Alcohol and Central Serotonin Metabolism in Man James C.

Ballenger, MD; Frederick

K.

Goodwin, MD; Leslie

F.

Major, MD; Gerald

\s=b\ Animal studies and some of the phenomena associated with alcoholism in humans suggest that some central effects of alcohol may involve serotonergic systems. The CSF metabolites of serotonin and dopamine, 5-hydroxyindoleacetic acid (5HIAA), and homovanillic acid (HVA) were studied in hospitalized alcoholics. There were no significant differences in HVA levels between groups. The level of 5HIAA of alcoholics in the abstinence phase, 28 to 63 days after their last drink, was significantly lower (21.8 \m=+-\1.9 ng/ml) than both a nonalcoholic comparison group (31.7 \m=+-\2.0 ng/ml) and alcoholics in the immediate postintoxication phase, within one to two days after their last drink (32.3 \m=+-\2.9 ng/mL). (Arch Gen Psychiatry 36:224-227, 1979)

body Alarge implicates

of evidence from animal and human studies the biogenic monoamines as important CNS neurotransmitters, particularly in those areas of the brain subserving "emotional" functions. Largely on the basis of their involvement in the mechanisms of action of psychoactive drugs, these amines have been implicated in various psychiatric states,' and CSF amine metabolites have constituted one approach to their study in disease states. However, despite a wealth of animal evidence of alcohol-amine interrelationships, there are little data on the effects of alcohol on CSF amine metabolites in humans. This article presents the results of a preliminary study in chronic alcoholics of the principal CSF amine metabolites of serotonin and dopamine, 5-hydroxyindoleacetic acid (5HIAA), and homovanillic acid (HVA), respectively; the metabolites were studied during both the immediate postintoxication phase and abstinence phase in subjects hospitalized for the treatment of alcoholism. Alterations were noted in 5HIAA, but not HVA, levels. .

Accepted

for publication Dec 28, 1977. From the Department of Psychiatry, National Naval Medical Center, Bethesda, Md (Drs Ballenger and Major), and the Clinical Psychobiology Branch (Dr Goodwin) and the Biological Psychiatry Branch (Dr Brown), National Institute of Mental Health, Bethesda, Md. Drs Ballenger and Major are now with the Intramural Research Program, National Institute of Mental Health, Bethesda, Md. The opinions or assertions contained herein are those of the authors and are not to be construed as official or reflecting the views of the Navy Department or the Naval Service at large. Reprint requests to National Institute of Mental Health, 9000 Rockville Pike, Bethesda, MD 20014 (Dr Ballenger).

L.

Brown, MD SUBJECTS AND METHODS

Thirty-seven men were studied on an alcohol rehabilitation inpatient unit at the National Naval Medical Center in Bethesda, Md. Subjects were limited to those who were free of medical problems and volunteered after careful explanation of the proce¬ dure involved. The age range was 19 to 55 years, with a mean of 28.8 years. All met criteria for the DSM II diagnosis of habitual excessive drinking and the diagnosis of alcoholism according to the research diagnostic criteria of Spitzer et al·' when applied independently by two psychiatrists. All subjects had been drinking more than 210 mL (7 oz) of absolute alcohol daily (eg, more than ten beers or seven drinks) for the six months prior to admission to the hospital. Most had been abusing alcohol for more than two years, with a range of VA to 25 years. All patients had a score of 10 or higher on the Michigan Screening Test for alcoholics, a series of 24 questions designed to gauge the depth of the patient's alcohol abuse. The mean score was 15.6, with 6 considered a cut-off score

alcohol problem. collected from both the immediate postintoxication period, the first two days of hospitalization and within 48 hours of last drink (14 patients) and from the abstinence period, after at least four weeks in the hospital (31 patients). As best could be determined by a careful history, subjects studied in the immediate postintoxication period were drug-free except for alcohol for the week prior to the study, with the exception of two patients who received chlordiazepoxide (75 mg/dL) 48 hours or more before the lumbar puncture. Other drugs, including aspirin and sedatives, were carefully avoided during the study period. All subjects were strictly abstinent from alcohol during hospitalization. For 24 hours prior to the lumbar puncture, foods were restricted to a controlled monoamine diet.11 Lumbar punctures were performed between 8 and 9 am after a night of bedrest, with the patients in the lateral decubitus position, and were atraumatic. Two thirds of the patients studied during the abstinence period received disulfiram, 250 or 500 mg/day. A comparison group of 28 patients with personality disorders was obtained from the general psychiatric wards of the same hospital; they were without histories of psychosis, affective illness, or neurological difficulties and had personality disorders similar to those of the alcoholic subjects. They differed from the alcoholic subjects in that they had no significant drinking histories and were younger (mean age, 23.3 years). The first 5 mL of CSF were collected in 8 mg of ascorbic acid and stored at -60 °C. Levels of 5HIAA and HVA were determined by the fluorometric method of Ashcroft and Sharman4 and Gerbode and Bowers.5 Except as otherwise indicated, statistical compari¬ sons were done by Student's t test for group or paired data.

