Striatal Tyrosine Hydroxylase Activity Research Articles

Blood phenylalanine reduction corrects CNS dopamine and serotonin deficiencies and partially improves behavioral performance in adult phenylketonuric mice.

Central nervous system (CNS) deficiencies of the monoamine neurotransmitters dopamine and serotonin have been implicated in the pathophysiology of neuropsychiatric dysfunction in human phenylketonuria (PKU). In this study, we confirmed the occurrence of brain dopamine and serotonin deficiencies in association with severe behavioral alterations and cognitive impairments in hyperphenylalaninemic C57BL/6-Pahenu2/enu2 mice, a model of human PKU. Phenylalanine-reducing treatments, including either dietary phenylalanine restriction or liver-directed gene therapy, initiated during adulthood were associated with increased brain monoamine content along with improvements in nesting behavior but without a change in the severe cognitive deficits exhibited by these mice. At euthanasia, there was in Pahenu2/enu2 brain a significant reduction in the protein abundance and maximally stimulated activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2), the rate limiting enzymes catalyzing neuronal dopamine and serotonin synthesis respectively, in comparison to levels seen in wild type brain. Phenylalanine-reducing treatments initiated during adulthood did not affect brain TH or TPH2 content or maximal activity. Despite this apparent fixed deficit in striatal TH and TPH2 activities, initiation of phenylalanine-reducing treatments yielded substantial correction of brain monoamine neurotransmitter content, suggesting that phenylalanine-mediated competitive inhibition of already constitutively reduced TH and TPH2 activities is the primary cause of brain monoamine deficiency in Pahenu2 mouse brain. We propose that CNS monoamine deficiency may be the cause of the partially reversible adverse behavioral effects associated with chronic HPA in Pahenu2 mice, but that phenylalanine-reducing treatments initiated during adulthood are unable to correct the neuropathology and attendant cognitive deficits that develop during juvenile life in late-treated Pahenu2/enu2 mice.

Evidence for a receptor-mediated feedback control of striatal tyrosine hydroxylase activity.

Journal Article Evidence for a receptor-mediated feedback control of striatal tyrosine hydroxylase activity Get access Wolfgang Kehr, Wolfgang Kehr Department of Pharmacology, University of Göteborg, Fack, S-400 33 Göteborg 33, Sweden Search for other works by this author on: Oxford Academic Google Scholar Arvid Carlsson, Arvid Carlsson Department of Pharmacology, University of Göteborg, Fack, S-400 33 Göteborg 33, Sweden Search for other works by this author on: Oxford Academic Google Scholar Margit Lindqvist, Margit Lindqvist Department of Pharmacology, University of Göteborg, Fack, S-400 33 Göteborg 33, Sweden Search for other works by this author on: Oxford Academic Google Scholar Tor Magnusson, Tor Magnusson Department of Pharmacology, University of Göteborg, Fack, S-400 33 Göteborg 33, Sweden Search for other works by this author on: Oxford Academic Google Scholar Colin Atack Colin Atack Department of Pharmacology, University of Göteborg, Fack, S-400 33 Göteborg 33, Sweden Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 24, Issue 9, September 1972, Pages 744–747, https://doi.org/10.1111/j.2042-7158.1972.tb09104.x Published: 12 April 2011 Article history Received: 30 June 1972 Published: 12 April 2011

Traumatic brain injury reduces striatal tyrosine hydroxylase activity and potassium-evoked dopamine release in rats

There is increasing evidence that traumatic brain injury (TBI) induces hypofunction of the striatal dopaminergic system, the mechanisms of which are unknown. In this study, we analyzed the activity of striatal tyrosine hydroxylase (TH) in rats at 1day, 1week, and 4weeks after TBI using the controlled cortical impact model. There were no changes in the level of TH phosphorylated at serine 40 site (pser40TH) at 1day or 4weeks. At 1week, injured animals showed decreased pser40TH to 73.9±7.3% (p≤0.05) of sham injured rats. The in vivo TH activity assay showed no significant difference between injured and sham rats at 1day. However, there was a decreased activity in injured rats to 62.1±8.2% (p≤0.05) and 68.8±6.2% (p≤0.05) of sham injured rats at 1 and 4weeks, respectively. Also, the activity of protein kinase A, which activates TH, decreased at 1week (injured: 87.8±2.8%, sham: 100.0±4.2%, p≤0.05). To study the release activity of dopamine after injury, potassium (80mM)-evoked dopamine release was measured by microdialysis in awake, freely moving rats. Dialysates were collected and analyzed by high-performance liquid chromatography. There were no significant differences in dopamine release at 1day and 4weeks between sham and injured groups. At 1week, there was a significant decrease (injured: 0.067±0.015μM, sham: 0.127±0.027μM, p≤0.05). These results suggest that TBI-induced dopamine neurotransmission deficits are, at least in part, attributable to deficits in TH activity.

