Effects of Dopamine D2 Receptor Partial Agonist Antipsychotic Aripiprazole on Dopamine Synthesis in Human Brain Measured by PET with L-[β-11C]DOPA

Dopamine D₂ receptor partial agonist antipsychotic drugs can modulate dopaminergic neurotransmission as functional agonists or functional antagonists. The effects of antipsychotics on presynaptic dopaminergic functions, such as dopamine synthesis capacity, might also be related to their therapeutic efficacy. Positron emission tomography (PET) was used to examine the effects of the partial agonist antipsychotic drug aripiprazole on presynaptic dopamine synthesis in relation to dopamine D₂ receptor occupancy and the resulting changes in dopamine synthesis capacity in healthy men. On separate days, PET studies with [¹¹C]raclopride and L-[β-¹¹C]DOPA were performed under resting condition and with single doses of aripiprazole given orally. Occupancy of dopamine D₂ receptors corresponded to the doses of aripiprazole, but the changes in dopamine synthesis capacity were not significant, nor was the relation between dopamine D₂ receptor occupancy and these changes. A significant negative correlation was observed between baseline dopamine synthesis capacity and changes in dopamine synthesis capacity by aripiprazole, indicating that this antipsychotic appears to stabilize dopamine synthesis capacity. The therapeutic effects of aripiprazole in schizophrenia might be related to such stabilizing effects on dopaminergic neurotransmission responsivity.     

Attenuated Tonic and Enhanced Phasic Release of Dopamine in Attention Deficit Hyperactivity Disorder

It is unclear whether attention deficit hyperactive disorder (ADHD) is a hypodopaminergic or hyperdopaminergic condition. Different sets of data suggest either hyperactive or hypoactive dopamine system. Since indirect methods used in earlier studies have arrived at contradictory conclusions, we directly measured the tonic and phasic release of dopamine in ADHD volunteers. The tonic release in ADHD and healthy control volunteers was measured and compared using dynamic molecular imaging technique. The phasic release during performance of Eriksen’s flanker task was measured in the two groups using single scan dynamic molecular imaging technique. In these experiments volunteers were positioned in a positron emission tomography (PET) camera and administered a dopamine receptor ligand ¹¹C-raclopride intravenously. After the injection PET data were acquired dynamically while volunteers either stayed still (tonic release experiments) or performed the flanker task (phasic release experiments). PET data were analyzed to measure dynamic changes in ligand binding potential (BP) and other receptor kinetic parameters. The analysis revealed that at rest the ligand BP was significantly higher in the right caudate of ADHD volunteers suggesting reduced tonic release. During task performance significantly lower ligand BP was observed in the same area, indicating increased phasic release. In ADHD tonic release of dopamine is attenuated and the phasic release is enhanced in the right caudate. By characterizing the nature of dysregulated dopamine neurotransmission in ADHD, the results explain earlier findings of reduced or increased dopaminergic activity.     

[3H]GBR-12935 Binding to the Dopamine Transporter Is Decreased in the Caudate Nucleus in Parkinson''s Disease

The specific binding of [3H]GBR-12935 to membranes prepared from human caudate nucleus is saturable (Bmax 1.36 +/- 0.18 pmol/mg protein), sodium dependent and of high affinity (KD 2.34 +/- 0.18 nM). Freezing of tissue from rat brain, or refrigeration followed by freezing, results in a small but significant (less than or equal to 20%) decrease in specific [3H]GBR-12935 binding when compared to the binding observed in fresh (nonfrozen) tissue, and this decrease may account, in part, for the differences in specific binding between rat and human brain membranes. Despite small differences in binding site density between fresh and frozen tissue there is a good correlation (r = 0.98; p less than 0.01) between the potencies of a series of drugs in displacing specific [3H]GBR-12935 binding to human caudate membranes and rat striatum as well as in inhibiting dopamine uptake in rat striatal synaptosomes (r = 0.96; p less than 0.01). The specific binding of [3H]GBR-12935 to membranes prepared from the caudate nuclei of patients with Parkinson's disease is decreased compared to membranes prepared from age- and sex-matched controls. These data suggest that [3H]GBR-12935 binds in a sodium-dependent fashion to the dopamine transport complex in human brain and that specific binding is decreased by a pathological degeneration of dopaminergic neurons to the caudate nucleus.     

