Influence of gonadal steroids on human and monkey cerebrospinal fluid homovanillic acid concentrations

The influence of gonadal steroids on central dopaminergic function was assessed by measuring concentrations of the dopamine metabolite homovanillic acid (HVA) in cerebrospinal fluid (CSF) in humans and monkeys. CSF HVA and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were measured by high performance liquid chromatography with electrochemical detection. Thirteen intact adult female monkeys (Macaca fascicularis) and six ovariectomized monkeys had a lumbar puncture to collect CSF. Ovariectomized monkeys had higher HVA concentrations in their CSF while 5-HIAA levels remained unchanged. In a second experiment, 40 human subjects were divided into six groups as follows: I, women with menses; II, menopaused or ovariectomized women taking estrogens; III, hysterectomized women of unknown hormonal status; IV, menopaused or ovariectomized women; V, women taking dopaminergic drugs or showing signs of parkinsonism; VI, men. CSF was collected by lumbar puncture. 5-HIAA levels were constant. Hysterectomized (III) as well as menopaused or ovariectomized (IV) women had significantly (p less than 0.05) higher CSF HVA concentrations compared to men. While women in group IV were older, those in group III were of the same age as the men. These results provide further evidence for the role of endogenous ovarian factors as modulators of central dopaminergic activity.     

Concentrations of dopamine and noradrenaline in some limbic and related regions of the human brain

The concentrations of dopamine and noradrenaline were determined in some limbic, cortical, striatal and mesencephalic regions of 12 humans. The highest concentrations of dopamine were found in the neostriatum and in the nucleus accumbens. Lower but significant values were detected in the globus pallidus, the substantia perforata anterior, the substantia nigra and in the region medial to the substantia nigra (area A 10). The concentrations of noradrenaline were generally low with the highest values in the area A 10 and the substantia perforata anterior.     

Measurement of plasma homovanillic acid concentrations in schizophrenic patients

1. Several lines of evidence suggest that abnormalities of central dopaminergic transmission may be involved in the expression of some schizophrenic symptoms. However, elucidation of the role of dopamine (DA) in schizophrenia has eluded investigative efforts partially because no accurate and easily repeatable measure of brain DA activity exists. 2. The development of a technique to measure homovanillic acid in plasma has offered the possibility of performing serial measurements of this major DA metabolite. 3. Assuming that plasma homovanillic acid (PHVA) concentrations is an index of brain DA activity, measurement of PHVA can play a role in elucidating the DA abnormality in schizophrenia. 4. Results to date suggest that plasma homovanillic acid concentrations are lower in chronic schizophrenic patients compared to normal controls, and that PHVA values correlate with schizophrenic symptom severity. 5. In addition, PHVA levels were shown to initially rise and subsequently decline during chronic neuroleptic administration in treatment responsive but not in treatment refractory schizophrenic patients.     

Reduced brain delivery of homovanillic acid to cerebrospinal fluid during human aging

BACKGROUND: Markers of human brain dopamine metabolism are reported to decline with age. However, the cerebrospinal fluid (CSF) concentration of homovanillic acid (HVA), a major dopamine metabolite, is reported to not change or to increase in elderly individuals. OBJECTIVE: To estimate the rate of delivery of HVA from the brain to CSF, taking into account the HVA concentration gradient in the spinal subarachnoid space and CSF flow. METHODS: Homovanillic acid concentrations were measured in 5 serial 6-mL aliquots of CSF removed from the L3-4 or L4-5 interspaces of 7 healthy young (mean +/- SD age, 28.7 +/- 4.6 years) subjects and 7 healthy elderly (mean +/- SD age, 77.1 +/- 6.3 years) subjects. Cisterna magna HVA concentrations were estimated from the slopes of the HVA concentrations along the spinal subarachnoid space. The products of cisternal HVA concentrations and published values for CSF flow were used to estimate lower limits for brain delivery of HVA to CSF, according to the Fick principle. RESULTS: The mean +/- SD HVA concentration in the initial lumbar CSF sample in the young subjects, 116 +/- 66 pmol/mL, did not differ significantly from 140 +/- 86 pmol/mL in the elderly subjects. Estimated cisternal HVA concentrations equaled 704 and 640 pmol/mL, respectively, in the young and elderly subjects. Multiplying these concentrations by CSF flow rates of 591 and 294 mL/d, respectively, gave lower limits for rates of delivery of HVA from the brain to CSF. These rates equaled 416 and 175 nmol/d, respectively. CONCLUSION: A 50% decline in the lower limit for the rate of HVA delivery from the brain to CSF in elderly individuals is consistent with other evidence that brain dopaminergic neurotransmission declines with age.     