Subthalamic stimulation increases striatal tyrosine hydroxylase phosphorylation

Subthalamic stimulation enhances striatal tyrosine hydroxylase activity, which is regulated by phosphorylation at different serine residues. Western blotting was performed to investigate phosphorylation at the serine residues 19, 31 and 40 in striatal tissue of rats that had received subthalamic stimulation or sham stimulation for 2 h. In animals that were killed directly after stimulation, the tyrosine hydroxylase protein content was unchanged, whereas phosphorylation at the serine residue 19 was increased and phosphorylation at the serine residues 31 and 40 tended to be higher compared with controls. By contrast, tyrosine hydroxylase protein content and phosphorylation were similar in rats that were killed 24 h after stimulation. Our results suggest that subthalamic stimulation may increase tyrosine hydroxylase activity via increased phosphorylation.

Dopamine and serotonin metabolism in response to chronic administration of fluvoxamine and haloperidol combined treatment

Treating primary 'negative symptoms' of schizophrenia with a combination of a typical antipsychotic and a selective serotonin reuptake inhibitor, is more effective than with antipsychotic alone and is similar to the effect of the atypical antipsychotic, clozapine. The mechanism of this treatment combination is unknown and may involve changes in dopaminergic and serotonin systems. We studied dopamine and serotonin metabolism in different rat brain areas at 1.5 and 24 h after the last dosage of chronic treatment (30 days), with haloperidol plus fluvoxamine, each drug alone, and clozapine. Haloperidol-fluvoxamine combination, haloperidol, and clozapine treatments increased striatal and frontal cortex dopamine turnover and reduced striatal tyrosine hydroxylase activity at 1.5 h. At 24 h both dopamine turnover and tyrosine hydroxylase activity were reduced. Thus, in chronically treated animals, release of striatal dopamine increases following a drug pulse and returns to baseline by 24 h. Serotonin and 5-hydroxyindoleacetic acid concentrations were decreased at 1.5 h in haloperidol-fluvoxamine and clozapine groups and returned to normal levels by 24 h. A limited behavioral assessment showed that treatment with haloperidol plus fluvoxamine reduced motor activity compared to haloperidol, and increased sniffing compared to haloperidol, fluvoxamine and clozapine. These findings indicate that combining antipsychotic with SSRI results in specific changes in dopaminergic and serotonergic systems and in behavior. The possibility that these may be relevant to the mechanism underlying the clinical effectiveness of augmentation treatment warrant further study.

Reduced tyrosine hydroxylase and GTP cyclohydrolase mRNA expression, tyrosine hydroxylase activity, and associated neurochemical alterations in Nurr1-null heterozygous mice

The nuclear receptor Nurr1 is essential for the development of midbrain dopamine neurons and appears to be an important regulator of dopamine levels as adult Nurr1-null heterozygous (+/−) mice have reduced mesolimbic/mesocortical dopamine levels. The mechanism(s) through which reduced Nurr1 expression affects dopamine levels has not been determined. Quantitative real-time PCR revealed a significant reduction in tyrosine hydroxylase (TH) and GTP cyclohydrolase (GTPCH) mRNA in ventral midbrain of +/− mice as compared to wild-type mice (+/+). The effect on TH expression was only observed at birth, while reduced GTP cyclohydrolase was also observed in the adult ventral tegemental area. No differences in dopamine transporter, vesicular monoamine transporter, dopamine D2 receptor or aromatic amino acid decarboxylase were observed. Since TH and GTPCH are both involved in dopamine synthesis, regulation of in vivo TH activity was measured in these mice. In vivo TH activity was reduced in nucleus accumbens and striatum of the +/− mice (24.7% and 15.7% reduction, respectively). In the striatum, γ-butyrolactone exacerbated differences on +/− striatal TH activity (29.8% reduction) while haloperidol equalized TH activity between the +/+ and +/−. TH activity in the nucleus accumbens was significantly reduced in all conditions measured. Furthermore, dopamine levels in the striatum of +/− mice were significantly reduced after inhibition of dopamine synthesis or after haloperidol treatment but not under basal conditions while dopamine levels in the nucleus accumbens were reduced under basal conditions. Based on these data the +/− genotype results in changes in gene expression and impairs dopamine synthesis which can affect the maintenance of dopamine levels, although with differential effects between mesolimbic/mesocortical and nigrostriatal dopamine neurons. Together, these data suggest that Nurr1 may function to modify TH and GTPCH expression and dopamine synthesis.