Evidence of dopaminergic processing of executive inhibition

Inhibition of unwanted response is an important function of the executive system. Since the inhibitory system is impaired in patients with dysregulated dopamine system, we examined dopamine neurotransmission in the human brain during processing of a task of executive inhibition. The experiment used a recently developed dynamic molecular imaging technique to detect and map dopamine released during performance of a modified Eriksen's flanker task. In this study, young healthy volunteers received an intravenous injection of a dopamine receptor ligand ((11)C-raclopride) after they were positioned in the PET camera. After the injection, volunteers performed the flanker task under Congruent and Incongruent conditions in a single scan session. They were required to inhibit competing options to select an appropriate response in the Incongruent but not in the Congruent condition. The PET data were dynamically acquired during the experiment and analyzed using two variants of the simplified reference region model. The analysis included estimation of a number of receptor kinetic parameters before and after initiation of the Incongruent condition. We found increase in the rate of ligand displacement (from receptor sites) and decrease in the ligand binding potential in the Incongruent condition, suggesting dopamine release during task performance. These changes were observed in small areas of the putamen and caudate bilaterally but were most significant on the dorsal aspect of the body of left caudate. The results provide evidence of dopaminergic processing of executive inhibition and demonstrate that neurochemical changes associated with cognitive processing can be detected and mapped in a single scan session using dynamic molecular imaging.     

Relationship between urinary excretion of homovanillic acid and norepinephrine metabolites in normal subjects and patients with orthostatic hypotension

Patients with neurogenic orthostatic hypotension due to multiple system atrophy (MSA) or pure autonomic failure (PAF) excrete lower amounts of homovanillic acid (HVA) than do normal subjects. There is a highly significant correlation between the rates of excretion of HVA and norepinephrine metabolites. The regression line relating excretion of the dopamine and norepinephrine metabolites suggests that about one third of dopamine formed in noradrenergic neurons is converted to norepinephrine and the remainder metabolized, mainly to HVA. About one fourth of urinary HVA appears to be derived from a source independent of norepinephrine; this source is probably brain dopaminergic neurons.     

Enhanced striatal dopamine release during food stimulation in binge eating disorder

Subjects with binge eating disorder (BED) regularly consume large amounts of food in short time periods. The neurobiology of BED is poorly understood. Brain dopamine, which regulates motivation for food intake, is likely to be involved. We assessed the involvement of brain dopamine in the motivation for food consumption in binge eaters. Positron emission tomography (PET) scans with [(11)C]raclopride were done in 10 obese BED and 8 obese subjects without BED. Changes in extracellular dopamine in the striatum in response to food stimulation in food-deprived subjects were evaluated after placebo and after oral methylphenidate (MPH), a drug that blocks the dopamine reuptake transporter and thus amplifies dopamine signals. Neither the neutral stimuli (with or without MPH) nor the food stimuli when given with placebo increased extracellular dopamine. The food stimuli when given with MPH significantly increased dopamine in the caudate and putamen in the binge eaters but not in the nonbinge eaters. Dopamine increases in the caudate were significantly correlated with the binge eating scores but not with BMI. These results identify dopamine neurotransmission in the caudate as being of relevance to the neurobiology of BED. The lack of correlation between BMI and dopamine changes suggests that dopamine release per se does not predict BMI within a group of obese individuals but that it predicts binge eating.     

