Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Behavioral effects of a dopamine uptake inhibitor, GBR-12909 (GBR), were evaluated by ambulatory activity in mice. The single administration of over 10 mg/kg of GBR, i.p. and p.o., significantly increased the ambulatory activity. The repeated administration of GBR, at only 10 mg/kg, produced a reverse tolerance to its ambulation-increasing effect. However, a cross-reverse tolerance was induced between GBR (10 and 20 mg/kg) and methamphetamine (2 mg/kg) in both directions. Furthermore, 5 mg/kg of GBR significantly enhanced the effects of methamphetamine, cocaine, imipramine, morphine, scopolamine and caffeine. R-THBP, a coenzyme of tyrosine hydroxylase, also enhanced the effect of GBR. In contrast, the ambulation-increasing effect of 10 mg/kg of GBR was markedly reduced by haloperidol, chlorpromazine, tetrabenazine, oxypertine, reserpine and alpha-methyl-p-tyrosine. On the other hand, the effect of GBR was only slightly and/or scarcely modified by apomorphine, caerulein, physostigmine, pilocarpine, N6-(L-2-phenylisopropyl)-adenosine and naloxone. The neurochemical experiment in rats, not in mice, revealed that GBR possessed more dominant action on dopaminergic systems than noradrenergic or serotonergic systems. However, the behavioral characteristics of GBR are similar to those of methamphetamine and cocaine, which possess less selective action than GBR on dopaminergic and noradrenergic systems.
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PMID:Characteristics of the ambulation-increasing effect of GBR-12909, a selective dopamine uptake inhibitor, in mice. 183 99

The cerebral free amino acids in neonatal rats, from dams given 0.04% caffeine in the drinking fluid ad libitum before and/or during pregnancy throughout the lactational period, were examined on days 1, 5 and 10. Significantly reduced cerebral weight was observed on day 1 with a mean caffeine level of 7 micrograms/g wet weight. The tyrosine concentration in the cerebrum, but not that in the liver, was increased on days 1 and 5 with approximate mean caffeine levels of above 1.5-2.0 micrograms/g wet weight. The tyrosine level showed a positive correlation with the caffeine level in neonatal cerebrum only on day 1 in the group with caffeine ingestion after pregnancy. There was no significant increase in the fetal cerebral concentration of MOPEG-SO4 on day 5 with maternal caffeine. These results suggest that maternal caffeine disturbs the neonatal cerebrum through tyrosine and tyrosine hydroxylase, and then produces behavioral abnormalities in developing rats.
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PMID:Maternal caffeine ingestion increases the tyrosine level in neonatal rat cerebrum. 231 Jul 91

The effects of caffeine on the activity of central and peripheral catecholaminergic structures have been studied in rats ingesting high doses of caffeine. The activities of the enzymes tyrosine hydroxylase and dopamine-beta-hydroxylase were measured as well as 3,4-dihydroxyphenylethylamine (dopamine), adrenaline, and noradrenaline concentrations, in brain (striatum and hypothalamus), heart, and adrenal gland. At the peripheral level, we observed a significant increase in the dopamine and adrenaline plus noradrenaline content in the heart, but an increase in dopamine content only was found in the adrenal gland. Dopamine-beta-hydroxylase activity in serum was increased, but the only significant enzymic change in brain was an increase in the dopamine-beta-hydroxylase activity of the hypothalamus. However, an increase in catecholamine content was observed in both structures of the brain. These data suggest that the mechanisms involved in caffeine-induced self-biting in rats are not limited to the dopaminergic system, because we have also observed an increase in noradrenaline turnover.
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PMID:Caffeine ingestion by rats increases noradrenaline turnover and results in self-biting. 287 91

Methamphetamine (METH)-induced neurotoxicity to nigrostriatal dopaminergic neurons in experimental animals appears to have a glutamatergic component because blockade of N-methyl-D-aspartate receptors prevents the neuropathologic consequences. Because adenosine affords neuroprotection against various forms of glutamate-mediated neuronal damage, the present studies were performed to investigate whether adenosine plays a protective role in METH-induced toxicity. METH-induced decrements in neostriatal dopamine content and tyrosine hydroxylase activity in mice were potentiated by concurrent treatment with caffeine, a nonselective adenosine antagonist that blocks both A1 and A2 adenosine receptors. In contrast, chronic treatment of mice with caffeine through their drinking water for 4 weeks, which increased the number of adenosine A1 receptors in the neostriatum and frontal cortex, followed by drug washout, prevented the neurochemical changes produced by the treatment of mice with METH treatment. In contrast, this treatment did not prevent 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-induced dopaminergic neurotoxicity. Furthermore, concurrent administration of cyclopentyladenosine, an adenosine A1 receptor agonist, attenuated the METH-induced neurochemical changes. This protection by cyclopentyladenosine was blocked by cyclopentyltheophylline, an A1 receptor antagonist. These results indicate that activation of A1 receptors can protect against METH-induced neurotoxicity in mice.
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PMID:Protection against methamphetamine-induced neurotoxicity to neostriatal dopaminergic neurons by adenosine receptor activation. 799 41