Elevated gamma-aminobutyric acid level in striatal but not extrastriatal brain regions in Parkinson's disease: correlation with striatal dopamine loss

We measured the concentration of gamma-aminobutyric acid (GABA), glutamic acid, and o-phosphoethanolamine in autopsied brain of 9 patients who died with idiopathic Parkinson's disease and 10 control subjects. In the control striatum GABA showed an uneven rostrocaudal distribution pattern with rostral subdivisions containing about 40 to 50% higher levels. When compared with controls, GABA concentrations in Parkinson's disease striatum were generally elevated. The GABA elevation was most pronounced in the caudal subdivision of the putamen; this striatal subdivision also showed the most severe dopamine loss. We observed in the caudal putamen a significant negative correlation between the (elevated) GABA and (reduced) dopamine levels (the latter expressed as the sum of dopamine plus 3-methoxytyramine). Milder nonsignificant elevations of GABA levels were observed in intermediate and rostral putamen followed by the caudate head subdivisions. GABA levels were normal in all extrastriatal brain areas examined. Striatal glutamic acid levels were markedly elevated in 3 of the 9 patients with Parkinson's disease. We suggest that the altered GABA metabolism in the striatum, especially the putamen, is consequent to the nigrostriatal deficiency in this disorder. This secondary change in striatal GABA function is likely to contribute to the basal ganglia dysfunction produced by the striatal dopamine loss and thus may be related to certain aspects of parkinsonian symptomatology.     

Reduced CSF concentrations of homovanillic acid and homovanillic acid to 5-hydroxyindoleacetic acid ratios in depressed patients: relationship to suicidal behavior and dexamethasone nonsuppression

Depressed patients who had attempted suicide (N = 19) had significantly lower CSF homovanillic acid (HVA) levels than patients who had not attempted suicide (N = 8) and control subjects (N = 41). Intergroup levels of 5-hydroxyindoleacetic acid (5-HIAA) were not significantly different. The ratio of CSF HVA to CSF 5-HIAA was significantly lower in both patient groups than in control subjects, and patients who had attempted suicide had CSF HVA/5-HIAA ratios that were nearly 50% those of the control subjects. The combinations of nonsuppression on the dexamethasone suppression test and either a low CSF HVA level or a low CSF HVA/5-HIAA ratio were significantly more common among patients who had attempted suicide than among those who had not.     

Light-dependent alteration of serotonin-1A receptor binding in cortical and subcortical limbic regions in the human brain

Abstract

Objective. Climate, in particular sunshine, influences mood and energy levels, creating a positive upswing of mood on bright, sunny days and negative downswing in cold, dark winter seasons. Higher serotonin transporter availability in healthy human subjects in times of lesser light exposure and lower serotonin levels have been shown in winter. Methods. We examined the light-dependent variations in serotonin-1A receptor binding in limbic regions in 36 drug-naive healthy human subjects. Receptor binding was quantified using positron emission tomography and the radioligand [carbonyl-¹¹C]WAY-100635. Binding potential values were related to the amount of individual exposure to sunlight (daily duration of sunshine) and global radiation (total light intensity). Results. We found a 20–30% lower serotonin-1A receptor binding in the group exposed to a lower amount of global light radiation. Partial correlation analysis revealed significant positive correlations between the regional postsynaptic serotonin-1A receptor binding and global radiation accumulated over a period of 5 days. Conclusions. Seasonal factors, such as daily amount of sunshine and global radiation, influence serotonin-1A receptor binding in limbic brain regions of healthy human subjects. Combined with recently demonstrated seasonal fluctuations in the serotonin transporter availability, our results underline the importance of seasonal factors in the regulation of the serotonergic transmission.     

A comparison of plasma homovanillic acid concentrations in schizophrenic patients and normal controls

Plasma homovanillic acid concentrations, a potential index of central dopamine turnover, were examined in normal control subjects and chronic schizophrenic patients over a 12-hour period, including the period of sleep. Plasma homovanillic acid concentrations were lower in schizophrenic patients compared with normal controls at all times; however, within the group of schizophrenics, the more symptomatic patients had higher plasma homovanillic acid concentrations than the less severely ill patients. These data are consistent with a more complex role of dopamine in schizophrenia than was previously conceptualized.     

Regional brain homovanillic acid following delta 9-tetrahydrocannabinol and cocaine

delta 9-Tetrahydrocannabinol (10 mg/kg) increased homovanillic acid in rat prefrontal cortex and olfactory tubercle. This dose did not affect homovanillic acid in the caudate. Higher doses increased homovanillic acid in all 3 regions. Cocaine (20, 30, or 50 mg/kg) did not affect homovanillic acid in any of these brain regions.     

Effects of neuroleptic treatment on symptoms of schizophrenia and plasma homovanillic acid concentrations

Measurement of plasma concentrations of the dopamine metabolite, homovanillic acid, is an indirect tool to assess changes in dopamine turnover in schizophrenic patients. Plasma homovanillic acid concentrations have been reported to decrease during neuroleptic treatment, with the decrement correlating with symptomatic improvement in symptoms of schizophrenia. The present study tested the hypothesis that neuroleptic drugs decrease plasma homovanillic acid concentrations in those schizophrenic patients who improve with administration of neuroleptic drugs but not in patients who fail to display a treatment response. Twenty schizophrenic men who remained drug free for at least 2 weeks were treated with 20 mg/d of haloperidol for 5 weeks. Symptoms and plasma homovanillic acid concentrations were assessed on the last drug-free day and weekly for 5 weeks. Mean plasma homovanillic acid concentrations decreased in the group of patients who responded to neuroleptic treatment and did not change in the group of patients who did not improve. These findings suggest that there may be a qualitative distinction between responders and nonresponders to dopamine antagonists.     