Association of Body Mass and Brain Activation during Gastric Distention: Implications for Obesity

Background

Gastric distention (GD), as it occurs during meal ingestion, signals a full stomach and it is one of the key mechanisms controlling food intake. Previous studies on GD showed lower activation of the amygdala for subjects with higher body mass index (BMI). Since obese subjects have dopaminergic deficits that correlate negatively with BMI and the amygdala is innervated by dopamine neurons, we hypothesized that BMI would correlate negatively with activation not just in the amygdala but also in other dopaminergic brain regions (midbrain and hypothalamus).

Methodology/Principal Findings

We used functional magnetic resonance imaging (fMRI) to evaluate brain activation during GD in 24 healthy subjects with BMI range of 20–39 kg/m². Using multiple regression and cross-correlation analyses based on a family-wise error corrected threshold P = 0.05, we show that during slow GD to maximum volumes of 500 ml and 700 ml subjects with increased BMI had increased activation in cerebellum and left posterior insula, and decreased activation of dopaminergic (amygdala, midbrain, hypothalamus, thalamus) and serotonergic (pons) brain regions and anterior insula, regions that were functionally interconnected with one another.

Conclusions

The negative correlation between BMI and BOLD responses to gastric distention in dopaminergic (midbrain, hypothalamus, amygdala, thalamus) and serotonergic (pons) brain regions is consistent with disruption of dopaminergic and serotonergic signaling in obesity. In contrast the positive correlation between BMI and BOLD responses in posterior insula and cerebellum suggests an opposing mechanism that promotes food intake in obese subjects that may underlie their ability to consume at once large food volumes despite increasing gastric distention.     

Immunocytochemical Quantification of Tyrosine Hydroxylase at a Cellular Level in the Mesencephalon of Control Subjects and Patients with Parkinson's and Alzheimer's Disease

Abstract: Parkinson's disease is characterized by massive degeneration of the melanized dopaminergic neurons in the substantia nigra. The functional capacity of the surviving nigral neurons is affected, as indicated by the subnormal levels of tyrosine hydroxylase (TH) mRNA in these neurons and the presence in the parkinsonian mesencephalon of melanized neurons lacking TH immunoreactivity. This is apparently in contradiction with the known overactivity of dopamine synthesis and release that occurs in the remaining dopaminergic terminals. To test the ability of the surviving neurons to express TH protein, a semiquantitative immunocytochemical method was developed. The relative amounts of TH were estimated with a computer-assisted image analysis system in the dopaminergic neurons of representative mesencephalic sections of control and parkinsonian brains and for comparison in brains from patients with Alzheimer's disease. In control brains, the mean TH content per neuron differed from one subject to another and between the different dopaminergic cell groups of the mesencephalon in the same subject. Within a given dopaminergic region, the level of TH was variable among neurons. In patients with Parkinson's disease, the ratio of TH protein content per neuron in the substantia nigra by reference to that of the central gray substance was reduced. In patients with Alzheimer's disease, the amount of TH was selectively reduced in the remaining dopaminergic neurons of the ventral tegmental area, a region characterized by a loss in dopaminergic neurons. The decrease in cellular TH content might therefore be related to the presence of the neurodegenerative process in the area considered. In patients with Parkinson's disease, the incapacity of the surviving neurons to express normal TH levels may reduce the efficiency of the hyperactivity mechanisms that develop in the remaining striatal dopaminergic terminals.     

Diffusion Tensor Tractography versus Volumetric Imaging in the Diagnosis of Behavioral Variant Frontotemporal Dementia

