In vivo enhancement of tyrosine hydroxylation in rat striatum by tetrahydrobiopterin

Kettler, R.; Bartholini, G.; Pletscher, A.

doi:10.1038/249476a0

Cited by 176 publications

(57 citation statements)

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“…The availability of the co-factor for tyrosine hydroxylase, tetrahydrobiopterin, has been shown to be a limiting factor for catecholamine synthesis in brain (Kettler, Bartholini & Pletscher, 1974). It was thus of interest in our experiments to determine whether exogenous co-factor would modify the synthesis of catecholamines in the carotid body.…”

Section: Methodsmentioning

confidence: 99%

Catecholamine synthesis in rabbit carotid body in vitro

Fidone

González

1982

The Journal of Physiology

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Section: Methodsmentioning

confidence: 99%

Catecholamine synthesis in rabbit carotid body in vitro

Fidone

González

1982

The Journal of Physiology

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“…Intraventricular administration of BH4 increases the biosynthesis of dopamine in nigrostriatal neurons (Kettler et al, 1974). Moreover, patients with Parkinson's disease and dementia not only have reduced levels of dopamine but also reduced levels of BH4.…”

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confidence: 99%

Involvement of α7 Nicotinic Acetylcholine Receptors in Gene Expression of Dopamine Biosynthetic Enzymes in Rat Brain

Serova

Sabban

2002

J Pharmacol Exp Ther

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Brain dopaminergic systems are critical in mediating the physiological responses to nicotine. The effects of several concentrations of nicotine (0.08, 0.17, or 0.33 mg/kg body weight) and involvement of ␣7 nicotinic acetylcholine receptors (nAChRs) in gene expression of key enzymes in dopamine biosynthesis were evaluated in the ventral tegmental area (VTA) and substantia nigra (SN), cell bodies of the mesocorticolimbic and nigrostriatal pathways. Nicotine elicited a dose-dependent elevation of mRNA for tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis in VTA and SN. The VTA was more sensitive to lower concentrations of nicotine with maximal response observed with the lowest dose of nicotine. Nicotine also elevated mRNA levels of GTP cyclohydrolase I (GTPCH), rate limiting in biosynthesis of TH's essential cofactor tetrahydrobiopterin in both dopaminergic locations. The changes in TH and GTPCH mRNAs were correlated. Pretreatment with the ␣7 nAChR antagonist methyllycaconitine prevented the nicotine-induced rise in TH or GTPCH mRNA in VTA and SN. Administration of ␣7 nAChR agonist 3-[2,4-dimethoxybenzilidene]anabaseine at 1 to 10 mg/kg or (E,E-3-(cinnamylidene)anabaseine at 0.3 to 1 mg/kg increased TH mRNA in VTA and SN, but not in peripheral catecholaminergic cells. Thus, agonists of ␣7 nAChRs have therapeutic potential for increasing TH gene expression in dopaminergic regions without some of nicotine's disadvantages, such as its harmful effects on the cardiovascular system. The findings indicate that nicotine may regulate dopamine biosynthesis by alterations in gene expression of TH and its cofactor. The ␣7 nAChRs are involved in mediating these effects of nicotine.Catecholaminergic systems are critical in mediating the physiological effects of nicotine. The self-administering and reinforcing properties of nicotine seem to arise from direct action on the mesocorticolimbic dopamine system. This system, with cell bodies in VTA, plays a key role in mediating the reinforcing effects of natural rewards as well as of drugs of abuse, including nicotine, through increased dopaminergic transmission in the nucleus accumbens. The nigrostriatal dopaminergic system, with cell bodies in the SN, innervates the caudate nucleus and putamen of the corpus striatum. Activation of striatal neuronal acetylcholine receptors (nAChRs) triggers release of dopamine. These receptors are also involved in mediating nicotine's effects on locomotion.