Tyrosine Hydroxylase Replacement in Experimental Parkinson's Disease with Transvascular Gene Therapy

Transvascular gene therapy of Parkinson's disease (PD) is a new approach to the gene therapy of PD and involves the global distribution of a therapeutic gene to brain after an intravenous administration and transport across the blood-brain barrier (BBB). This is enabled with the development of a nonviral gene transfer technology that encapsulates plasmid DNA inside pegylated immunoliposomes or PILs. An 85- to 100-nm liposome carries the DNA inside the nanocontainer, and the liposome surface is conjugated with several thousand strands of 2000-Da polyethyleneglycol (PEG). This PEGylation of the liposome stabilizes the structure in the blood stream. The liposome is targeted across the BBB via attachment to the tips of 1-2% of the PEG strands of a receptor-specific monoclonal antibody (mAb) directed at a BBB receptor, such as the insulin receptor or transferrin receptor (TfR). Owing to the expression of the insulin receptor or the TfR on both the BBB and the neuronal plasma membrane, the PIL is able to reach the neuronal nuclear compartment from the circulation. Brain-specific expression is possible with the combined use of the PIL gene transfer technology and brain-specific gene promoters. In the 6-hydroxydopamine rat model of experimental PD, striatal tyrosine hydroxylase (TH) activity is completely normalized after an intravenous administration of TfRmAb-targeted PILs carrying a TH expression plasmid. A treatment for PD may be possible with dual gene therapy that seeks both to replace striatal TH gene expression with TH gene therapy, and to halt or reverse neurodegeneration of the nigro-striatal tract with neurotrophin gene therapy.

Tyrosine hydroxylase replacement in experimental Parkinson’s disease with transvascular gene therapy

Transvascular gene therapy of Parkinson’s disease (PD) is a new approach to the gene therapy of PD and involves the global distribution of a therapeutic gene to brain after an intravenous administration and transport across the blood-brain barrier (BBB). This is enabled with the development of a nonviral gene transfer technology that encapsulates plasmid DNA inside pegylated immunoliposomes or PILs. An 85- to 100-nm liposome carries the DNA inside the nanocontainer, and the liposome surface is conjugated with several thousand strands of 2000-Da polyethyleneglycol (PEG). This PEGylation of the liposome stabilizes the structure in the blood stream. The liposome is targeted across the BBB via attachment to the tips of 1–2% of the PEG strands of a receptor-specific monoclonal antibody (mAb) directed at a BBB receptor, such as the insulin receptor or transferrin receptor (TfR). Owing to the expression of the insulin receptor or the TfR on both the BBB and the neuronal plasma membrane, the PIL is able to reach the neuronal nuclear compartment from the circulation. Brain-specific expression is possible with the combined use of the PIL gene transfer technology and brain-specific gene promoters. In the 6-hydroxydopamine rat model of experimental PD, striatal tyrosine hydroxylase (TH) activity is completely normalized after an intravenous administration of TfRmAb-targeted PILs carrying a TH expression plasmid. A treatment for PD may be possible with dual gene therapy that seeks both to replace striatal TH gene expression with TH gene therapy, and to halt or reverse neurodegeneration of the nigro-striatal tract with neurotrophin gene therapy.