MRI diffusion tensor imaging (DTI) studies of white matter integrity in behavioral variant frontotemporal dementia have consistently shown involvement of frontal and temporal white matter, corresponding to regional loss of cortical volume. Volumetric imaging has a suboptimal sensitivity as a diagnostic tool and thus we wanted to explore if DTI is a better method to discriminate patients and controls than volumetric imaging. We examined the anterior cingulum bundle in 14 patients with behavioral variant frontotemporal dementia and 22 healthy controls using deterministic manual diffusion tensor tractography, and compared DTI parameters with two measures of cortical atrophy, VBM and cortical thickness, of the anterior cingulate cortex (ACC). Statistically significant changes between patients and controls were detected in all DTI parameters, with large effect sizes. ROC-AUC was for the best DTI parameters: 0.92 (fractional anisotropy) to 0.97 (radial diffusivity), 0.82 for the best cortical parameter, VBM of the ACC. Results from the AUC were confirmed with binary logistic regression analysis including demographic variables, but only for fractional anisotropy and mean diffusivity. Ability to classify patient/nonpatient status was significantly better for mean diffusivity vs. VBM (p=0.031), and borderline significant for fractional anisotropy vs. VBM (p=0.062). The results indicate that DTI could offer advantages in comparison with the assessment of cortical volume in differentiating patients with behavioral variant frontotemporal dementia and controls.     

Behavioral and neurophysiological evidence for a facilatory interaction between co-existing transmitters: cholecystokinin and dopamine

Cholecystokinin (CCK) and dopamine (DA) co-exist in ventral tegmental neurons which project via the mesencephalic pathway to the nucleus accumbens of the rat. CCK and DA are located in separate neurons in the substantia nigra which projects via the nigrostriatal pathway to the caudate nucleus in the rat. The functional significance of this peptide-amine co-localization was investigated using behavioral and neurophysiological techniques. CCK injected directly into the nucleus accumbens potentiated apomorphine-induced stereotypy and dopamine-induced hyperlocomotion. CCK injected directly into the caudate nucleus had no effect on apomorphine-induced stereotypy or dopamine-induced hyperlocomotion CCK injected alone into either site did not induce stereotypy or hyperlocomotion. The dose-response curve to apomorphine induction of stereotypy was shifted to the left by CCK, indicating increased sensitivity to the dopaminergic agonist. Neurophysiological analysis of the firing rate of ventral tegmental neurons demonstrated that CCK produced a left-shift in the dose-response curve of apomorphine on inhibition of neuronal firing. These data suggest that CCK acts as a modulator of dopamine, increasing neuronal responses to dopaminergic agonists. The potentiation of dopamine by CCK may be specific to the mesolimbic neurons, where CCK and DA co-exist in the rat.     

帕金森病模型大鼠行为学改变与黒质致密部多巴胺能神经元存活率之间的相关性

目的探讨线刀损毁内侧前脑束建立的帕金森病模型大鼠行为学改变与黒质致密部多巴胺能神经元存活率之间的相关性。方法采用可伸缩线刀切断大鼠内侧前脑束建立单侧损伤的帕金森病大鼠模型;皮下注射阿朴吗啡后测试大鼠的旋转行为;取中脑黑质切片进行酪氨酸羟化酶免疫组织化学染色,通过计数黑质致密部酪氨酸羟化酶阳性神经元的数目得到多巴胺能神经元存活率。结果模型组大鼠损伤侧酪氨酸羟化酶阳性神经元的数目明显下降,而由阿朴吗啡诱导的旋转行为明显增加。结论线刀损毁术后4周,帕金森病模型大鼠由阿朴吗啡诱导的旋转行为和黒质致密部多巴胺能神经元存活率之间存在着明显的负相关。     

Dopamine receptors and transporters in Parkinson's disease and schizophrenia

The loss of midbrain dopamine in Parkinson's disease is accompanied by a matching loss in the dopamine transporter and a rise in the D1 and D2 receptor densities. This is found in the brain putamen and caudate tissues from unmedicated patients, and may account for the good early clinical response to L-dopa. Long-term L-dopa treatment reverts the receptor densities toward normal levels. Positron emission tomography (PET) data and in vitro data generally concur. In schizophrenia the density of the dopamine transporter as well as that of the D1 dopamine receptor is normal. The D2 receptor density, however, is consistently elevated in postmortem brain putamen and caudate nucleus, even in tissues from neuroleptic-free or drug-naive patients. Three sets of PET and single photon emission computed tomography (SPECT) data support the postmortem findings. Early evidence indicating abnormal D2 structure as well as a reduced link between D1 and D2 warrant a detailed study of the genes for these two receptors in schizophrenia.     

