-amino acid decarboxylase activity was accompanied by elevated enzyme protein content but not mRNA. The dopamine D2-like receptor agonists, bromocriptine, quinpirole and (±)-7-hydroxydipropylaminotetralin (7-OH-DPAT), all decreased striatal tyrosine hydroxylase. Under the conditions used, bromocriptine and 7-OH-DPAT, but not quinpirole, decreased aromatic l-amino acid decarboxylase activity of striatum. Both the dopamine D1- and D2-like receptor antagonists enhanced the turnover of striatal dopamine to differing degrees, as judged by the ratio of acid metabolites of dopamine to dopamine. Taken together our results indicate that aromatic l-amino acid decarboxylase can be modulated independently of tyrosine hydroxylase. © Elsevier Science B.V. All rights reserved.

Introduction

There is now abundant experimental evidence that aromatic l-amino acid decarboxylase (EC 4.1.1.28), the second enzyme in the biosynthetic pathway for catecholamines and serotonin, and the apparent rate-limiting enzyme for the biosynthesis of trace amines, is regulated. Although the functional role for aromatic l-amino acid decarboxylase regulation has yet to be elucidated, much is known about the possible regulatory mechanisms involved. Physiological stimuli (Hadjiconstantinou et al., 1988), neurotransmitter receptors (Rossetti et al., 1989, Rossetti et al., 1990; Zhu et al., 1992; Hadjiconstantinou et al., 1993, Hadjiconstantinou et al., 1995), and second messenger pathways (Young et al., 1993, Young et al., 1994) have been shown to modulate aromatic l-amino acid decarboxylase activity associated with dopaminergic neurons of retina and striatum.

Tyrosine hydroxylase (EC 1.14.16.2) is thought to be the rate-controlling and regulated step for the synthesis of dopamine and other catecholamine transmitters. Similar to aromatic l-amino acid decarboxylase, physiological stimuli (Murrin et al., 1976; Iuvone et al., 1978), neurotransmitter receptors (Zivkovic et al., 1974; Cohen et al., 1981; Iuvone and Rauch, 1983; Hadjiconstantinou et al., 1995), and second messenger-dependent pathways (Young et al., 1995) modulate tyrosine hydroxylase activity in dopaminergic neurons in vivo, suggesting that both enzymes might share common regulatory mechanisms. An interesting facet of the regulation of tyrosine hydroxylase and aromatic l-amino acid decarboxylase is the ability of dopamine to regulate its own biosynthesis via dopamine receptors. From the existing literature it appears that the dopamine D2-like receptors regulate both tyrosine hydroxylase and aromatic-l-amino acid decarboxylase activities of striatum (Zivkovic et al., 1974; Zhu et al., 1992; Hadjiconstantinou et al., 1993), whereas dopamine D1-like receptors only regulate aromatic l-amino acid decarboxylase activity (Rossetti et al., 1990; Hadjiconstantinou et al., 1993; Zhu et al., 1992; Onali et al., 1985). We studied the effects of dopamine receptor drugs on the activity, protein content and mRNA of tyrosine hydroxylase and aromatic l-amino acid decarboxylase in the mouse brain. We now present evidence that tyrosine hydroxylase and aromatic l-amino acid decarboxylase of striatum are differentially regulated by the dopamine D1-like and D2-like receptors, and that each enzyme is under distinct regulatory control.

Section snippets

Materials and methods

Male, Swiss-Webster mice (Harlan Labs), 25–30 g, were housed under a 12 h light/dark cycle with water and food ad libitum. The studies were carried out in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the National Institutes of Health, USA. The following relatively selective dopamine agonists and antagonists were administered intraperitoneally (i.p.). Agonists: (±)-SKF 38393 ((±)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol)

Results

The dopamine D1-like antagonist SCH 23390 elevated aromatic l-amino acid decarboxylase activity in a biphasic manner (Fig. 1). Within 15 min enzyme activity rose and then declined. Enzyme activity again rose significantly by 3 h and reached about 50% over the control values by 6 h. The mRNA of aromatic l-amino acid decarboxylase in midbrain increased by 30 min, reached a maximal of about 65% over control at 60 min and returned to control values by 6 h (Fig. 2). SCH 23390 also increased the

Discussion

The hydroxylation of tyrosine to form dopamine is considered to be the rate-limiting step for the formation of catecholamines. There is, however, circumstantial evidence to suggest that aromatic l-amino acid decarboxylase may be a regulatory step for the synthesis of dopamine under certain conditions. For example, aromatic l-amino acid decarboxylase would be critical for the synthesis of dopamine in Parkinson's disease when l-DOPA is the therapeutic modality. Aromatic l-amino acid decarboxylase

Acknowledgements

This work was supported, in part, by NS34571 and a Parkinson's Disease Foundation Fellowship to S.C.

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