CSF monoamine metabolite concentrations vary according to age,rearing, and sex,and are influenced by the stressor of social separation in rhesus monkeys

In humans, CSF monoamine metabolite concentrations have been shown to vary as a complex function of age, sex, psychiatric diagnosis, and stress. To test for such relationships in rhesus monkeys, 28 subjects, reared either in anxiety producing peer-only groups or in mother-infant dyads, were studied at 6, 18 or 50 months of age. Each monkey underwent a series of four 4-day social separations, each followed by 3 days of reunion. Prior to and during the first and fourth separations, CSF was obtained from the cisterna magna and assayed for the serotonin metabolite 5-HIAA, the dopamine metabolite HVA, and the norepinephrine metabolite MHPG. CSF 5-HIAA showed an age-related decline which was greater in the mother-reared subjects. Peer-only-reared males had an increased 5-HIAA concentration relative to females, and higher 5-HIAA levels than mother-reared males. MHPG was also higher in peer-only-reared monkeys than in mother-reared subjects at all ages. In both groups HVA declined across the three ages, and MHPG increased from the 18- to the 50-month measurements. Both MHPG and 5-HIAA concentrations increased during the initial social separation, although only MHPG remained elevated across the repeated separations; HVA, on the other hand declined during social separation. These results are discussed in terms of established anxiety and aggression differences between peer-only and mother-reared monkeys.     

Central nervous system monoamine correlates of social dominance in cynomolgus monkeys (Macaca fascicularis).

Social dominance is a fundamental component of both human and nonhuman primate sociality. However, its neurobiological correlates remain incompletely understood. We evaluated the association between dominance status and monoamine metabolite concentrations in cisternal cerebrospinal fluid (CSF) in adult male (n = 25) and female (n = 21) cynomolgus macaques (Macaca fascicularis) housed in unisexual social groups. Concentrations of the metabolites of dopamine (homovanillic acid [HVA]), norepinephrine (3-methoxy-4-hydroxyphenylglycol [MHPG]) and serotonin (5-hydroxyindoleacetic acid [5-HIAA]) were assayed. Dominant monkeys, both males and females, had significantly higher CSF HVA concentrations than did subordinates (p values <.05). Among males, but not females, dominants also had lower CSF 5-HIAA than subordinates (p <.05). The Dominance-HVA association observed here is consistent with recent speculation that social extraversion, a dominance-related personality trait in humans, may also reflect heightened central nervous system dopaminergic activity.     

Repetitive measurement of monoamine metabolite levels in cerebrospinal fluid of conscious rats: effects of reserpine and haloperidol

A simple high performance liquid chromatographic method with electrochemical detection is described for the simultaneous determination of unconjugated 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), the principal central nervous system (CNS) metabolites of noradrenaline, serotonin and dopamine (DA), respectively, in small samples of cisternal cerebrospinal fluid (CSF) obtained repeatedly from freely moving rats. Amounts of 30-50 microliter of CSF could be collected repeatedly every 30-60 min allowing monitoring of monoamine metabolite concentration levels in CSF under physiological conditions. None of the metabolites showed any clear diurnal variation. A single injection of reserpine caused a prominent elevation in the concentrations of MHPG, 5-HIAA and HVA in CSF. However, after a rapid increase, the concentration of MHPG was decreased by 85% from the control values. Haloperidol caused a 3-fold increase in the concentration of HVA, indicating increased DA turnover in the CNS. The method enables the reliable quantitative determination of three major monoamine metabolites in small samples of CSF from freely moving rats and appears to be a useful tool in the evaluation of the validity of the clinically used research methods of monitoring drug-induced alterations in CNS monoaminergic activity by metabolite measurements in CSF.     

Dopamine and serotonin metabolites in rat cerebroventricular fluid following withdrawal of haloperidol or electroshock treatment

Levels of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and of the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were determined in the CSF of rats at various times after repeated electroshock treatment (EST) or chronic administration of haloperidol. The acidic metabolites were analyzed in 25 l CSF using HPLC with an electrochemical detector. A significant decrease in the CSF levels of DOPAC and HVA was found 4 days after the last administration of chronic haloperidol, EST, or both. The decrease in the level of the dopamine metabolites indicated a slower dopamine turnover, which might have resulted from hypersensitivity of presynaptic dopamine receptors after these treatments. Rats treated with haloperidol also showed an increase in 5-HIAA levels, possibly due to enhanced serotonin turnover. The 5-HIAA increase following haloperidol was prevented by a concurrent administration of EST, suggesting attenuation by EST of the haloperidol-induced enhancement of serotonin turnover.     

