Dopamine Metabolites In Cerebrospinal Fluid Research Articles

Accelerated high frequency rTMS induces time-dependent dopaminergic alterations: a DaTSCAN brain imaging study in healthy beagle dogs.

The neurobiological effects of repetitive transcranial magnetic stimulation are believed to run in part through the dopaminergic system. Accelerated high frequency rTMS (aHF-rTMS), a new form of stimuli delivery, is currently being tested for its usefulness in treating human and canine mental disorders. However, the short-and long-term neurobiological effects are still unclear, including the effects on the dopaminergic system. In aHF-rTMS, multiple sessions are delivered within 1 day instead of one session per day, not only to accelerate the time to response but also to increase clinical efficacy. To gain more insight into the neurobiology of aHF-rTMS, we investigated whether applying five sessions in 1 day has direct and/or delayed effects on the dopamine transporter (DAT), and on dopamine metabolites of cerebrospinal fluid (CSF) in beagles. Thirteen beagles were randomly divided into two groups: five active stimulation sessions (n = 9), and 5 sham stimulation sessions (n = 4). Using DaTSCAN, DAT binding indices (BI) were obtained at baseline, after 1 day, 1 month, and 3 months post stimulation. CSF samples were collected after each scan. Active aHF-rTMS significantly reduced striatal DAT BI 1 day post-active stimulation session (p < 0.01), and the effect lasted to 1 month (p < 0.01). No significant DAT BI change was found in sham group. No significant changes in dopamine metabolites of CSF were found. Although no significant effects on CSF dopamine metabolites were observed, five sessions of active aHF-rTMS significantly decreased striatal DAT BI after 1 day and up to 1 month post stimulation, indicating immediate and delayed effects on the brain dopaminergic system. Our findings in healthy beagles further substantiate the assumption that (a)HF-rTMS affects the brain dopaminergic system and it may pave the way to apply (a)HF-rTMS treatment in behaviorally disturbed dogs.

AJ76 and UH232 as potential agents for diagnosing early-stage Parkinson's disease

We recently reported that the “Dopamine Neuron Challenge Test” (DNC Test), a diagnostic method that measures the levels of dopamine metabolites in cerebrospinal fluid (CSF) and plasma samples after pharmacologically inducing a transient dopamine release, can detect early-stage Parkinson's disease (PD) with high sensitivity and selectivity in mouse models. The use of haloperidol in the original DNC test to challenge dopamine neurons was less than ideal, as it may cause extrapyramidal motor symptoms. Here we report an improved DNC Test, in which the original challenging agents, haloperidol and methylphenidate, are replaced by a single challenging agent, a dopamine autoreceptor preferring antagonist AJ76 or UH232. We show that the improved DNC Test can achieve the same level of sensitivity and selectivity in detecting early PD in a mouse model without causing motor side effects. These findings significantly improve the practicality of using the DNC Test as a screening or diagnostic test for detecting early-stage PD in the high-risk population in humans.

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine.

Motivational and motor deficits are common in patients with depression and other psychiatric disorders, and are related to symptoms of anhedonia and motor retardation. These deficits in motivation and motor function are associated with alterations in corticostriatal neurocircuitry, which may reflect abnormalities in mesolimbic and mesostriatal dopamine (DA). One pathophysiologic pathway that may drive changes in DAergic corticostriatal circuitry is inflammation. Biomarkers of inflammation such as inflammatory cytokines and acute-phase proteins are reliably elevated in a significant proportion of psychiatric patients. A variety of inflammatory stimuli have been found to preferentially target basal ganglia function to lead to impaired motivation and motor activity. Findings have included inflammation-associated reductions in ventral striatal neural responses to reward anticipation, decreased DA and DA metabolites in cerebrospinal fluid, and decreased availability, and release of striatal DA, all of which correlated with symptoms of reduced motivation and/or motor retardation. Importantly, inflammation-associated symptoms are often difficult to treat, and evidence suggests that inflammation may decrease DA synthesis and availability, thus circumventing the efficacy of standard pharmacotherapies. This review will highlight the impact of administration of inflammatory stimuli on the brain in relation to motivation and motor function. Recent data demonstrating similar relationships between increased inflammation and altered DAergic corticostriatal circuitry and behavior in patients with major depressive disorder will also be presented. Finally, we will discuss the mechanisms by which inflammation affects DA neurotransmission and relevance to novel therapeutic strategies to treat reduced motivation and motor symptoms in patients with high inflammation.

The Role of Dopamine in Inflammation-Associated Depression: Mechanisms and Therapeutic Implications.