Striatal adenosine A 2A receptor blockade increases extracellular dopamine release following l-DOPA administration in intact and dopamine-denervated rats

The influence of the selective adenosine A 2A receptor antagonist ZM 241385 on exogenous l-DOPA-derived dopamine (DA) release in intact and dopamine-denervated rats was studied using an in vivo microdialysis in freely moving animals. Local infusion of l-DOPA (2.5 μM) produced a marked increase in striatal extracellular DA level in intact and malonate-lesioned rats. Intrastriatal perfusion of ZM 241385 (50–100 μM) had no effect on basal extracellular DA level, but enhanced dose-dependently the l-DOPA-induced DA release in intact and malonate-lesioned animals. A non-selective adenosine A 2A receptor antagonist DMPX (100 μM), similarly to ZM 241385, accelerated conversion of l-DOPA in intact and malonate-denervated rats. This effect was not produced by the adenosine A 1 receptor antagonist, CPX (10–50 μM). However, ZM 241385 did not affect the l-DOPA-induced DA release in rats pretreated with reserpine (5 mg/kg i.p.) and α-methyl- p-tyrosine (AMPT, 300 mg/kg i.p.). Obtained results indicate that blockade of striatal adenosine A 2A receptors increases the l-DOPA-derived DA release possibly by indirect mechanism exerted on DA terminals, an effect dependent on striatal tyrosine hydroxylase activity. Selective antagonists of adenosine A 2A receptors may exert a beneficial effect at early stages of Parkinson’s disease by enhancing the therapeutic efficacy of l-DOPA applied exogenously.

EGb761 pretreatment reduces monoamine oxidase activity in mouse corpus striatum during 1-methyl-4-phenylpyridinium neurotoxicity.

EGb761 produces reversible inhibition of both monoamine oxidase (MAO) isoforms in the central nervous system. 1-Methyl-4-phenylpyridinium (MPP+) neurotoxicity is prevented by treatment with the MAO inhibitor pargyline. We investigated EGb761's effect on striatal MAO activity during MPP+ neurotoxicity. C-57 black mice were pretreated with EGb761 (10 mg/kg) daily for 17 days followed by administration of MPP+ (0.72 mg/kg). MPP+ enhanced striatal MAO (30%) activity at 6 h, and EGb761 prevented this effect. MAO-B activity in striatum was enhanced (70%) 6 h after MPP+ administration and was reduced to almost normal levels in EGb761 + MPP+ group compared to MPP+ group. Pretreatment with EGb761 partially prevented (32%) the striatal dopamine-depleting effect of MPP+ and prevented the reduction in striatal tyrosine hydroxylase activity (100%). Results suggest that EGb761 supplements may be effective in reducing MAO activity as well as enhancement in dopamine metabolism, thereby preventing MPP+-neurotoxicity.

Normalization of striatal tyrosine hydroxylase and reversal of motor impairment in experimental parkinsonism with intravenous nonviral gene therapy and a brain-specific promoter.

The goal of this work was to normalize striatal tyrosine hydroxylase (TH) activity with intravenous nonviral TH gene therapy and at the same time eliminate ectopic TH gene expression in peripheral organs such as liver in the rat. TH-expression plasmids, containing either the SV40 promoter or the glial fibrillary acidic protein (GFAP) gene promoter, were globally delivered to the brain across the blood-brain barrier (BBB) after intravenous administration of pegylated immunoliposomes (PILs). The GFAP-TH- or SV40-TH-expression plasmids were encapsulated in the interior of 85-nm PILs, which were targeted across both the BBB and the neuronal cell membrane with a monoclonal antibody (mAb) to the transferrin receptor (TfR). Striatal TH activity was 98% depleted with the unilateral intracerebral injection of 6-hydroxydopamine. TH in the striatum ipsilateral to the lesion was normalized 3 days after the intravenous injection of 10 microg per rat of either the SV40-TH or the GFAP-TH plasmid DNA. Whereas the SV40-TH gene caused a 10-fold increase in hepatic TH activity, there was no increase in liver TH with the GFAP-TH gene. The GFAP-TH gene therapy caused an 82% reduction in apomorphine-induced rotation in the lesioned rats. Confocal microscopy using antibodies to TH, GFAP, and neuronal nuclei (NeuN) showed the GFAP-TH gene was selectively expressed in nigra-striatal neurons, with no expression in either cortical neurons, or astrocytes. These studies demonstrate that global delivery of exogenous genes to the brain is possible with intravenous nonviral gene transfer, and that ectopic gene expression is eliminated with the use of brain-specific gene promoters.

