Aromaticl-amino acid decarboxylase immunoreactive cells in the rat striatum: a possible site for the conversion of exogenousl-DOPA to dopamine

Mura, Anna; Jackson, Denise; Manley, Michael S.; Young, Stephen J.; Groves, Philip M.

doi:10.1016/0006-8993(95)01104-8

Cited by 108 publications

(75 citation statements)

References 39 publications

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“…Eighty percent of the striatal AAAD is located in dopaminergic neurons, and the remainder is in noradrenergic, serotonergic, and intrinsic AAADpositive neurons Eaton et al, 1993;Mura et al, 1995), all of which add to the AAAD activity assayed in striatum homogenates. Clozapine up-regulated the expression of AAAD mRNA in substantia nigra pars compacta and ventral tegmental area, indicating that enzyme activity is modulated in dopaminergic neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Although the site for the conversion of L-DOPA to dopamine in the parkinsonian brain is still debated (Hefti et al, 1980Mura et al, 1995), boosting or stabilizing the activity of AAAD might be of therapeutic importance because it would reduce the required dose of L-DOPA, ameliorate adverse motor symptoms associated with high or fluctuating levels of L-DOPA, and perhaps prolong the responsiveness of dopaminergic neurons to L-DOPA. Thus, drugs that modulate AAAD activity theoretically could be used as an adjuvant when developing strategies for L-DOPA treatment augmentation.…”

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confidence: 99%

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Clozapine Modulates Aromatic l-Amino Acid Decarboxylase Activity in Mouse Striatum

Neff¹,

Wemlinger²,

Duchemin³

et al. 2006

J Pharmacol Exp Ther

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Clozapine is efficacious for treating dopaminergic psychosis in Parkinson's disease and ameliorates L-DOPA-induced motor complications. Based on its pharmacology and reported enhancing effects on dopamine metabolism and tyrosine hydroxylase activity, we investigated whether it could modulate the activity of aromatic L-amino acid decarboxylase (AAAD), the second enzyme for the biosynthesis of catecholamines and indoleamines. A single dose of clozapine increased AAAD activity of striatum in a dose-and time-dependent manner. At 1 h, enhanced enzyme activity was characterized by an increased V max for substrate and cofactor and was accompanied by elevated levels of protein in striatum and mRNA in substantia nigra, ventral tegmental area, locus coeruleus, and raphe nuclei. Acute clozapine increased tyrosine hydroxylase activity in striatum but with differing temporal patterns from AAAD and heightened dopamine metabolism. Interestingly, the response of the dopaminergic markers to clozapine was greater following a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion. Chronically administered clozapine increased AAAD activity and protein and dopamine metabolism in striatum without affecting tyrosine hydroxylase. Exogenous L-DOPA decarboxylation was accelerated in the striatum of intact and MPTPlesioned mice following acute clozapine, and the effect was exaggerated in the MPTP mice. To identify receptors involved, antagonists of receptors occupied by clozapine were employed. D4, 5-HT1 A , and 5-HT2 A , in addition to D1, D2, and D3, antagonists, augmented AAAD activity in striatum, whereas 5-HT2 C , 5-HT3, muscarinic, and ␣-1 and ␣-2 adrenergic antagonists were ineffective. For the first time, these studies provide evidence that clozapine modulates AAAD activity in the brain and suggests that dopamine and serotonin receptors are involved.Aromatic L-amino acid decarboxylase (AAAD) is a ubiquitous enzyme essential for the formation of catecholamines, indoleamines, and trace amines (Berry et al., 1996). AAAD is not considered to be the rate-limiting enzyme for catecholamine or indoleamine synthesis; however, it is the rate-limiting step for the synthesis of trace amines and becomes rate-limiting for dopamine formation in Parkinson's disease patients treated with L-DOPA. AAAD is a regulated enzyme, and accumulated evidence suggests that its activity in the rodent brain is tuned by short-and long-term mechanisms that apparently involve enzyme activation and induction.Physiological stimuli (Hadjiconstantinou et al., 1988), neurotransmitter receptors (Rossetti et al., 1989(Rossetti et al., , 1990Zhu et al., 1992;Hadjiconstantinou et al., 1993Hadjiconstantinou et al., , 1995Cho et al., 1997;Fisher et al., 1998) and second messenger systems (Young et al., 1998) participate in the regulation of enzyme activity. In nigrostriatal neurons, dopamine appears to regulate AAAD via D1-and D2-like receptors. Indeed, acute blockade of dopamine D1-like receptors with SCH23390 and of dopamine D2-like receptors with haloperidol, ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Clozapine Modulates Aromatic l-Amino Acid Decarboxylase Activity in Mouse Striatum

