Relationship between 3-methoxy-4-hydroxyphenylglycol and homovanillic acid in saliva and plasma of healthy volunteers.

Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) levels may reflect changes in central noradrenergic and dopaminergic activity, respectively. The relationship between MHPG and HVA in saliva and plasma was investigated to evaluate the utility of salivary metabolite measurement as a relatively noninvasive and useful alternative to plasma analysis. MHPG and HVA in saliva and plasma, collected concurrently, from 12 healthy volunteers, were measured by high-performance liquid chromatography. Concentration of free MHPG in saliva correlated significantly with plasma free MHPG. Salivary free MHPG was significantly higher than in plasma. Enzymatic hydrolysis of conjugated MHPG corroborated other work that plasma free MHPG, MHPG-glucuronide, and MHPG-sulfate were in roughly equal proportions. Unpredictably, in saliva, free MHPG was greater than 80% of the total. Salivary and plasma free HVA concentrations also correlated significantly, but salivary HVA levels were significantly lower than in plasma. Conjugated HVA was consistently less than 10% of total both in saliva and plasma. These findings suggest that salivary MHPG and HVA can reflect plasma metabolite levels. Although local factors may influence their formation and concentration in saliva, large changes in plasma free MHPG or HVA could be reflected by parallel changes in saliva.

Reproducibility of plasma catecholamine metabolites in normal subjects.

BACKGROUND: Plasma homovanillic acid (HVA) and methoxy-hydroxy-phenylglycol (MHPG) are often used in repeated measurement designs to assess dopamine and norepinephrine metabolism in clinical research. However, only limited data on the reproducibility of these metabolites are currently available. METHODS: Plasma HVA and MHPG were measured in normal volunteers on five nonconsecutive mornings under fasting conditions and restricted smoking and physical activity. RESULTS: Intraclass correlation coefficients (ICC) for plasma HVA and MHPG across 5 days were determined to be 0.85 and 0.79, respectively. ICC improved to 0.90 for HVA and 0.91 for MHPG when the average of the first 2 days was examined against the average of the last 2 days. CONCLUSIONS: Results suggested that under controlled conditions plasma HVA and MHPG measurements have good reproducibility.

Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) and clinical symptoms in Alzheimer's disease.

Postmortem findings point to significant abnormalities in central noradrenergic function in Alzheimer's disease (AD) which may be associated with changes in peripheral markers. In this study, the relationship between the peripheral noradrenergic marker, plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), and clinical symptoms was examined in 23 patients with probable AD. Basal MHPG levels correlated significantly with increased cognitive impairment (r = .58, p = .005), controlling for age, age at onset, gender, and time interval between plasma MHPG determination and cognitive testing. These results suggest that plasma MHPG increases as cognitive function in AD deteriorates, further supporting preliminary evidence for increases in noradrenergic indices in association with disease severity in AD.

Genetic antecedents of dopamine dysfunction in schizophrenia.

BACKGROUND: Relatives of schizophrenic probands frequently manifest attenuated features of this illness including the negative symptoms and the milder positive psychotic symptoms. These two symptom dimensions are hypothesized to be associated with decreased and increased brain dopamine (DA) functions, respectively, raising the possibility that DA abnormalities may be present in the relatives of schizophrenic probands. METHODS: Plasma homovanillic acid (HVA), the major DA metabolite and an indicator of brain DA activity, was measured in nonpsychotic, physically healthy first-degree relatives (n = 55) of schizophrenic probands and in normal subjects (n = 20) without a family history of schizophrenia. RESULTS: Plasma HVA inversely correlated with negative symptoms and positively correlated with attenuated positive symptoms. Also, relatives had decreased plasma HVA compared to normal subjects, consistent with the fact that these relatives are characterized by negative symptoms. These findings were not related to major peripheral factors that could affect plasma HVA suggesting that the findings may reflect changes in brain DA activity. CONCLUSIONS: Negative symptoms indicating a genetic diathesis to schizophrenia in relatives may have a biologic basis in reduced DA activity and the DA dysfunction of schizophrenia may have genetic antecedents. This opens an important new avenue for further study of DA in this illness.

Phenytoin-salicylate interaction.

Ten healthy adult subjects took a single daily dose of phenytoin for 9 days to achieve a steady-state serum phenytoin concentration in the therapeutic range. While continuing on phenytoin, subjects took increasing doses of salicylate in a step-wise fashion, each dose (325, 650, and 975 mg) given every 4 hr for 48 hr. Serum (total) and salivary (free) phenytoin concentrations and serum salicylate concentrations were measured before and after each dose level of salicylate. Protein binding displacement of phenytoin by salicylate occurred only at the highest salicylate dose. Serum phenytoin control levels fell from 13.5 +/- 1.2 to 10.3 +/- 0.8 micrograms/ml (p less than 0.01), salivary phenytoin levels rose from 0.97 +/- 0.09 to 1.13 +/- 0.12 micrograms/ml (p less than 0.05), and phenytoin free fraction (salivary/serum ratio) increased from 7.14 +/- 0.34% to 10.66 +/- 0.57% (p less than 0.01) in the highest salicylate dose periods. There was no difference in these parameters during low-dose or intermediate-dose salicylate therapy. Linear-regression analysis failed to show a relationship between serum salicylate concentration and serum or salivary phenytoin concentration. Although high-dose salicylate induced protein binding displacement of phenytoin, it is unlikely that this is of clinical importance since the rise (16%) in the free (salivary) phenytoin concentration was small. Serum total phenytoin concentration may fall during salicylate therapy but the dose of phenytoin should not be altered unless there are overt signs of toxicity.