Attenuation of MPTP-induced dopaminergic neurotoxicity by TV3326, a cholinesterase-monoamine oxidase inhibitor.

(R)-[(N-propargyl-(3R) aminoindan-5-yl) ethyl methyl carbamate] (TV3326) is a novel cholinesterase and brain-selective monoamine oxidase (MAO)-A/-B inhibitor. It was developed for the treatment of dementia co-morbid with extra pyramidal disorders (parkinsonism), and depression. On chronic treatment in mice it attenuated striatal dopamine depletion induced by MPTP and prevented the reduction in striatal tyrosine hydroxylase activity, like selective B and non-selective MAO inhibitors. TV3326 preferentially inhibits MAO-B in the striatum and hippocampus, and the degree of MAO-B inhibition correlates with the prevention of MPTP-induced dopamine depletion. Complete inhibition of MAO-B is not necessary for full protection from MPTP neurotoxicity. Unlike that seen after treatment with other MAO-A and -B inhibitors, recovery of striatal and hippocampal MAO-A and -B activities from inhibition by TV3326 did not show first-order kinetics. This has been attributed to the generation of a number of metabolites by TV3326 that cause differential inhibition of these enzymes. Inhibition of brain MAO-A and -B by TV3326 resulted in significant elevations of dopamine, noradrenaline and serotonin in the striatum and hippocampus. This may explain its antidepressant-like activity, resembling that of moclobemide in the forced-swim test in rats.

High-frequency stimulation of the subthalamic nucleus enhances striatal dopamine release and metabolism in rats.

High-frequency stimulation of the subthalamic nucleus is believed to exert its main effects via the basal ganglia output structures. Previously, we have shown a concomitant increase in striatal dopamine (DA) metabolites in normal and 6-hydroxydopamine-lesioned rats. The present study was designed to determine whether this increase in striatal DA metabolites reflects enhanced intraneuronal DA turnover or, alternatively, is due to increased DA release with subsequent rapid and efficient reuptake and/or metabolism. Thus, high-frequency stimulation of the subthalamic nucleus was performed in normal rats after inhibition of DA reuptake, metabolism or DA depletion. Extracellular levels of striatal DA and its metabolites were assessed using microdialysis. Our data suggest that subthalamic high-frequency stimulation increases striatal DA release and activates independent striatal DA metabolism. Since such changes could be triggered by modification of either the activity or the gene expression of the rate-limiting enzyme tyrosine hydroxylase, an activity assay and RT-PCR of striatal and nigral samples were performed. Subthalamic stimulation increased striatal tyrosine hydroxylase activity without affecting gene expression. We, therefore, conclude that the application of subthalamic high-frequency stimulation could partially compensate for the DA deficit by inducing increased striatal DA release and metabolism.

The Neurotoxin 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Induces Apoptosis in Mouse Nigrostriatal Glia: RELEVANCE TO NIGRAL NEURONAL DEATH AND STRIATAL NEUROCHEMICAL CHANGES

Swiss mice were given 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 25 mg/kg/day, for 5 consecutive days and killed at different days after MPTP discontinuance. Decreases in striatal tyrosine hydroxylase activity and levels of dopamine and its metabolites were observed 1 day after MPTP discontinuance. Ascorbic acid and glutamate levels had increased, dehydroascorbic acid and GSH decreased, whereas catabolites of high-energy phosphates (inosine, hypoxanthine, xanthine, and uric acid) were unchanged. In addition, gliosis was observed in both striatum and substantia nigra compacta (SNc). Sections of SNc showed some terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL)-positive cells. Neurochemical parameters of dopaminergic activity showed a trend toward recovery 3 days after MPTP discontinuance. At this time point, TUNEL-positive cells were detected in SNc; some of them showed nuclei with neuronal morphology. A late (days 6-11) increase in striatal dopamine oxidative metabolism, ascorbic acid oxidative status, and catabolites of high-energy phosphates were observed concomitant with nigral neuron and nigrostriatal glial cell apoptotic death, as revealed by TUNEL, acridine orange, and Hoechst staining, and transmission electron microscopy. These data suggest that MPTP-induced activation/apoptotic death of glial cells plays a key role in the sequential linkage of neurochemical and cellular events leading to dopaminergic nigral neuron apoptotic death.