Peripheral iron dextran induced degeneration of dopaminergic neurons in rat substantia nigra

Iron accumulation is considered to be involved in the pathogenesis of Parkinson's disease. To demonstrate the relationship between peripheral iron overload and dopaminergic neuron loss in rat substantia nigra (SN), in the present study we used fast cyclic voltammetry, tyrosine hydroxylase (TH) immunohistochemistry, Perls' iron staining, and high performance liquid chromatography-electrochemical detection to study the degeneration of dopaminergic neurons and increased iron content in the SN of iron dextran overloaded animals. The findings showed that peripheral iron dextran overload increased the iron staining positive cells and reduced the number of TH-immunoreactive neurons in the SN. As a result, dopamine release and content, as well as its metabolites contents were decreased in caudate putamen. Even more dramatic changes were found in chronic overload group. These results suggest that peripheral iron dextran can increase the iron level in the SN, where excessive iron causes the degeneration of dopaminergic neurons. The chronic iron overload may be more destructive to dopaminergic neurons than the acute iron overload.     

Neuropsychological Outcome and Diffusion Tensor Imaging in Complicated versus Uncomplicated Mild Traumatic Brain Injury

This study examined whether intracranial neuroimaging abnormalities in those with mild traumatic brain injury (MTBI) (i.e., “complicated” MTBIs) are associated with worse subacute outcomes as measured by cognitive testing, symptom ratings, and/or diffusion tensor imaging (DTI). We hypothesized that (i) as a group, participants with complicated MTBIs would report greater symptoms and have worse neurocognitive outcomes than those with uncomplicated MTBI, and (ii) as a group, participants with complicated MTBIs would show more Diffusion Tensor Imaging (DTI) abnormalities. Participants were 62 adults with MTBIs (31 complicated and 31 uncomplicated) who completed neurocognitive testing, symptom ratings, and DTI on a 3T MRI scanner approximately 6-8 weeks post injury. There were no statistically significant differences between groups on symptom ratings or on a broad range of neuropsychological tests. When comparing the groups using tract-based spatial statistics for DTI, no significant difference was found for axial diffusivity or mean diffusivity. However, several brain regions demonstrated increased radial diffusivity (purported to measure myelin integrity), and decreased fractional anisotropy in the complicated group compared with the uncomplicated group. Finally, when we extended the DTI analysis, using a multivariate atlas based approach, to 32 orthopedic trauma controls (TC), the findings did not reveal significantly more areas of abnormal DTI signal in the complicated vs. uncomplicated groups, although both MTBI groups had a greater number of areas with increased radial diffusivity compared with the trauma controls. This study illustrates that macrostructural neuroimaging changes following MTBI are associated with measurable changes in DTI signal. Of note, however, the division of MTBI into complicated and uncomplicated subtypes did not predict worse clinical outcome at 6-8 weeks post injury.     

Diffusion Tensor Imaging Studies of Cervical Spondylotic Myelopathy: A Systemic Review and Meta-Analysis