Studies investigating the impact of a variety of inflammatory stimuli on the brain and behavior have consistently reported evidence that inflammatory cytokines affect the basal ganglia and dopamine to mediate depressive symptoms related to motivation and motor activity. Findings have included inflammation-associated reductions in ventral striatal responses to hedonic reward, decreased dopamine and dopamine metabolites in cerebrospinal fluid, and decreased availability of striatal dopamine, all of which correlate with symptoms of anhedonia, fatigue, and psychomotor retardation. Similar relationships between alterations in dopamine-relevant corticostriatal reward circuitry and symptoms of anhedonia and psychomotor slowing have also been observed in patients with major depression who exhibit increased peripheral cytokines and other inflammatory markers, such as C-reactive protein. Of note, these inflammation-associated depressive symptoms are often difficult to treat in patients with medical illnesses or major depression. Furthermore, a wealth of literature suggests that inflammation can decrease dopamine synthesis, packaging, and release, thus sabotaging or circumventing the efficacy of standard antidepressant treatments. Herein, the mechanisms by which inflammation and cytokines affect dopamine neurotransmission are discussed, which may provide novel insights into treatment of inflammation-related behavioral symptoms that contribute to an inflammatory malaise.

The Dopamine Hypothesis of Schizophrenia: An Historical and Philosophical Analysis

Abstract: The dopamine (DA) hypothesis of schizophrenia (DHS) has, since its inception over 30 years ago, been among the most prominent etiologic theories in psychiatry. This essay begins by summarizing the history of its emergence and efforts to empirically test it through the examination of (i) cerebrospinal fluid DA metabolites, (ii) neuroendocrine measures, (iii) clinical response to psychostimulants, (iv) brain levels of DA and its metabolites, (v) brain studies of DA receptors, and (vi) genetic association studies. We then examine how successful the DHS has been and by what criteria its performance should be evaluated. In this process, it is critical to distinguish the etiological DHS from the pharmacological DA hypothesis of neuroleptic action. Although the DHS stimulated much science, most efforts to empirically validate it have failed, in contrast with the well-supported pharmacological DA hypothesis of neuroleptic action. Nonetheless, the DHS has held the status of a scientific paradigm defended by some with great avidity. Like other temporally extended theories, the DHS in its most general form is relatively nonspecific and protean in nature. In its evolution through successive more specific forms, often embodying ad hoc modifications of subsidiary hypotheses, it became very difficult to falsify. Although stimulating much research, it has not produced a progressive research program generating various novel and confirmed predictions about schizophrenia. For most of its history, the DHS has lacked a viable competing alternative theory against which it could be incisively compared. Sociological factors, especially the rise to prominence of the biological psychiatry movement, and the conflation of the DHS and the DA theory of antipsychotic drug action have probably played an important role in its persistence. Psychiatry needs theories with higher levels of specificity and falsifiability. As the science of psychiatry matures, the field needs to become more self-critical about the validity of its theories.

Dopamine transporter defect: Infantile parkinsonism-dystonia with elevated dopamine metabolites in cerebrospinal fluid is genetically resolved

Aim of the study: To describe the clinical features and underlying etiology of a group of patients with a unique complex movement disorder. Methods: The clinical features (including video footage) and results of CSF investigation of 10 patients (from 9 distinct unrelated kindreds) were reviewed. Autozygosity mapping studies were undertaken in order to identify the disease-causing gene. Results: The movement disorder is heterogeneous, especially in infancy. However, some features are almost universally present, such as intense and frequent dystonic crises during the first years of life, development of severe swallowing difficulties and anarthria. The movement disorder in infancy is characterised by both hyperkinetic and hypokinetic features, however severe hypokinesia/akinesia and rigidity predominate later in childhood. Over time some children develop ocular flutter and saccade initiation failure. Whereas the motor disorder is progressive (4 patients died at ages 9, 13, 14 and 16 years respectively) cognitive function is relatively spared. Numerous treatment strategies have shown limited therapeutic response. Magnetic resonance imaging studies (including in-vivo spectroscopy in one patient) did not reveal abnormalities in most patients although periventricular white matter changes were evident in 3 patients. Investigations of cerebrospinal fluid (CSF) revealed paradoxically elevated concentrations of dopamine metabolites (ratios of dopamine metabolite homovanillic acid (HVA) [nmol/l]/serotonine metabolite 5-Hydroxy-inddole acetic acid (HIAA) [nmol/l] between 5 an 13, normal ratios between 1.5 and 4). Molecular genetic investigation identified the gene encoding the pre-synaptic dopamine transporter (DAT), SLC6A3 as the causative gene and germline mutations were identified in all 10 patients. DAT scan (undertaken in one patient) showed almost complete loss of basal nuclei DAT activity. Conclusions: Genetic DAT deficiency is identified as a new cause of a complex extrapyramidal movement disorder evolving into severe parkinsonism-dystonia with paradoxically elevated dopamine metabolites in CSF.