Chronic administration of pharmacological levels of melatonin does not ameliorate the MPTP-induced degeneration of the nigrostriatal pathway

An extensive literature suggests that melatonin may protect from the degenerative effects of central neurotoxins by acting as a free radical scavenger. The purpose of this study was to determine if melatonin would protect male C57BL6 mice from the toxicity of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to nigral dopamine (DA) neurons. Melatonin was initially dissolved in dimethyl sulfoxide (DMSO), diluted to 16 μg/ml and then provided in the drinking water for 4 weeks. Control mice drank the same final concentration of the DMSO diluent. One week before the termination of the experiment, randomly selected mice from the melatonin-treated and the DMSO-treated groups received two, three or four doses of 2.5 mg/kg MPTP free base administered subcutaneously at 2-h intervals. Additional DMSO-treated and melatonin-treated mice did not receive MPTP. Following tissue collection, melatonin concentration was measured in blood plasma collected from each animal and found to be 20-fold higher in melatonin-treated compared to DMSO-treated mice. Tyrosine hydroxylase (TH) activity and the levels of DA and dihydroxyphenylacetic acid (DOPAC) were not different in striata collected from melatonin-treated versus DMSO-treated mice which did not receive MPTP. Treatment with MPTP significantly reduced striatal TH activity, DA and DOPAC, but there were no significant differences in the reductions in any of these parameters observed in the melatonin-treated versus the DMSO-treated control mice that received the same total dosage of MPTP. These results show that the long-term administration of a high pharmacological dose of melatonin was ineffective in protecting nigral dopaminergic neurons from the neurotoxic effects of MPTP.

Decreased messenger RNA expression of key markers of the nigrostriatal dopaminergic system following vitamin E deficiency in the rat

We have evaluated the effect of a vitamin E-deficient diet on the rat nigrostriatal dopaminergic system. After 15 days of deficient diet, the amount and activity of striatal and nigral tyrosine hydroxylase increased, which contrasted with a decreased messenger RNA expression for tyrosine hydroxylase and the dopamine transporter in the ventral mesencephalon. When we prolonged the deficiency of vitamin E for 30 days, dopamine levels did not differ in both areas. In contrast, messenger RNA levels for tyrosine hydroxylase and the dopamine transporter were markedly reduced in 30-day deficient rats. In addition, the number of oxidatively modified proteins significantly increased in the striatal and nigral areas studied. Overall, we propose that these changes suggest an important role of vitamin E in maintaining the normal equilibrium of the dopaminergic nigrostriatal system.

Increase of striatal dopamine release by cadmium in nursing rats and its prevention by dexamethasone-induced metallothionein

Repeated daily intraperitoneal (i.p.) administrations of cadmium (CdCl 2, 1 mg/kg per day for 5 days) increased striatal dopamine (DA) release (180% of controls) and turnover (150% of controls) in 13-day-old rats. Cd treatment also increased striatal metallothionein (MT) content (161%), Cd (127%) and lipid peroxidation (LPO, 190%). In addition, Cd treatment decreased striatal tyrosine hydroxylase (TH) activity (−28%), and such an effect may result from D-2 receptor blockade as a consequence of excessive dopamine release, since sulpiride (a specific D-2 receptor antagonist) administration to Cd-treated rats abolished the effect of Cd on TH. No effect was observed on striatal monoamine oxidase (MAO) activity. Dexamethasone (Dx) treatment increased striatal MT content and caused no effect on either DA release or turnover. However, Dx administration prevented the effects caused by Cd, including the increased DA release and enhanced striatal lipid peroxidation. These results indicate that toxic effects on the brain are to be expected as a result of Cd exposure and that Dx administration can attenuate them.

Parallel modulation of striatal dopamine synthetic enzymes by second messenger pathways

The activity of tyrosine hydroxylase and aromatic l-amino acid decarboxylase in the striatum and their mRNA content in the midbrain were assayed in mice following the intracerebroventricular injection of forskolin or phorbol-12,13-myristic acid (PMA). Control and 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned animals were studied. Both forskolin and PMA induced a rapid and transient increase of tyrosine hydroxylase and aromatic l-amino acid decarboxylase activity in the striatum that lasted less than 45 and 60 min, respectively. A second belated increase of striatal tyrosine hydroxylase and aromatic l-amino acid decarboxylase activities was seen only after forskolin, and it was accompanied by a rise of tyrosine hydroxylase and aromatic l-amino acid decarboxylase mRNA in the midbrain. In the MPTP-lesioned mouse, the rise of tyrosine hydroxylase and aromatic l-amino acid decarboxylase following forskolin appeared exaggerated, while the response to PMA was not. These studies suggest that tyrosine hydroxylase and aromatic l-amino acid decarboxylase of striatum can be modulated in parallel by protein kinase A and protein kinase C, and that exaggerated responsiveness to protein kinase A is observed in the partially denervated striatum.