A meta-analysis was conducted to assess alterations in measures of diffusion tensor imaging (DTI) in the patients of cervical spondylotic myelopathy (CSM), exploring the potential role of DTI as a diagnosis biomarker. A systematic search of all related studies written in English was conducted using PubMed, Web of Science, EMBASE, CINAHL, and Cochrane comparing CSM patients with healthy controls. Key details for each study regarding participants, imaging techniques, and results were extracted. DTI measurements, such as fractional anisotropy (FA), apparent diffusion coefficient (ADC), and mean diffusivity (MD) were pooled to calculate the effect size (ES) by fixed or random effects meta-analysis. 14 studies involving 479 CSM patients and 278 controls were identified. Meta-analysis of the most compressed levels (MCL) of CSM patients demonstrated that FA was significantly reduced (ES -1.52, 95% CI -1.87 to -1.16, P < 0.001) and ADC was significantly increased (ES 1.09, 95% CI 0.89 to 1.28, P < 0.001). In addition, a notable ES was found for lowered FA at C2-C3 for CSM vs. controls (ES -0.83, 95% CI -1.09 to -0.570, P < 0.001). Meta-regression analysis revealed that male ratio of CSM patients had a significant effect on reduction of FA at MCL (P = 0.03). The meta-analysis of DTI studies of CSM patients clearly demonstrated a significant FA reduction and ADC increase compared with healthy subjects. This result supports the use of DTI parameters in differentiating CSM patients from health subjects. Future researches are required to investigate the diagnosis performance of DTI in cervical spondylotic myelopathy.     

D-2 dopamine autoreceptor selective drugs: do they really exist?

The catecholamine dopamine plays an important role as a neurotransmitter or neurohormone in the brain and pituitary gland. Dopamine exerts its effects through activation of two types of receptors called D-1 and D-2. These receptors are distinguished by their different pharmacological characteristics and signal transduction mechanism(s). Release of dopamine inhibits the activity of dopaminergic neurons through activation of so-called dopamine autoreceptors which are of the D-2 type. In general, these receptors occur both in the soma-dendritic region of the dopaminergic neuron, where they are involved in the inhibition of the firing rate and on the dopaminergic terminals where they mediate the inhibition of dopamine synthesis and release. D-2 receptors occur also on the target cells of dopaminergic neurons both in the brain (postsynaptic D-2 receptors) and pituitary gland. On the basis of data gathered from in vivo (behavioral- as well as electrophysiological) studies it has been concluded that D-2 agonists are much more potent at dopamine autoreceptors as compared to postsynaptic D-2 receptors, indicating the possibility of a pharmacological distinction between these differentially located D-2 receptors. This concept led to the introduction of a whole group of drugs allegedly displaying a selective agonist profile at the dopamine autoreceptor. In contrast, biochemical (in vitro) studies with brain tissue as well as the pituitary gland, did not reveal any significant difference between the pharmacological profiles of autoreceptors and postsynaptic D-2 receptors. In the present minireview a balanced discussion is presented of these in vivo and in vitro findings and it is concluded that both autoreceptors as well as postsynaptic D-2 receptors are similar if not identical entities.     

A comparison of domperidone and haloperidol effects on different dopaminergic neurons in the rat brain

Domperidone, a dopamine (DA) receptor antagonist with reportedly preferential actions outside of the blood-brain barrier, and haloperidol, a centrally active DA antagonist, were compared with respect to their abilities to increase the activity of dopaminergic neurons in the rat brain. The activity of nigrostriatal, mesolimbic, tuberohypophyseal and tuberoinfundibular dopamine nerves was estimated by measuring the $\text{in vivo}$ rate of DA synthesis (dihydroxyphenylalanine accumulation following administration of an inhibitor of aromatic L-amino acid decarboxylase) in the striatum, olfactory tubercle, posterior pituitary and median eminence, respectively. In an initial study, the rates of DA synthesis in striatum, olfactory tubercle, and posterior pituitary were determined at 2, 8, and 16 h after subcutaneous administration of 0.25, 2.5, or 25 mg/kg domperidone. At the lowest dose of domperidone, DA synthesis was increased only in the posterior pituitary at 8 and 16 h; at the intermediate dose, DA synthesis increased in the posterior pituitary at 8 and 16 h and in the olfactory tubercle at 8 h. Only at 8 h after the highest dose of domperidone was DA synthesis increased in the striatum. When 2.5 mg/kg of doperidone or haloperidol were administered, DA synthesis in posterior pituitary and median eminence was increased in a similar fashion (in the latter region only at 16 h). In contrast, domperidone promoted only modest and delayed increases in DA synthesis in the olfactory tubercle and had no effect in the striatum. These results indicate that systemically administered domperidone preferentially increases DA synthesis in neurons terminating outside the blood-brain barrier, but after a pronounced delay, high doses of the drug can also activate DA neurons which project to the forebrain.     