Neff¹,

Wemlinger²,

Duchemin³

et al. 2006

J Pharmacol Exp Ther

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“…Arai et al (1995) have demonstrated that serotonergic fibers of the striatum, raphe nuclei, and neocortex produce DA after intraperitoneal injection of L-DOPA. The existence of AADC in different types of non-monoaminergic striatal neurons (Hefti et al 1981;Mura et al 1995) and extrastriatal areas of central nervous system (Jaeger et al 1983;Brown et al 1999) has also been reported.…”

Section: Introductionmentioning

confidence: 92%

Long-Term L-DOPA Treatment Causes Indiscriminate Increase in Dopamine Levels at the Cost of Serotonin Synthesis in Discrete Brain Regions of Rats

Borah

Mohanakumar

2007

Cell Mol Neurobiol

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(1) The treatment of choice for Parkinson's disease (PD) is 3,4-dihydroxyphenylalanine (L-DOPA) with peripheral decarboxylase inhibitor, but long-term therapy leads to motor and psychiatric complications. In the present study we investigated 5-hydroxytryptamine (5-HT) and dopamine concentrations in serotonergic and dopaminergic nuclei following chronic administration of L-DOPA to find whether the neurotransmitter synthesis in these brain areas are compensated. (2) Rats were administered L-DOPA (250 mg/kg) and carbidopa (25 mg/kg) daily for 59 and 60 days, and killed on the 60th day, respectively at 24 h and 30 min after the last dose. L-DOPA, norepinephrine, 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), dopamine, homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in striatum, nucleus raphe dorsalis (NRD), nucleus accumbens (NAc), substantia nigra, cerebellum, and cortex employing HPLC-electrochemical procedure. (3) Prolonged treatment of L-DOPA caused depression in the animals as revealed in a forced swim test. Serotonin content was significantly decreased in all brain regions studied 30 min after long-term L-DOPA, except in NAc. The cortex and striatum showed lowered levels of this indoleamine 24 h after 59 doses of L-DOPA. Dopamine, HVA, and DOPAC concentrations were significantly higher in all the regions studied after 30 min, and in the cerebellum after 24 h of L-DOPA. The levels of DOPAC were elevated in all the brain areas studied 24 h after prolonged L-DOPA treatment. (4) The present results suggest that long-term L-DOPA treatment results in significant loss of 5-HT in serotonergic and dopaminergic regions of the brain. Furthermore, while L-DOPA metabolism per se was uninfluenced, dopamine synthesis was severely impaired in all the regions. The imbalance of serotonin and dopamine formation may be the cause of overt cognitive, motor, and psychological functional aberrations seen in parkinsonian patients following prolonged L-DOPA treatment.

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“…The fluctuation of Ddc activity is one of the most important causes leading to the severe side-effects of chronic L-Dopa administration, such as the ''on-off'' phenomenon [10]. Although the exact site of decarboxylation of exogenous levodopa to dopamine in the brain is unknown, striatal neurons which are immunoreactive to L-Dopa decarboxylase (D-neurons) may participate in the efficacy of the pharmacotherapy of Parkinson's disease in the advanced stages [11][12][13][14]. Furthermore, certain types of tumors are characterized by an increase in Ddc activity.…”

Section: Introductionmentioning

confidence: 99%

Detection, Purification and Identification of An Endogenous Inhibitor of l-Dopa Decarboxylase Activity from Human Placenta

Vassiliou

Fragoulis²,

Vassilacopoulou³

2008

Neurochem Res

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An endogenous inhibitor of L-Dopa decarboxylase activity was identified and purified from human placenta. The endogenous inhibitor of L-Dopa decarboxylase (Ddc) was localized in the membrane fraction of placental tissue. Treatment of membranes with phosphatidylinositol-specific phospholipase C or proteinase K did not affect membrane-associated Ddc inhibitory activity, suggesting that a population of the inhibitor is embedded within membranes. Purification was achieved by extraction from a nondenaturing polyacrylamide gel. The purification scheme resulted in the isolation of a single 35 kDa band, bearing L-Dopa decarboxylase inhibitory activity. The purified inhibitor was identified as Annexin V. The elucidation of the biological importance of the presence of an L-Dopa decarboxylase activity inhibitor in normal human tissues could provide us with new information leading to the better understanding of the biological pathways that Ddc is involved in.

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Aromaticl-amino acid decarboxylase immunoreactive cells in the rat striatum: a possible site for the conversion of exogenousl-DOPA to dopamine

Cited by 108 publications

References 39 publications

Clozapine Modulates Aromatic l-Amino Acid Decarboxylase Activity in Mouse Striatum

Clozapine Modulates Aromatic l-Amino Acid Decarboxylase Activity in Mouse Striatum

Long-Term L-DOPA Treatment Causes Indiscriminate Increase in Dopamine Levels at the Cost of Serotonin Synthesis in Discrete Brain Regions of Rats

Detection, Purification and Identification of An Endogenous Inhibitor of l-Dopa Decarboxylase Activity from Human Placenta

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