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“…Several lines of evidence suggest that H4B is present in concentrations substantially less than Km for TyrOase in monoaminergic neurons. The administration of exogenous cofactor results in enhanced hydroxylation in rat striatum in vivo (7), in cultures of sympathetic neurons (8), in striatal synaptosomes (9), and in the isolated hypogastric nerve-vas deferens preparation (10,11). A second line of evidence is the increase in dopamine synthesis produced by cyclic AMP or stimulation of catecholaminergic terminals that apparently is the result of the increased affnity of TyrOase for the pterin cofactor (12)(13)(14)(15).…”

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confidence: 99%

Tetrahydrobiopterin increases in adrenal medulla and cortex: a factor in the regulation of tyrosine hydroxylase.

Abou‐Donia¹,

Viveros²

1981

Proc. Natl. Acad. Sci. U.S.A.

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Tetrahydrobiopterin, the cofactor for tyrosine hydroxylase and other monooxygenases, is present in tissues at apparent concentrations much less than those necessary to saturate the corresponding enzymes. Reserpine treatment or insulininduced hypoglycemia in rats produces a statistically significant increase in the tetrahydrobiopterin content of both the adrenal medulla and the cortex. Adrenal denervation and hypophysectomy selectively block the increases in cofactor level in medulla and cortex, respectively, while cycloheximide prevents the increase in both tissues. Reserpine did not increase cofactor levels in liver, kidney, or corpus striatum but decreased that of the pineal gland. These results suggest that tetrahydrobiopterin is under neural control in the medulla and hormonal control in the cortex and that increases in cofactor may result from induction ofenzyme(s) in the biosynthetic pathway. These results demonstrate regulation of tissue tetrahydrobiopterin and are consistent with the suggestion that cofactor levels participate in the regulation of tyrosine hydroxylase in the adrenal medulla and may have a function, as yet undetermined, in the adrenal cortex.L-erythro-5,6,7,8-tetrahydrobiopterin (H4B) is an essential cofactor for tyrosine 3-monooxygenase [TyrOase; tyrosine hydroxylase; L-tyrosine, tetrahydropteridine:oxygen oxido reductase (3-hydroxylating); EC 1.14.16.2] (1), the rate-limiting enzyme in the biosynthesis ofthe neurotransmitters dopamine, norepinephrine, and epinephrine (2). There is considerable evidence for the short-term regulation oftyrosine hydroxylation by a decrease in the Km of TyrOase for its cofactor, H4B (for recent reviews, see refs. 3 and 4). Delayed or long-term regulation of tyrosine hydroxylation and catecholamine synthesis is obtained by increased synthesis ofTyrOase, dopamine-,B-hydroxylase, and catecholamine storage vesicles (5, 6). Several lines of evidence suggest that H4B is present in concentrations substantially less than Km for TyrOase in monoaminergic neurons. The administration of exogenous cofactor results in enhanced hydroxylation in rat striatum in vivo (7), in cultures of sympathetic neurons (8), in striatal synaptosomes (9), and in the isolated hypogastric nerve-vas deferens preparation (10, 11). A second line of evidence is the increase in dopamine synthesis produced by cyclic AMP or stimulation of catecholaminergic terminals that apparently is the result of the increased affnity of TyrOase for the pterin cofactor (12-15). Finally, induction ofrat hypothalamus TyrOase by reserpine administration failed to enhance tyrosine hydroxylation in synaptosomes prepared from this tissue (16) unless exogenous H4B was added to the incubation medium (17). Although regulation of monoamine synthesis through changes in the availability of reduced biopterin has been proposed (18), there is no experimental evidence for physiological regulation of endogenous cofactor levels. The long-term regulation of catecholamine synthesis could create a paradoxical situation if t...

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In vivo enhancement of tyrosine hydroxylation in rat striatum by tetrahydrobiopterin

Cited by 176 publications

References 10 publications

Catecholamine synthesis in rabbit carotid body in vitro

Catecholamine synthesis in rabbit carotid body in vitro

Involvement of α7 Nicotinic Acetylcholine Receptors in Gene Expression of Dopamine Biosynthetic Enzymes in Rat Brain

Tetrahydrobiopterin increases in adrenal medulla and cortex: a factor in the regulation of tyrosine hydroxylase.

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