Control of renal factors in plasma homovanillic acid measurements.

To identify and control renal factors affecting plasma homovanillic acid (HVA), a dopamine metabolite and an indicator of brain dopamine activity in clinical research, nine healthy subjects were studied on 5 nonconsecutive days. First study day was the baseline and on the other days base, salt, water, or probenecid loads were given. On each day serial concentrations of HVA and serotonin metabolite 5-hyroxyindoleacetic acid (HIAA), another organic anion, in plasma were measured. Results suggested that base, salt, and water loads did not affect plasma concentrations of either metabolite. Probenecid, which partially blocks renal organic anion transport, induced similar increases in plasma HVA and HIAA. When plasma HVA:HIAA ratio was used to control for the effect of probenecid, differences between baseline and probenecid days were no longer significant. Results suggest that HVA and HIAA are similarly handled by the kidney and that simultaneously measured plasma HIAA could be used to distinguish renal influences in plasma HVA studies.

Rapid effects of environmental disturbance on rat plasma unesterified fatty acid and tryptophan concentrations and their prevention by antilopolytic drugs.

1 Changes of plasma unesterified fatty acid (UFA) and tryptophan concentration in group-housed rats following removal of their cage-mates and the effects of antilipolytic drugs on these changes were investigated. 2 Removal of group-housed 24 h fasted rats but not fed rats from cages resulted in increased plasma UFA concentration in the remaining rats which was associated with significant increases of the proportion of free tryptophan but significant falls of total tryptophan concentration. These rapid changes were not associated with brain tryptophan changes. Plasma tyrosine concentration was unaffected. 3 The fall of plasma tryptophan did not appear to be due to passage into red cells as erythrocyte tryptophan concentration remained unchanged. 4 Plasma UFA concentrations correlated positively and significantly with corticosterone concentrations which were also increased following removal of cage-mates. 5 Plasma UFA increases and tryptophan changes in the fasting rats were both prevented by nicotinic acid or propranolol. Corticosterone concentration was increased by nicotinic acid but unaffected by propranolol. 6 The possible importance of these rapid changes of plasma tryptophan and of their prevention by antilipolytic drugs is discussed.

Effects on plasma and brain tryptophan in the rat of drugs and hormones that influence the concentration of unesterified fatty acid in the plasma.

1 The effects on tryptophan distribution and metabolism of drugs altering plasma unesterified fatty acid (UFA) concentration were investigated in the rat.2 UFA and plasma free (i.e. ultrafilterable) tryptophan altered in the same direction.3 Catecholamines and L-DOPA increased both plasma UFA and free tryptophan. L-DOPA also increased brain tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) but decreased brain 5-hydroxytryptamine (5-HT).4 Aminophylline increased plasma UFA and free tryptophan and also brain tryptophan, 5-HT and 5-HIAA. Food deprivation had qualitatively similar effects.5 Insulin decreased plasma UFA and free tryptophan in both fed and food-deprived rats. However, while in fed rats these changes were associated with small decreases of brain indoles, in food-deprived animals small increases occurred.6 Nicotinic acid had only small effects in fed rats but it opposed both the UFA and indole changes in food-deprived animals. Total plasma tryptophan increased in nicotinic acid treated, food-deprived rats.7 There was a tendency towards inverse relations between changes of plasma free and total tryptophan.8 The results suggest that drugs which influence plasma UFA through actions on cyclic AMP thereby alter the binding of tryptophan to plasma protein and that this leads to altered distribution and metabolism of tryptophan.

In vivo voltammetric evidence of production of uric acid by rat caudate.

Linear sweep in vivo voltammetry with carbon paste electrodes records a prominent peak at about 340 mV in the anterior caudate of rat brain. This peak is increased by microinfusion of uric acid or xanthine oxidase (which enhances conversion of hypoxanthine and xanthine to uric acid) and is decreased or eliminated by microinfusion of uricase. Allopurinol (a specific xanthine oxidase inhibitor) also decreases this peak when given either intracranially or intraperitoneally. Co-administration of uricase and allopurinol reliably eliminate the peak in question. These data suggest that uric acid, a purine metabolite that has been thought to be absent in brain, is formed locally in rat caudate and that uric acid is the sole component of the peak at 340 mV. In vivo voltammetry may be a useful new tool for studying brain purine metabolism.

Excessive serotonin release, not depletion, leads to memory impairments in rats.