Effects of tiapride on homovanillic acid levels in human cerebrospinal fluid drawn at pneumoencephalography

The effect of tiapride on HVA and 5-HIAA levels in the CSF drawn at pneumoencephalography (PEG) was studied. Five consecutive 5 ml fractions of CSF were drawn from control and tiapride-treated subjects. In both groups, a linear increase in HVA concentrations was found between the first and subsequent fractions. On the contrary, no significant difference in 5-HIAA concentrations was found in sequential CSF samples. Tiapride increased the mean HVA concentrations and caused a steeper caudocranial gradient of this metabolite but failed to modify 5-HIAA concentrations. The results suggest that tiapride blocks dopamine (DA) receptors and increases DA synthesis.     

Determinations of 5-hydroxyindoleacetic acid and homovanillic acid in human CSF with monitoring of probenecid levels in CSF and plasma

The accumulation of 5-HIAA and HVA in cerebrospinal fluid (CSF) was studied in eight healthy volunteers after oral administration of probenecid. Simulation indicated that a dose of 4.5 g probenecid should be used to achieve probenecid plasma concentrations between 200 and 400 g/ml. Almost complete inhibition of the active transport of the acidic metabolites was assumed to be obtained at these concentrations. Probenecid 4.5 g was administered in two doses (2.5 g and 2 g), separated by 4 h. Plasma samples were drawn at varying intervals over a period of 46 h and lumbar puncture (LP) was performed at either 14 h or 20 h after the first administration of probenecid. The concentration of probenecid, 5-HIAA and HVA in CSF was estimated and the probenecid-induced accumulation of 5-HIAA and HVA was compared with their baseline values. There were no statistically significant differences (P>0.05) in the accumulation of the monoamine metabolites between the two LP (14 h and 20 h), neither were there any differences in CSF concentrations of probenecid at the time of LP. There were only small differences in probenecid plasma concentrations, although statistically significant. Due to maximum blockade of the active transport system no correlation was observed between the CSF concentration of probenecid and the induced accumulation of 5-HIAA and HVA, respectively. The range of probenecid-induced accumulation for 5-HIAA and HVA in these volunteers was 156–429% and 183–600%, respectively. The suggested monitoring of probenecid plasma levels is proposed as a suitable model to investigate central neuronal activity of dopamine and serotonin in the central nervous system.     

Reduced cerebrospinal HVA concentrations and HVA/5-HIAA ratios in suicide attempters. Monoamine metabolites in 120 suicide attempters and 47 controls.

Dysfunctions of central monoaminergic systems are important elements of the leading biological hypotheses of suicide and depression. The purpose of the present paper was to study the levels and the relationships between the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the dopamine metabolite homovanillic acid (HVA) and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in the cerebrospinal fluid (CSF) in 120 hospitalised suicide attempters and 47 controls (healthy volunteers or patients admitted for minor surgery). The suicide attempters showed significantly lower HVA levels (174+/-82 vs. 216+/-96 nmol/L, P=0.004), HVA/5HIAA ratios (1.6+/-0.5 vs. 2.1+/-0.6, P=0.0001) and HVA/MHPG ratios (4.2+/-2.1 vs. 4.8+/-1.7, P=0.02) than the controls. The correlations between the monoamine metabolites were markedly lower in patients than in controls. CSF 5-HIAA showed no significant differences between patients and controls (107+/-40 vs. 108+/-51 nmol/L) or between violent and non-violent attempters (112+/-58 vs. 105+/-33 nmol/L). The monoamine metabolites showed no significant differences between survivors and patients who subsequently completed suicide, or between suicide attempters subgrouped by psychiatric diagnoses. The results suggest that low HVA levels and altered relationships between the monoamine metabolites are associated with suicidal behaviour.     