In the present study we assessed the effect of chronic treatment with caffeine on the levels of the messenger RNA molecule encoding the enzyme tyrosine hydroxylase (TH) by in situ hybridization histochemistry in the ventral tegmental area (VTA) and the substantia nigra compacta (SNc) of the rat brain. Animals that received caffeine for nine consecutive days at doses of 20, 40 and 80 mg/kg of body weight displayed increased TH mRNA levels in the SNc (up to 64% above vehicle-injected controls) and the VTA (33% above controls). Moreover, the increases observed at 80 mg/kg of caffeine were prevented by concurrent administration of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (0.25 mg/kg). These results demonstrate that chronic exposure to caffeine, an adenosine A2 receptor antagonist, alters the levels of expression of the mRNA encoding the rate limiting enzyme in catecholamine biosynthesis.
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PMID:Accumulation of tyrosine hydroxylase messenger RNA molecules in the rat mesencephalon by chronic caffeine treatment. 898 77

We sought neurochemical correlates to the stimulatory action of caffeine in rats and to adaptations during development of tolerance. Acute intraperitoneal injections of caffeine (7.5 mg/kg) increased locomotion and NGFI-A mRNA, a marker of neuronal activity, in the hippocampal area CA1, but decreased NGFI-A mRNA in rostral striatum and nucleus accumbens. Rats that received caffeine (0.3 gm/l) in their drinking water for 14 d developed tolerance to the stimulatory effect of a challenge with caffeine (7.5 mg/kg) and responded with a less pronounced decrease of NGFI-A mRNA in rostral striatum and nucleus accumbens. Metabolism of caffeine to its active metabolites was increased in tolerant animals, but the total level of active metabolites in brain was not significantly altered. Thus, there are changes in caffeine metabolism after long-term caffeine treatment, but they cannot explain development of tolerance. Caffeine-tolerant animals had downregulated levels of adenosine A2A receptors and the corresponding mRNA in rostral parts of striatum, but an increased expression of adenosine A1 receptor mRNA in the lateral amygdala. No changes in mesencephalic tyrosine hydroxylase mRNA were found in caffeine-tolerant rats. Thus, we have identified neuronal pathways that are regulated by adenosine A1 and/or A2A receptors and are targets for the stimulatory action of caffeine. Furthermore, adaptive changes in gene expression in these brain areas were associated with the development of locomotor tolerance to caffeine.
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PMID:The stimulatory action and the development of tolerance to caffeine is associated with alterations in gene expression in specific brain regions. 1023 30

Adenosine and caffeine modulate locomotor activity and striatal gene expression, partially through the activation and blockade of striatal A(2A) receptors, respectively. The elucidation of the roles of these receptors benefits from the construction of A(2A) receptor-deficient mice (A(2A)-R(-/-)). These mice presented alterations in locomotor behaviour and striatal expression of genes studied so far, which are unexpected regarding the specific expression of A(2A) receptor by striatopallidal neurones. To clarify the functions of A(2A) receptors in the striatum and to identify the mechanisms leading to these unexpected modifications, we studied the basal expression of immediate early and constitutive genes as well as dopamine and glutamate neurotransmission in the striatum. Basal zif268 and arc mRNAs expression was reduced in mutant mice by 60-80%, not only in the striatum but also widespread in the cerebral cortex and hippocampus. Striatal expression of substance P and enkephalin mRNAs was reduced by about 50% and 30%, respectively, whereas the expression of GAD67 and GAD65 mRNAs was slightly increased and unaltered, respectively. In vivo microdialysis in the striatum revealed a 45% decrease in the extracellular dopamine concentration and three-fold increase in extracellular glutamate concentration. This was associated with an up-regulation of D(1) and D(2) dopamine receptors expression but not with changes in ionotropic glutamate receptors. The levels of tyrosine hydroxylase and of striatal and cortical glial glutamate transporters as well as adenosine A(1) receptors expression were indistinguishable between A(2A)-R(-/-) and wild-type mice. Altogether these results pointed out that the lack of A(2A) receptors leads to a functional hypodopaminergic state and demonstrated that A(2A) receptors are necessary to maintain a basal level in immediate early and constitutive genes expression in the striatum and cerebral cortex, possibly via their control of dopamine pathways.
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PMID:Functional striatal hypodopaminergic activity in mice lacking adenosine A(2A) receptors. 1143 85