indicating Data

a severe

were

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± 5.2 ng/mL) does not differ significantly from that of the 28 nonalcoholic comparison patients (34.5 ± 3.8 ng/mL), or from the 14 alcoholics in the imme¬ diate postintoxication phase (37.1 ± 4.8 ng/mL). Neither the 5HIAA nor the HVA level correlated with length of alcohol abuse or amount consumed in the previous year. However, there was a nonsignificant trend for the 5HIAA level to be lowest in the patient group in which the greatest amount of time had elapsed since their last drink.

period (33.1

E

30-

COMMENT

I IO

28-35 DAYS

1-2 DAYS

TIME FROM LAST DRINK of 5-hydroxyindoleacetic acid (5HIAA) in postintoxi¬ cation and abstinence periods (N 8, < .02, paired f test).

Comparison

=

CSF, 5-Hydroxyindoleacetic Acid (5HIAA), and Homovanilllc Acid (HVA) Levels in Alcoholics During Immediate Postintoxication and Abstinence Phases and in Control Patients

Experimental Groups

Mean

Age

SEM,

yr

Mean 5HIAA SEM,

ng/mL*

Abstinence

Mean HVA

SEM, ng/mL

±

5.2

33.1

Immediate postin¬ toxication

10)t

31

27.7 ± 1.5

21.8

1.9

(n

14

31.2 ±2.5

32.3 ± 2.9

37.1

±

4.8

28

23.3 ±1.0

31.7 ±2.0

34.5

±

3.8

±

Comparison

group (person¬

ality disorders)

"Adjusted for age contribution by an analysis of covariance. fSince disulfiram has been demonstrated to lower HVA values,9 only the abstinent alcoholics not taking disulfiram are reported.

RESULTS The relationship between age and CSF metabolites was examined for the population as a whole. The HVA level did not correlate with age (r .03); however, there was a modest but significant correlation between age and < .05). As illustrated in the 5HIAA level (r + .25; Table, after correction for age by analysis of covariance, the mean 5HIAA level of the 31 alcoholics in the abstinence phase (21.8 ± 1.9 ng/mL) was significantly lower than that of the 28 patients with personality disorders (31.7 ± 2.0 ng/mL) (P < .01), and was also significantly lower than that of the same or different alcoholic patients (N 14) studied during the immediate postintoxication period (32.3 ± 2.9 ng/mL) (P < .001). Similarly, in the eight patients studied during both periods, the 5HIAA level was lower in the abstinence phase than in the immediate =

=

=

postintoxication phase (P < .02, paired t test) (Figure).

As is seen in the Table, the mean HVA level from the ten not taking disfulfiram during the abstinence

patients

A variety of factors can be considered in the interpreta¬ tion of the results reported here. Since disulfiram is known to inhibit various aldehyde dehydrogenases, we might expect reduced formation of 5HIAA in our patients taking disulfiram by its action to block oxidation of the interme¬ diate indoleacetaldehyde to the acid metabolite, 5HIAA. However, animal experiments indicate that disulfiram either has no effect on 5HIAA formation, or increases it.6"8 In our patients in the abstinence phase, the mean 5HIAA level was not significantly different between the patients who received 250 or 500 mg daily of disulfiram (21.9 ± 1.7 ng/mL) and those patients not receiving the medication (22.8 ± 2.7 ng/mL). We have reported elsewhere a signifi¬ cant reduction in HVA levels in these same patients taking disulfiram.9 Differences in physical activity prior to lumbar puncture have been shown to be a source of variance in CSF metabolite studies1"; this potential artifact was controlled by strict bedrest for nine hours prior to the lumbar puncture in all subjects. One of the principal factors controlling the rate of serotonin synthesis in the brain is the concentration of plasma-free tryptophan relative to the neutral amino acids with which it competes for uptake into brain.11·12 To our knowledge, there are no studies in humans of the effects of ethanol on serum tryptophan, and since serum tryptophan was not measured in these alcoholics, its contribution to the present findings is not known. All three groups were on a standardized monoamine diet for the 24 hours prior to the lumbar puncture, and it can probably be assumed that the immediate postintoxication group had a deficient diet during the weeks prior to admission to the hospital. This relative starvation effect would tend to decrease serum tryptophan levels and therefore, decrease brain serotonin and 5HIAA levels in the immediate postintoxication group, opposite to the effect we observed. On the other hand, the carbohydrate load of the alcohol might itself increase the serum tryptophan level.11 What is known of the direct effect of alcohol on the serum tryptophan level is also complicated, and varies between species. Acute administration of alcohol to rats initially produces a significant increase in serum and brain free tryptophan levels and in brain serotonin and 5HIAA levels; however, these changes are followed by significant decreases in all measures at seven hours.13 The initial changes appear to be secondary to transient ethanolinduced increases in serum free tryptophan by catecholamine-mediated lipolysis, as well as by displacement of protein-bound serum tryptophan. This increase in the

