The antiparkinsonian drug budipine stimulates the activity of aromatic L-amino acid decarboxylase and enhances L-DOPA-induced dopamine release in rat substantia nigra

Biggs, C.S.; Fisher, Andrew; Starr, Michael S.

doi:10.1002/(sici)1098-2396(199811)30:3<309::aid-syn8>3.0.co;2-f

Cited by 8 publications

(3 citation statements)

References 40 publications

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“…In the same line, PET studies measuring 18 F‐L‐DOPA uptake have shown suppressed AAAD activity in the ventral striatum of drug‐free schizophrenics, which is increased with typical or atypical antipsychotic treatment [38]. Finally, depletion of dopamine by reserpine increases AAAD activity in striatum [7,39,40].…”

Section: Receptors and Regulation Of Striatal Aaadmentioning

confidence: 99%

“…Notwithstanding, in vivo dialysis studies investigating the effect of NMDA receptor blockade on L‐DOPA decarboxylation in reserpine treated and 6‐OHDA‐lesioned rats have provided in general supportive results. Systemic administration or local infusion of budipine markedly increases the magnitude and duration of L‐DOPA‐stimulated dopamine release in the striatum and substantia nigra of rats treated with reserpine [39,40,54], and AAAD inhibition blocks the response [40]. Likewise, systemic administration of MK‐801 or amantadine enhances the L‐DOPA‐induced dopamine release in the 6‐OHDA denervated striatum [65,66].…”

Section: Aaad Activity and L‐dopa Decarboxylation In Pd Modelsmentioning

confidence: 99%

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Enhancing Aromatic L‐amino Acid Decarboxylase Activity: Implications for L‐DOPA Treatment in Parkinson's Disease

Hadjiconstantinou

Neff

2008

CNS Neuroscience & Therapeutics

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Aromatic L-amino acid decarboxylase (AAAD) is an essential enzyme for the formation of catecholamines, indolamines, and trace amines. Moreover, it is a required enzyme for converting L-DOPA to dopamine when treating patients with Parkinson's disease (PD). There is now substantial evidence that the activity of AAAD in striatum is regulated by activation and induction, and second messengers play a role. Enzyme activity can be modulated by drugs acting on a number of neurotransmitter receptors including dopamine (D1-4), glutamate (NMDA), serotonin (5-HT(1A), 5-HT(2A)) and nicotinic acetylcholine receptors. Generally, antagonists enhance AAAD activity; while, agonists may diminish it. Enhancement of AAAD activity is functional, as the formation of dopamine from exogenous L-DOPA mirrors activity. Following a lesion of nigrostriatal dopaminergic neurons, AAAD in striatum responds more robustly to pharmacological manipulations, and this is true for the decarboxylation of exogenous L-DOPA as well. We review the evidence for parallel modulation of AAAD activity and L-DOPA decarboxylation and propose that this knowledge can be exploited to optimize the formation of dopamine from exogenous L-DOPA. This information can be used as a blue print for the design of novel L-DOPA treatment adjuvants to benefit patients with PD.

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Section: Receptors and Regulation Of Striatal Aaadmentioning

confidence: 99%

Section: Aaad Activity and L‐dopa Decarboxylation In Pd Modelsmentioning

confidence: 99%

Enhancing Aromatic L‐amino Acid Decarboxylase Activity: Implications for L‐DOPA Treatment in Parkinson's Disease

Hadjiconstantinou

Neff

2008

CNS Neuroscience & Therapeutics

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“…There is evidence that particular psychostimulants, such as dexamphetamine and cocaine, differentially affect these two pools (1)(2)(3). When reserpine and/or AMPT are used to study the role of these distinct pools on drug-induced effects, they are given systemically (4)(5)(6)(7)(8). It is unknown whether or not these agents are also effective when administered locally.…”