Effects of acute cannabis use on urinary neurotransmitter metabolites and cyclic nucleotides in man

The noradrenaline, dopamine and serotonin metabolites methoxy-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), as well as the cyclic nucleotides c-AMP and c-GMP were estimated in urine samples of five normal volunteers. Ten control samples and two samples after cannabis use were analyzed for each volunteer. Cannabis use caused significant decreases in MHPG and c-AMP, and increases in HVA, while 5-HIAA and c-GMP excretion remained unchanged. The results indicate that cannabis use interferes with catecholaminergic mechanisms in man, decreasing the noradrenaline and increasing dopamine turnover, probably through action on presynaptic receptors.     

Effects of pentylenetetrazol and trimethadione on feline brain monoamine metabolism

The effects of pentylenetetrazol on behavioral excitation and brain monoamine metabolism were compared by monitoring the EEG and assaying feline cerebrospinal fluid (CSF) for monoamine metabolites. After a non-convulsant dose of pentylenetetrazol, neither the concentrations of the 5-hydroxytryptamine (5-HT) metabolite, 5-hydroxyindoleacetic acid (5-HIAA), nor the dopamine(DA) metabolite, homovanillic acid (HVA), were altered in CSF if the rectal temperature of the cat was maintained. After a convulsant dose there was an increase in 5-HIAA and HVA levels. The norepinephrine (NE) metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), was also increased, but returned to control within 3 hr, while 5-HIAA and HVA levels were elevated for 24 hr. Trimethadione produced a transient decrease in HVA levels. When the convulsions, but not EEG excitation, are prevented by trimethadione pretreatment, brain monoamine metabolism is increased. Plasma tryptophan levels decreased after convulsant doses of pentylenetetrazol. Pentylenetetrazol was not detectable in plasma or CSF 24 hr after injection, while CSF 5-HIAA and HVA levels were still increased. These data show that pentylenetetrazol directly increases brain NE, DA and 5-HT metabolism while causing EEG excitatory changes, an effect which may precede convulsions.     

Effect of probenecid on free 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and its sulphate in human cerebrospinal fluid

In a mixed group of 46 patients with affective disorder, or with various neurologic disorders, high doses of probenecid (100 mg/kg over 18 hr) produced a significant increase in lumbar cerebrospinal fluid (CSF) levels of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), the major metabolite of norepinephrine centrally. This increase (averaging 60%) is modest in comparison to probenecid induced increases in homovanillic acid (HVA) or 5-hydroxyindo-leacetic acid (5-HIAA). Analysis for free MHPG and its sulfate showed no significant differences for either compound after nine hours. After 18 hours of treatment significant increases in free MHPG and small but not significant increases of MHPG.SO₄ were found. These results suggest that a probenecid sensitive active transport mechanism for MHPG.SO₄ of the degree demon-strated for HVA and 5-HIAA in humans, and for MHPG.SO₄ in rats, does not occur in human CSF.     

Rhesus monkey cerebrospinal fluid amine metabolite changes following treatment with the reversible monoamine oxidase type-A inhibitor cimoxatone

The effects of cimoxatone, a reversible inhibitor of monoamine oxidase type A (MAO-A), on the deaminated metabolites of norepinephrine, dopamine, and serotonin were examined in continuously collected rhesus monkey cerebrospinal fluid (CSF). Cimoxatone, 0.5–8 mg/kg given PO, produced dose-proportionate reductions of 24-h mean CSF 3-methoxy, 4-hydroxy phenylglycol (MHPG) concentrations of 21%–52%. Homovanillic acid (HVA) concentrations also decreased 27%–55%, while CSF 5-hydroxyindoleacetic acid (5-HIAA) decreases were somewhat smaller (7%–32% from baseline). All three metabolite concentrations reached a nadir approximately 6–10 h after drug administration, and required over 40 h to gradually return towards baseline following drug discontinuation. HVA concentration reductions in particular persisted during the entire 24-h period following treatment and were the slowest to return to baseline values. CSF concentrations of cimoxatone and its MAO-inhibiting O-demethyl metabolite showed a parallel time course peaking 6–10 h after treatment and persisting for up to 24 h in the case of cimoxatone and over 48 h for its metabolite. Single simultaneous time point determinations revealed 10-to 20-fold lower concentrations of cimoxatone and its metabolite in CSF compared to plasma 2 h after treatment. MAO-B activity in platelet-rich plasma was not inhibited by 8 mg/kg cimoxatone, indicating that this drug maintains MAO-A selectivity in vivo. As cimoxatone's preferential effects on catecholamine metabolites were similar to those previously observed with the irreversible MAO-A inhibiting antidepressant, clorgyline, our results are consistent with limited clinical trials data suggesting that cimoxatone may also prove to be an effective antidepressant.     