Cerebrospinal dopamine metabolites in rats after intrastriatal administration of 6-hydroxydopamine or 1-methyl-4-phenylpyridinium ion

Dopamine (DA) and its main cerebral metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured in striatum and cerebrospinal fluid (CSF) from cisterna magna in rats bilaterally lesioned by intrastriatal administration of 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenylpyridinium ion (MPP +). 6-OHDA caused a progressive lesion in striatum that is only moderately reflected in the decrease in dopamine metabolite concentration in CSF. MPP + caused an acute but less selective lesion in the dopamine striatal system, as indicated by a significant reduction in striatal GABA content, followed by a slow recovery in dopamine striatal metabolism and content. The locomotor activity was dramatically reduced in both groups 48 hours after the treatment but remained significantly decreased after two months only in 6-OHDA lesioned animals. A positive correlation was found between HVA CSF concentration and striatal DA content in MPP + lesioned rats, but not in 6-OHDA lesioned rats. It is concluded that the concentration of dopamine metabolites in CSF can be altered only after a severe striatal lesion: reduction of striatal dopamine content below 50% of normal values and involvement of neuronal or non-neuronal elements other than the dopaminergic system, similarly to the lesions caused by MPP +. These results may partly explain why CSF dopamine metabolites concentrations were significantly decreased both in advanced stages of parkinsonism and in other neurodegenerative disorders.

Monoamines and their metabolites in plasma and lumbar cerebrospinal fluid of Chinese patients with Parkinson's disease

Ten free monoamines and their metabolites in plasma and cerebrospinal fluid (CSF) were simultaneous measured in 6 levodopa-untreated (LU), 18 levodopa-treated (LT) and 37 levodopa-withdrawn (LW) Chinese patients with Parkinson's disease (PD) and 26 controls. We found that the levels of these substances in LW patients were not significantly different from those in LU patients. In LU- and LW-PD patients, CSF epinephrine (EPI) was higher ( P < 0.05) than that of the controls. 3-methoxy-DOPA (3-OMDOPA) might not inhibit the accumulation of 3,4-dihydroxyphenylalanine (DOPA) and dopamine metabolites in CSF. Levodopa treatment might change the dopaminergic and serotoninergic neuronal systems, but not the noradrenergic or adrenergic neuronal systems, in CNS of PD patients. Benserazide (a peripheral decarboxylase inhibitor) in Madopar might decrease the levels of serotonin (5-HT) and norepinephrine (NE), but not those of DOPA and homovanillic acid (HVA), in plasma. HVA, NE and EPI in plasma were not good indices for those in CSF. Otherwise, our results were consistent with some other studies by showing a significantly lower level ( P < 0.01) of HVA in CSF of LU- and LW-PD patients than that of the controls, while no difference for NE, 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindole acetic acid (5-HIAA) or 3-OMDOPA was noted. The severity of clinical disability was related to the deficiency of CSF HVA and DOPAC in LU- and LW-PD patients; however, there was no relationship between clinical symptoms of tremor, rigidity-bradykinesia, autonomic dysfunction, dementia, depression or levodopa-induced dyskinesia and CSF monoamines or their metabolites.

Effect of adjuvant reserpine treatment on catecholamine metabolism in schizophrenic patients under long-term neuroleptic treatment.

The clinical and biochemical effects of adjuvant reserpine treatment were investigated in 12 chronic schizophrenic patients on long-term neuroleptic medication. The global severity of the symptoms using the Brief Psychiatric Rating Scale did not change significantly in the whole group, however, a moderate decrease in positive symptoms (factors though disturbance, activation and hostile-suspiciousness) was observed for 5 patients. Cerebrospinal fluid (CSF) noradrenaline levels showed a consistent decrease, but other biochemical parameters (CSF dopamine metabolites, platelet MAO and serum dopamine-beta-hydroxylase activities) did not change significantly. The changes of clinical symptoms and biochemical parameters did not show any correlation.

Dopamine Agonists in the Treatment of Schizophrenia

Behavioral, neurochemical, ligand binding, and single cell unit recording studies suggest the existence of two distinct classes of dopamine (DA) receptors: autoreceptors, which are present on the membranes of dopamine neurons, and postsynaptic receptors located on the neurons with which dopamine neurons synapse. Various pharmacological studies have suggested an overactivity of dopaminergic neurons in schizophrenic patients, however, studies on the concentrations of dopamine metabolites in cerebrospinal fluid (CSF) and post-mortem brain tissue, and clinical studies with schizophrenic patients who are free of drugs do not support this interpretation. Attention has therefore turned to the studies on the central dopamine receptors in schizophrenia. The use of binding techniques with tritiated ligands to study dopamine receptor density in post-mortem brain tissue has produced a number of interesting results. At present, it is accepted that the density of dopamine receptors in post-mortem brain tissue from schizophrenic patients is significantly increased in the striatum and in the nucleus accumbens.

Nomifensine antagonizes the ouabain-induced increase in dopamine metabolites in cerebrospinal fluid of the rat

The effect of the Na+, K+-ATPase inhibitor, ouabain, on cerebrospinal fluid dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) levels was studied in pentobarbitone-anesthetized rats. An intracerebroventricular injection of ouabain (100 nmol) dramatically increased DOPAC and HVA levels. A dopamine uptake inhibitor, nomifensine (10 mg/kg i.p.) injected prior to ouabain, completely abolished the effect of ouabain on dopamine metabolites. These results are in agreement with the ouabain-induced increase in dopamine efflux described in vitro and favour the role of a carrier-mediated cytosolic release of dopamine.