Dopamine Synthesis as a Mechanism of Brain Plasticity in Nigrostriatal System Pathology

Using an experimental Parkinson’s disease model (symptoms develop in mice after the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), we studied the characteristics of the synthesis of dopamine as a possible compensatory mechanism aimed at maintaining the dopamine level in the dopaminergic neurons that survived in this pathology. We found no correlation between the content and activity of tyrosine hydroxylase in the nigrostriatal system. The enzyme activity and the dopamine content showed unidirectional changes in the substantia nigra, but not in the striatum, which is apparently due to triggering other compensatory mechanisms.     

Enhancement of tyrosine hydroxylase phosphorylation and activity by glial cell line-derived neurotrophic factor

Although glial cell-line derived neurotrophic factor (GDNF) acts as a potent survival factor for dopaminergic neurons, it is not known whether GDNF can directly alter dopamine synthesis. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for dopamine biosynthesis, and its activity is regulated by phosphorylation on three seryl residues: Ser-19, Ser-31, and Ser-40. Using a TH-expressing human neuroblastoma cell line and rat primary mesencephalic neuron cultures, the present study examined whether GDNF alters the phosphorylation of TH and whether these changes are accompanied by increased enzymatic activity. Exposure to GDNF did not alter the TH protein level in either neuroblastoma cells or in primary neurons. However, significant increases in the phosphorylation of Ser-31 and Ser-40 were detected within minutes of GDNF application in both cell types. Enhanced Ser-31 and Ser-40 phosphorylation was associated with increased TH activity but not dopamine synthesis in neuroblastoma cells, possibly because of the absence of l-aromatic amino acid decarboxylase activity in these cells. In contrast, increased phosphorylation of Ser-31 and Ser-40 was found to enhance dopamine synthesis in primary neurons. Pharmacological experiments show that Erk and protein kinase A phosphorylate Ser-31 and Ser-40, respectively, and that their inhibition blocked both TH phosphorylation and activity. Our results indicate that, in addition to its role as a survival factor for dopaminergic neurons, GDNF can directly increase dopamine synthesis.     

Vulnerability to glutamate toxicity of dopaminergic neurons is dependent on endogenous dopamine and MAPK activation

Dopaminergic neurons are more vulnerable than other types of neurons in cases of Parkinson disease and ischemic brain disease. An increasing amount of evidence suggests that endogenous dopamine plays a role in the vulnerability of dopaminergic neurons. Although glutamate toxicity contributes to the pathogenesis of these disorders, the sensitivity of dopaminergic neurons to glutamate toxicity has not been clarified. In this study, we demonstrated that dopaminergic neurons were preferentially affected by glutamate toxicity in rat mesencephalic cultures. Glutamate toxicity in dopaminergic neurons was blocked by inhibiting extracellular signal-regulated kinase (ERK), c- jun N-terminal kinase, and p38 MAPK. Furthermore, depletion of dopamine by α-methyl- dl - p -tyrosine methyl ester (α-MT), an inhibitor of tyrosine hydroxylase (TH), protected dopaminergic neurons from the neurotoxicity. Exposure to glutamate facilitated phosphoryration of TH at Ser31 by ERK, which contributes to the increased TH activity. Inhibition of ERK had no additive effect on the protection offered by α-MT, whereas α-MT and c- jun N-terminal kinase or p38 MAPK inhibitors had additive effects and yielded full protection. These data suggest that endogenous dopamine is responsible for the vulnerability to glutamate toxicity of dopaminergic neurons and one of the mechanisms may be an enhancement of dopamine synthesis mediated by ERK.