The ability of caffeine-induced store Ca(2+) mobilization to activate tyrosine hydroxylase was studied in bovine adrenal chromaffin cells. Caffeine increased tyrosine hydroxylase activity over 10 min with an EC(50) of 3 mm and maximum effect at 20 mm. The maximum response to caffeine was substantial, being almost one third that of the strongest agonists acetylcholine and PACAP-27, about half that for K(+) and similar to that for histamine. In contrast, catecholamine secretion evoked by caffeine was small, being less than 10% of the response to strong agonists. Caffeine-induced tyrosine hydroxylase activation was not mimicked or prevented by phosphodiesterase inhibition with isobutylmethylxanthine, nor was it mimicked by an equimolar concentration of sucrose. However, the effect of caffeine was prevented by depleting intracellular Ca(2+) stores by thapsigargin pretreatment, and reduced substantially by removing extracellular Ca(2+), by blocking Ca(2+) channels with Co(2+) or Ni(2+), or by inhibiting store-operated channels with 2-aminoethyl diphenylborate. It was not affected by inhibiting Ca(2+) entry through voltage-operated Ca(2+)-channels or by tetrodotoxin. The effect of caffeine was mimicked by acute thapsigargin treatment or by depleting intracellular Ca(2+) stores in Ca(2+)-free buffer and then reintroducing extracellular Ca(2+). The results indicate that mobilizing store Ca(2+) with caffeine is a very effective mechanism for activating tyrosine hydroxylase and that the majority of this response depends on extracellular Ca(2+) entry through store-operated channels. They also suggest that extracellular Ca(2+) entry through such channels regulates cellular responses differently to Ca(2+) entry through voltage-operated Ca(2+) channels.
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PMID:Caffeine stimulates Ca(2+) entry through store-operated channels to activate tyrosine hydroxylase in bovine chromaffin cells. 1202 58

In Parkinson's disease (PD), the striatal dopamine depletion and the following overactivation of the indirect pathway of the basal ganglia leads to very early disinhibition of the subthalamic nucleus (STN) that may contribute to the progression of PD by glutamatergic overstimulation of the dopaminergic neurons in the substantia nigra. Adenosine A2A antagonism has been demonstrated to attenuate the overactivity of the striatopallidal pathway. To investigate whether neuroprotection exerted by the A2A antagonist 8-(3-chlorostyryl)caffeine (CSC) correlates with a diminution of the striatopallidal pathway activity, we have examined the changes in the mRNA encoding for enkephalin, dynorphin, and adenosine A2A receptors by in situ hybridization induced by subacute systemic pretreatment with CSC in rats with striatal 6-hydroxydopamine(6-OHDA) administration. Animals received CSC for 7 days until 30 min before 6-OHDA intrastriatal administration. Vehicle-treated group received a solution of dimethyl sulfoxide. CSC pretreatment partially attenuated the decrease in nigral tyrosine hydroxylase immunoreactivity induced by 6-OHDA, whereas no modification of the increase in preproenkephalin mRNA expression in the dorsolateral striatum was observed. The neuroprotective effect of the adenosine A2A antagonist CSC in striatal 6-OHDA-lesioned rats does not result from a normalization of the increase in striatal PPE mRNA expression in the DL striatum, suggesting that other different mechanisms may be involved.
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PMID:Neuroprotection induced by the adenosine A2A antagonist CSC in the 6-OHDA rat model of parkinsonism: effect on the activity of striatal output pathways. 1596 57

A large portion of the central catecholaminergic nerve terminals of the rat are destroyed by administering 6-hydroxydopamine (6-HDA) via the cerebrospinal fluid. Animals lesioned in this way often appear normal, yet show many subtle behavioural abnormalities. We have been examining one example of this phenomenon, the failure of 6-HDA-lesioned rats to increase food intake when given a systemic injection of 2-deoxy-D-glucose (2-DG) (refs 5, 6). This glucose analogue seems to elicit feeding in intact rats due to its inhibition of glycolysis in cerebral chemoreceptor cells. We have proposed that lesioned animals do not eat because of an insufficient central catecholaminergic response to the severe decrease in glucose utilisation induced by 2-DG (ref. 10). If so, then pretreatments which serve to augment this neurochemical response might be expected to reinstate behavioural function. Consistent with this hypothesis, very large increases in telencephalic tyrosine hydroxylase activity in 6-HDA-lesioned animals, which occur following chronic insulin treatment, are associated with the restoration of 2-DG-induced feeding. Many of the physiological effects of catecholamines in the sympathetic nervous system seem to be mediated by an increase in the cyclic AMP concentration of the target cells. Methylxanthenes, such as caffeine and theophylline, inhibit phosphodiesterase, prevent cyclic AMP degradation, and thereby potentiate the catecholamine-stimulated rise in cyclic nucleotide. They also enhance many of the behavioural and physiological effects of catecholamines, presumably by the same mechanism. We therefore sought to determine whether the acute administration of those sympathomimetic agents, in intact and 6-HDA-lesioned rats, also would potentiate 2-DG-induced feeding, a behaviour that seems to be mediated, in part, by central catecholaminergic neurons. We report that caffeine restores the 2-DG-induced feeding response.
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PMID:Caffeine restores feeding response to 2-deoxy-D-glucose in 6-hydroxydopamine-treated rats. 1607 37


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