Lowering ambient or core body temperature elevates striatal MPP+ levels and enhances toxicity to dopamine neurons in MPTP-treated mice

The neuroprotective effects of lowering body temperature have been well documented in various models of neuronal injury. The present study investigated the effects a lower ambient or core body temperature would have on damage to striatal dopamine (DA) neurons produced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mice received systemic MPTP treatment at two different temperatures, 4°C and 22°C. MPTP-treated mice maintained at 4°C demonstrated (1) a greater hypothermic response, (2) a significant reduction in striatal DA content and tyrosine hydroxylase (TH) activity, and (3) significantly greater striatal 1-methyl-4-phenylpyridinium (MPP+) levels, as compared to mice dosed with MPTP at room temperature. Parallel studies with methamphetamine (METH) were conducted since temperature appears to play a pivotal role in the mediation of damage to DA neurons by this CNS stimulant in rodents. As previously reported, METH-induced hyperthermia and the subsequent loss of striatal DA content were attenuated in animals dosed at 4°C. We also evaluated the effects a hypothermic state induced by pharmacological agents would have on striatal neurochemistry and MPP+ levels following MPTP treatment. Concurrent administration of MK-801 or 8-OHDPAT increased the striatal MPP+ levels following MPTP treatment. However, only 8-OHDPAT potentiated the MPTP-induced decrements of striatal DA content and TH activity; MK-801 did not affect MPTP decreases in these striatal markers of dopaminergic damage. Altogether, these findings indicate that temperature has a profound effect on striatal MPP+ levels and MPTP-induced damage to DA neurons in mice.

Fluid flow and metasomatism in the genesis of the amphibolites-facies, pelite-hosted Kanmantoo copper deposit, South Australia

Daily treatment of neonatal rats with 1-triiodothyronine for 30 days increased locomotor activity as well as the synthesis and presumably, release of brain norepinephrine, dopamine and 5-hydroxytryptamine. Whereas administration of lithium carbonate (60 mg/kg) to normal rats for 10 days, beginning from the 20th day of age, produced no significant effect, this antimanic drug significantly decreased the observed increase in spontaneous locomotor activity in l-triiodothyronine-treated rats. Lithium treatment in normal rats increased the activity of striatal tyrosine hydroxylase, but produced no significant effect on the endogenous levels of norepinephrine and dopamine in several discrete brain regions examined. Lithium, enhanced deamination of catecholamines as evidenced by increased level of 3,4-dihydroxyphenylacetic acid and monoamine oxidase activity in normal rats. The activity of catechol o-methyltransferase was decreased to 82 and 59% in midbrain and crebral cortex of normal rats, respectively. Furthermore, chronic treatment with lithium increased endogenous levels of tryptophan, tryptophan hydroxylase, 5-hydroxytryptamine and its metabolite, 5-hydroxyindoleacetic acid, in normal animals. In contrast to the effects seen in normal rats, admininstration of lithium in l-triiodothyronine-treated animals significantly decreased tyrosine hydroxylase as well as dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid, suggesting that this antimanic drug reduced the synthesis and turnover of dopamine. However, the steady-state levels of norepinephrine were raised in hypothalamus, pons-medulla, midbrain and striatum of lithium-treated hyperthyroid rats. As seen in normal animals, lithium in l-triidothyronine-treated rats increased trytophan, tryptophan hydroxylase and 5-hydroxytryptamine levels, but decreased the concentration of 5-hydroxyindoleacetic acid. The results show that the suppressed behavioral activity seen in lithium-treated hyperthyroid rats may be associated with decreased synthesis of norepinephrine and dopamine in the brain. Finally, the effects exerted by lithium on the brain catecholamine metabolizing system of young hyperthyroid rats were not similar to those seen in normal rats of the corresponding age group.