Neurochemical changes in pigeon cerebrospinal fluid during chronic administration of buspirone or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)

Cerebrospinal fluid (CSF), collected repeatedly from White Carneau pigeons chronically implanted with guide cannulae located in the lateral ventricles, was analyzed for metabolites of serotonin, dopamine and norepinephrine after acute and chronic administration of buspirone or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Following the acute administration of 3.0 mg/kg buspirone, levels of 5-hydroxyindoleacetic acid (5-HIAA) decreased, while increases occurred in the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC). Decreases in 5-HIAA persisted throughout the chronic dosing regimen (36 days), while dopamine metabolites returned to control levels within 8 days. When chronic buspirone was discontinued, levels of 5-HIAA were restored to predrug control levels, while levels of HVA, DOPAC and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) decreased. All metabolites returned to predrug control levels within one week following buspirone discontinuation except for MHPG, which remained depressed. When the acute effects of buspirone were reexamined, levels of 5-HIAA were again significantly decreased, while HVA and DOPAC levels, as well as those of MHPG, increased significantly. Acute administration of the 5-HT1A receptor ligand 8-OH-DPAT (3.0 mg/kg) resulted in large decreases in 5-HIAA levels that persisted throughout the period of chronic administration. Neither acute nor daily administration of 8-OH-DPAT changed levels of HVA, DOPAC or MHPG. Large increases in 5-HIAA occurred when chronic 8-OH-DPAT was discontinued but declined within one week to control levels. Following a two-week drug-free period, 8-OH-DPAT again caused a significant reduction in 5-HIAA levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebrospinal fluid monoaminergic metabolites differ in wild anubis and hybrid (Anubis hamadryas) baboons: possible relationships to life history and behavior.

The article reports monoaminergic metabolite [homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG)], values from the cerebrospinal fluid (CSF) of 27 wild baboons (Papio hamadryas) aged 40 to 140 months. Animals were either anubis, or anubis with hamadryas admixture; males of the latter subspecies generally have a reduced tendency to disperse from their natal groups. Overall, the values and interrelationships among the CSF monoamine metabolites resembled data reported from closely related, captive-housed animals. For example, age was significantly correlated with HVA concentrations (r = -60, p < .05), but not with the other metabolites. Notably, males characterized by hamadryas admixture had significantly higher concentrations of HVA, 5-HIAA, and MHPG (p < .05, respectively), a result possibly driven by differences in serotonergic activity. These data provide initial evidence that variation in central monoaminergic activity, as indicated by CSF monoamine metabolite concentrations, may reflect differences in behavior and life history that have taxonomic and, perhaps, evolutionary significance.     

Differential effects of clorgyline on catecholamine and indoleamine metabolites in the cerebrospinal fluid of rhesus monkeys

The effects of acute and chronic administration of clorgyline, an irreversible inhibitor of monoamine oxidase type A (MAO-A), on the deaminated metabolites of norepinephrine, dopamine and serotonin were examined in rhesus monkey cerebrospinal fluid (CSF). Acute clorgyline treatment resulted in highly significant, dose-dependent reductions in 3-methoxy-4-hydroxyphenylglycol (MHPG) of 50% (1 mg/kg) and 68% (2 mg/kg) compared to pretreatment values. Chronic clorgyline administration (0.25 to 0.5 mg/kg X 24 days) resulted in a 67% reduction in CSF MHPG. In contrast, the concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were less affected by acute clorgyline administration, being reduced significantly only after the 2 mg/kg dose, which lowered 5-HIAA 27% and HVA 48%. Chronic clorgyline treatment had no significant effect on the CSF concentrations of HVA and 5-HIAA. These data, which suggest that MAO-A inhibition by clorgyline in vivo is more closely associated with changes in the noradrenergic than the serotonergic or dopaminergic systems in nonhuman primates, are in general agreement with the effects of clorgyline on CSF and urinary biogenic amine metabolites in man. They differ from several in vitro studies which indicate a primary role of MAO-A in the metabolism of serotonin and of MAO-B in norepinephrine degradation in primate brain. The discrepancies may reflect modulating effects of synaptic feedback mechanisms on the actions of clorgyline in vivo or perhaps a failure of CSF metabolites to adequately reflect brain amine metabolism changes. The lack of change in platelet MAO-B activity during clorgyline treatment together with the minimal changes in HVA concentrations indicate that the selective inhibitory effects of clorgyline on MAO-A were maintained during chronic administration of low drug doses.     