Changes in plasma homovanillic acid concentrations in schizophrenic patients following neuroleptic discontinuation.

Changes in plasma levels of the dopamine metabolite homovanillic acid have been reported to correlate with changes in the severity of schizophrenic symptoms during neuroleptic administration and after neuroleptic discontinuation. This study examined the effects of discontinuation of neuroleptic treatment on plasma homovanillic acid levels in 23 patients with chronic schizophrenia. It was hypothesized that clinical decompensation would be associated with increased plasma homovanillic acid levels. Plasma homovanillic acid was measured during administration of neuroleptic medication and during a subsequent 6-week drug-free period. Nine patients decompensated during the drug-free period and 14 patients did not. Following drug discontinuation, plasma homovanillic acid concentrations were higher in schizophrenic patients who decompensated than in those who did not. Furthermore, peak plasma homovanillic acid elevation after discontinuation of neuroleptic medication was significantly correlated with peak Brief Psychiatric Rating Scale increase. The data suggest that, in some schizophrenic patients, symptomatic decompensation after discontinuation of neuroleptic treatment is associated with increases in dopamine turnover.     

Monoamine concentrations in brain regions of the developing rabbit

Growth patterns in selected areas of rabbit brain were studied neurochemically by assaying for norepinephrine, dopamine and serotonin from the neonatal to adult stages of development. These measurements showed that the various monoamines reached adult concentrations at different rates within a brain region; each region had a unique pattern of amine development. Changes in content were most marked in the first 2 weeks of life. Concentration increases were pronounced for norepinephrine and serotonin in the hypothalamus and for dopamine in the caudate nucleus. By contrast, norepinephrine concentrations in the pons-medulla and colliculi were relatively stable. The marked changes and differences in amine concentrations of maturing rabbit brain provide basic data on monoaminergic innervation of discrete regions and indicate the rabbit merits consideration in neurochemical and physiologic studies on the development of neurotransmission.     

Decreased CSF concentrations of homovanillic acid and gamma-aminobutyric acid in Alzheimer's disease. Age- or disease-related modifications?

Fifteen patients, 48 to 72 years old, with Alzheimer's disease were studied. Clinical status was assessed by neurologic and neuropsychologic examinations and psychometric testing. Patients were divided into two groups on the basis of clinical assessment: group 1, little mental deterioration, and group 2, serious mental deterioration. Nineteen subjects, 27 to 72 years old, without neurologic disease served as controls. Levels of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and gamma-aminobutyric acid (GABA) were determined in lumbar CSF by fluorimetric or radioreceptor binding (GABA) methods. The HVA concentrations increased with age in the controls, whereas the GABA levels decreased with age and 5-HIAA levels were not modified. When compared with the age-matched controls, the patients with Alzheimer's disease showed low concentrations of HVA but not of 5-HIAA or GABA. The decrease in HVA level was more pronounced in patients with severe mental deterioration and therefore appeared to be disease related.     

Regional brain homovanillic acid followingδ-tetrahydrocannabinol and cocaine

δ⁹-Tetrahydrocannabinol (10 mg/kg) increased homobanillic acid in rat prefrontal cortex and olfactory tubercle. This dose did not affect homobanillic acid in the caudate. Higher doses increased homobanillic acid in all 3 regions. Cocaine (20, 30, or 50 mg/kg) did not affect homobanillic acid in any of these brain regions.     

Effects of renal clearance on plasma concentrations of homovanillic acid. Methodologic cautions

Recently, there has been considerable interest in plasma concentrations of homovanillic acid (HVA) in various psychiatric disorders. Homovanillic acid is a weak organic acid, and its excretion probably resembles that of other organic acids (eg, p-aminohippuric acid) that are actively secreted by the kidney. Alterations in renal plasma flow can affect clearance of organic acids, resulting in changes in plasma concentrations. In our study, concentrations of plasma HVA and urinary HVA (from 24-hour urine collections) were measured in 20 prepubescent boys who received 3 weeks of placebo, dextroamphetamine sulfate, and fenfluramine hydrochloride in a randomized, double-blind, counterbalanced study of the treatment of attention-deficit disorder. Plasma HVA concentrations were significantly lower during fenfluramine treatment than during amphetamine treatment. This difference, however, seemed to be caused by alterations in renal clearance of HVA rather than changes in production. Whole-body production of HVA, as indexed by total urinary HVA excretion, was unaffected by the different treatments, while renal clearance of HVA did differ significantly between amphetamine and fenfluramine treatment. It seems that alterations in renal clearance can affect plasma HVA concentrations, which should be taken into account when plasma HVA is studied.