Section: Introductionmentioning

confidence: 99%

Effects of alpha-methyl-p-tyrosine on extracellular dopamine levels in the nucleus accumbens and the dorsal striatum of freely moving rats

et al. 2005

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Alpha-methyl-p-tyrosine (AMPT) is known to inhibit the formation of dopamine (DA) in the cytosol of dopaminergic neurons and is therefore used to study the role of the cytosolic DA pools. AMPT is usually administered systemically. In the present study, however, the effects of locally infused AMPT on the efflux of DA from the nucleus accumbens and dorsal striatum were analyzed, using in vivo brain microdialysis in unanesthetized rats. The administration of AMPT (100 microM, 4 h) into the nucleus accumbens reduced accumbal DA output to 30% of its baseline level. When it was infused into the dorsal striatum, however, it reduced striatal DA output to 60% of its baseline level. At first sight, these data suggest that the amount of DA available from the AMPT-sensitive pool is larger in the nucleus accumbens than in the striatum. However, this cannot be the case, as the decrease in accumbal and striatal DA efflux induced by systemic administration of AMPT (250 mg/kg given intra-peritoneally) was identical. These results show that local infusion of AMPT is a valuable tool for analyzing the role of AMPT-sensitive pools within a particular brain area, but it cannot be used to compare effects across different brain structures because a fixed dose of AMPT differentially affected the nucleus accumbens and the dorsal striatum.

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Microdialysis study of the effects of the antiparkinsonian drug budipine onL-DOPA-induced release of dopamine and 5-hydroxytryptamine by rat substantia nigra and corpus striatum

Biggs

Starr

1999

Synapse

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The purpose of this study was to determine if systemic treatment with the antiparkinsonian drug budipine was capable of influencing the release of dopamine newly synthesised from L-DOPA in the substantia nigra and corpus striatum of the monoamine-depleted rat. Dual probe microdialysis was therefore employed in freely moving animals pretreated with reserpine (4 mg/kg i.p. 18-20 h earlier) and alpha-methyl-p-tyrosine (200 mg/kg i.p. 45 min earlier). Budipine (10 mg/kg i.p.) alone evoked a small but significant increase in basal dopamine efflux in nigra, though not in striatum, but did not affect the spontaneous outputs of DOPAC, 5-HT, or 5-HIAA in either structure. A threshold amount of L-DOPA (25 mg/kg i.p.) stimulated the release of dopamine, DOPAC, and 5-HT (but not 5-HIAA), both in nigra and striatum. The L-DOPA-induced releases of dopamine and DOPAC were greatly accentuated by pretreatment with budipine (10 mg/kg i.p. 45 min earlier), which delayed rather than potentiated the nigral and striatal effluxes of 5-HT. A higher dose of L-DOPA (100 mg/kg i.p.) did not significantly raise the outputs of dopamine or 5-HT, but greatly magnified that of DOPAC. In these experiments, pretreatment with budipine (10 mg/kg i.p.) facilitated the formation of DOPAC from L-DOPA, without increasing the extracellular concentration of dopamine. We conclude from these findings that budipine, at a therapeutically relevant dose, potentiates the release of dopamine newly synthesised from L-DOPA from either end of the nigrostriatal dopamine axis. This effect of budipine could be related to the drug's recently described ability to increase the activity of the converting enzyme, aromatic L-amino acid decarboxylase, and could explain the clinical efficacy of budipine as an adjunct to L-DOPA therapy of Parkinson's disease in man. The significance of 5-HT release to the antiparkinsonian L-DOPA, and the delay in this release caused by budipine, remain to be established.

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The antiparkinsonian drug budipine stimulates the activity of aromatic L-amino acid decarboxylase and enhances L-DOPA-induced dopamine release in rat substantia nigra

Cited by 8 publications

References 40 publications

Enhancing Aromatic L‐amino Acid Decarboxylase Activity: Implications for L‐DOPA Treatment in Parkinson's Disease

Enhancing Aromatic L‐amino Acid Decarboxylase Activity: Implications for L‐DOPA Treatment in Parkinson's Disease

Effects of alpha-methyl-p-tyrosine on extracellular dopamine levels in the nucleus accumbens and the dorsal striatum of freely moving rats

Microdialysis study of the effects of the antiparkinsonian drug budipine onL-DOPA-induced release of dopamine and 5-hydroxytryptamine by rat substantia nigra and corpus striatum

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