Eight experiments compared and contrasted the effects of serotonin release and depletion on performance by rats in two tests of memory. Most experiments (Experiments 1-5) examined the effects of the serotonergic releasing/depleting agent p-chloroamphetamine on passive avoidance performance. Additional experiments explored p-chloroamphetamine's effects on retention performance by animals trained in an 8-arm radial maze (Experiment 6), and the effects of dorsal raphe nucleus lesions on passive avoidance in animals treated with (Experiment 8) or not treated with (Experiment 7) p-chloroamphetamine. In general, acute increases in serotonin release produced consistent and extensive retention performance deficits in both passive avoidance and radial arm maze. Results from an ancillary control experiment indicated that the p-chloroamphetamine-induced passive avoidance impairment was not related to drug-induced alterations in pain sensitivity. Other experiments ruled out the possibility that p-chloroamphetamine was disrupting passive avoidance retention performance by affecting post-trial consolidation processes, producing state-dependent retention, having direct effects at postsynaptic receptors, or indirectly by affecting non-serotonergic neurotransmitter systems. Depletion of serotonin resulting from either the long-term residual effects of p-chloroamphetamine or lesions of the dorsal raphe nucleus failed to alter passive avoidance retention scores although it produced extensive depletion (45-85%) of serotonin and 5-hydroxyindoleacetic acid in the cortex and hippocampus. These data contribute to the growing body of literature indicating an important role of serotonin in cognitive processes by demonstrating that excessive release, but not depletion, of serotonin produces profound retention performance impairment.

Assessment of the central dopaminergic index of plasma HVA in schizophrenia.

Under fasting conditions, the dopamine (DA) metabolite homovanillic acid (HVA) in plasma originates mainly from central DA neurons or from central and peripheral noradrenergic (NA) neurons. The latter source contributes, in addition to HVA, the norepinephrine metabolites, for example, 3-methoxy-4-hydroxyphenylglycol (MHPG). It has been shown in primates that the association between HVA and MHPG in plasma or urine under varying rates of NA metabolism can be used to obtain an estimate of the central DA neuronal contribution of HVA to plasma or urine. This estimate is called the central dopaminergic index (CDI). Two studies presented here examine the applicability of this model in schizophrenia patients. The results were consistent with the proposed model and suggested that only about 30 percent of the total plasma HVA concentrations in our patients were derived from central DA neurons. A convenient modification of this model is proposed for future studies. Since the CDI of plasma HVA is not likely to be confounded by NA activity, this tool may prove useful in disentangling the roles played by the DA and NA systems in schizophrenia.

L-dihydroxyphenylalanine-induced asymmetric changes in striatal uric acid peak: determination by in vivo electrochemical detection in rats with unilateral nigrostriatal lesions.

Rats were unilaterally lesioned with 6-hydroxydopamine to destroy the nigrostriatal pathway. Following injection with 25 mg/kg L-dopa, circling behavior away from the lesioned side was monitored. Concurrently, in vivo electrochemical detection was used to compare changes in striatal extracellular levels of ascorbic acid (Peak 1) and uric acid (Peak 2) on the lesioned and unlesioned sides. Peak 1 changes did not differ, but Peak 2 changed asymmetrically on the two sides. The difference in the changes in Peak 2 was highly correlated with the circling behavior, with the greater increase on the lesioned side.

Post-mortem examination of dopaminergic parameters in Alzheimer's disease: relationship to noncognitive symptoms.

Dopaminergic mechanisms have been implicated in depression, agitation, and psychosis--symptoms that are frequently observed in patients with Alzheimer's disease (AD). In a longitudinal study, 23 prospectively assessed AD patients underwent autopsies in which concentrations of dopamine, homovanillic acid, and dihydroxyphenylacetic acid were assayed in the temporal lobe (Brodmann areas 20 and 21). Data-reduction techniques were used to minimize the number of relationships tested. For this series of AD patients, no significant correlation was found between indices of dopaminergic neurotransmission and maximal severity of psychosis, depression, or agitation.

Fatty acid and tryptophan changes on disturbing groups of rats and caging them singly.

The effects of disturbing groups of 24 hr fasted rats on plasma unesterified fatty acid (UFA) and tryptophan concentrations and brain tryptophan concentrations were investigated. Removing rats from cages rapidly increased plasma UFA and corticosterone and decreased plasma and whole blood tryptophan of cage mates. The disturbance also appeared to influence biochemical values of rats in other cages within the same chamber. Effects specific to individual cages were also suggested. In subsequent experiments 24 fasting rats caged together were rapidly transferred to 24 separate cages and killed at intervals. Plasma UFA rose to a maximum by 12 min and then fell toward initial values. Plasma total tryptophan concurrently fell then rose. Its percentage in the free (ultrafilterable) state, and in some experiments the absolute values of free tryptophan rose then fell. When the latter rise was marked then brain tryptophan and the 5-HT metabolite 5-hydroxyindoleacetic acid rose. Tyrosine changes were negligible. Thus altered brain tryptophan level and 5-HT metabolism may be associated with plasma tryptophan changes caused by brief environmental disturbance.