Minipump clorgyline administration and CSF amine metabolites in unrestrained monkeys.

The irreversible MAO-A inhibitor clorgyline was administered in doses of 0.5 mg/kg (N = 1), 1 mg/kg (N = 3), and 2 mg/kg (N = 1) to 5 young (age 5.5 to 23.9 months) pigtail (M. nemestrina) monkeys using a 28-day (Alza 2ML4) osmotic minipump. CSF MHPG, 5-HIAA, HVA, and plasma MHPG were measured before and at approximately weekly intervals after pump implantation. Implants were well tolerated. CSF MHPG decreased about 75%, 5-HIAA 30%, and HVA from 30-50% with a tendency to plateau by the second week. Plasma MHPG decreased to undetectable levels. The findings demonstrate that long-term inhibition of MAO-A can be produced in unrestrained monkeys by minipump administered clorgyline. There is an apparently greater effect on the norepinephrine system relative to the serotonin and dopamine systems.     

The effect of olanzapine treatment on monoamine metabolite concentrations in the cerebrospinal fluid of schizophrenic patients.

The mechanism of action of both typical antipsychotics and the atypical antipsychotic, clozapine, may be related to the (changing) interaction of dopamine and serotonin in schizophrenia. This study examined the effect of olanzapine in schizophrenic patients on cerebrospinal fluid (CSF) metabolites of dopamine (homovanillic acid, HVA) and serotonin (5-hydroxyindoleacetic acid, 5-HIAA). Twenty-three male schizophrenic patients, who were drug-free for at least 2 weeks (mean drug-free period of 35 days +/- 43; median 16 days), underwent a lumbar puncture (LP). Patients were subsequently treated with olanzapine 10 mg/day for 6 weeks, after which the LP was repeated. CSF was assayed for HVA and 5-HIAA concentrations. Psychiatric symptoms were rated once a week. Olanzapine significantly increased HVA concentrations and the HVA/5-HIAA ratio while 5-HIAA concentrations were not altered. These changes did not significantly correlate with treatment response. A negative correlation was found between HVA concentrations and negative symptoms after olanzapine treatment. In conclusion, olanzapine treatment increases HVA concentrations and the HVA/5-HIAA ratio in CSF of schizophrenic patients, but these changes are unrelated to its clinical efficacy.     

The effects of amiflamine on cerebrospinal fluid amine metabolites in the rhesus monkey

Amiflamine, a drug reported to be a reversible inhibitor of monoamine oxidase type A (MAO-A) selective for serotonergic neurons in rodents, was administered to rhesus monkeys over a 12-fold dosage range (0.5-6 mg/kg). Amiflamine produced small, essentially equivalent reductions in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA, 1-28%), 3-methoxy-4-hydroxyphenylglycol (MHPG, 4-26%), and homovanillic acid (HVA, 7-29%), suggesting that the effects of amiflamine are approximately equal on serotonin, norepinephrine and dopamine metabolism in nonhuman primates. Concentrations of amiflamine were very low in CSF 3-6 h after drug administration (less than 7 nmol/l), while those of its two major, biologically active metabolites were higher (22-150 nmol/l) and varied in relative proportions among the monkeys. Further investigation is required of some preliminary observations of a possible association between drug metabolite variations and the substantial individual differences in the amine metabolite changes following amiflamine treatment. MAO-B in platelets was not inhibited by 6 mg/kg amiflamine, indicating that MAO-A selectivity was maintained. At low amiflamine doses, early and transient increases in CSF 5-HIAA and HVA concentrations were observed, suggesting an amine-releasing effect of the drug within brain serotonergic and dopaminergic neurons.     

Monoamine metabolite levels in rat CSF: kinetic studies

The kinetics of monoamine metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), in cisternal CSF were determined after monoamine oxidase (MAO) inhibition (pargyline, 100 mg/kg) and tyrosine hydroxylase inhibition (alpha-methyl-p-tyrosine, alpha-MPT, 250 mg/kg) in awake rats. In addition, the possibility of a peripheral contribution to CSF MHPG levels was investigated by infusing large amounts of the metabolite into vena jugularis. Pargyline induced an exponential decrease of CSF MHPG, 5-HIAA and HVA, with respective half-lives of 51, 86 and 46 min. alpha-MPT caused a slower decline of MHPG and HVA, while 5-HIAA was unaffected. Results from the MHPG-infusion experiments indicate minor peripheral contribution to CSF MHPG levels in acute pharmacological studies. The present paper gives further support for the validity of our new animal model in detecting acute changes in central monoaminergic activity.     

Serotonin uptake inhibition during treatment of depression with nortriptyline caused by parent drug and not by 10-hydroxymetabolites

Treatment of endogenous depression with nortriptyline (NT), at a daily dose of 150 mg, resulted in a pronounced improvement of seven of ten patients investigated. The concentration of the norepinephrine metabolite HMPG in cerebrospinal fluid (CSF) decreased by 29% (P<0.01) after 3 weeks of treatment. There was no significant effect of treatment on the serotonin and dopamine metabolites 5-HIAA and HVA. In previous larger materials, however, a decrease of 5-HIAA in CSF has been demonstrated.Platelets from the patients showed an increase in K _m for serotonin uptake in response to NT treatment. The IC₅₀ value of NT for serotonin uptake inhibition was 940 nM, while the corresponding value of the major metabolite of NT, i.e. E-10-OH-NT, was much higher (6700 nM). Thus, during treatment, the parent drug and not the metabolite was responsible for the serotonin uptake inhibition in platelets. There was a close correlation between K _m and the plasma concentration of NT after 1 week of treatment (r=0.88, P<0.01) but not after 3 weeks of treatment (r=0.48; ns). There was no uniform effect of NT treatment on V _max. It is concluded that clinical NT treatment results in uptake inhibition not only in norepinephrine but also in serotonin neurons.     

In vivo effects of some histamine H1-receptor antagonists on monoamine metabolism in the mouse brain

Summary The in vivo effects of four Hr-antagonists, diphenhydramine, chlorpheniramine, mepyramine, and promethazine, on the metabolism of noradrenaline (NA), dopamine (DA), and 5-hydroxytryptamine (5-HT) were investigated in the whole mouse brain. Diphenhydramine and chlorpheniramine had no significant effect on levels of NA, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), DA, and 5-HT, but they significantly decreased levels of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA). In particular chlorpheniramine markedly decreased 5-HIAA levels at doses as low as 1 mg/kg, i. p. Mepyramine significantly decreased 5-HIAA levels but not those of other substances. High doses of promethazine significantly decreased NA levels but markedly increased those of MHPG, DOPAC, HVA, 5-HT, and 5-HIAA. The DA reduction induced by -methyl-p-tyrosine (-MT) was significantly inhibited by diphenhydramine, chlorpheniramine, and promethazine, but the -MT-induced NA decrease was significantly enhanced by promethazine. The 5-HIAA accumulations induced by probenecid were significantly inhibited by chlorpheniramine and mepyramine. These results suggest: (1) Diphenhydramine and chlorpheniramine inhibit the turnover of both DA and 5-HT by blocking their neuronal uptake. (2) Promethazine and mepyramine inhibit DA and 5-HT turnover, respectively, as a result of the inhibition of the uptake mechanism. (3) Promethazine increases NA turnover by enhancing NA release. The discriminative effects of these drugs on the monoamine systems may be related to some differences in their CNS actions. Send offprint requests to K. Saeki at the above address