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serum tryptophan level induces hepatic tryptophan pyrrolase, resulting in increased hepatic metabolism of trypto¬ phan and resultant decreases in serum and brain trypto¬

levels. On the other hand, in one study of chronic ethanol administration to rats, tryptophan pyrrolase was inhibited, but on withdrawal, enzyme activity returned to normal over four days and then increased above normal for up to ten days.14 Certainly, the reported inhibition of pyrrolase activity with chronic alcohol administration is consistent with our findings of increased 5HIAA levels in the imme¬ diate postintoxication group. However, it seems unlikely that the low 5HIAA levels we observed in the abstinent alcoholics four weeks and longer after their last drink was related to a rebound increase in pyrrolase activity, since 5HIAA levels tended to be lowest in those alcoholics studied with the greatest amount of time elapsed since their last drink. A basic question concerns the origin of 5HIAA in lumbar CSF. Data from a variety of sources suggest that although there is a contribution to lumbar 5HIAA from serotonin neurons in the spinal cord, some portion of the lumbar 5HIAA is derived from serotonin neurons of the brain.15 Additionally, most of the serotonin nerve terminals in the spinal cord have their cell bodies in brain stem and midbrain structures.16 An increase in CSF levels of 5HIAA secondary to a decrease in the active transport of 5HIAA out of the CSF under the influence of alcohol has been reported in the cat.17 Although we cannot rule out this possibility with our patients, we might expect the transport of HVA to be similarly inhibited, but we found no difference in HVA between the immediate postintoxication period and the abstinence period. We are not reporting data from subjects to whom alcohol was experimentally administered, but from subjects who were studied after previous drinking, while they were still mildly intoxicated or beginning early withdrawal. Most animal studies report that the ethanol-induced changes in the serotonergic systems continue for many hours (eg, 10 to 96 hours) after alcohol levels return to zero. Although the differences we have observed could be related to effects on serotonin neurons of decreasing brain alcohol levels (with¬ drawal), this does not appear to be a simple withdrawal effect. The mean 5HIAA level of the patients in the immediate postintoxication period with symptoms of with¬ drawal (diaphoresis, tremulousness, fever) (34.2 ± 4.7 ng/ mL) was not significantly different from those without withdrawal symptoms (33.7 ± 5.0 ng/mL). A frequently cited action of ethanol on serotonin levels is a shift in the peripheral metabolism of the amine from the oxidative to the reductive pathway.1819 The resultant decrease in urinary 5HIAA levels is accounted for by a concomitant increase in the reductive product, 5-hydroxytryptophol. Although this shift to the reductive pathway has also been demonstrated in rat liver slices,20 it has not been observed to occur in the central nervous system.2027 Even if such a shift had occurred in our acute intoxication group, its effect on 5HIAA levels would be opposite to the increases we observed. Despite multiple animal studies demonstrating that

phan

ethanol

acutely

and

chronically

affects central serotonin relationship remains unclear. Although initial studies of the acute effects of ethanol administration on serotonin content in rabbit brain revealed decreases of serotonin of up to 40%,283° these changes were not replicated in subsequent studies in other species3135; in fact, some studies find increases in rat brain serotonin levels after acute ethanol administra¬ tion.3638 Both increases30·39 and decreases28 29·3'1 of serotonin content have been noted following chronic administration of alcohol. In regard to central serotonin turnover, the majority of studies using a variety of techniques report that acute and chronic ethanol administration increase turnover of serotonin.21·27 3945 Only a few studies have explored the effects of ethanol on central serotonin metabolism in man. An autopsy study failed to demonstrate any significant differences in whole brain serotonin levels between controls and alcoholic and depressed suicide victims.46 Data from CSF studies are limited to two early case reports of no change in 5HIAA levels47·48 and three recent studies. In recent studies report¬ ing no change after chronic intoxication49 and a decrease after one day of intoxication,50 samples were obtained seven days and ten hours after the last drink, respectively, perhaps too late to observe transient changes. In the one study where alcoholics were studied while intoxication was maintained,51 5HIAA was increased over baseline. In two previous reports of CSF levels of 5HIAA in a small number of chronic alcoholics during abstinence,s"·51 the metabolite was noted to be "below the normal range." Also, alcoholics abstinent for six months have been reported to have lowered urinary 5HIAA levels,52 but this was not replicated in a follow-up study.53 Despite the preliminary nature of these findings, it is tempting to speculate briefly about the possible clinical relevance of the differences we observed between these groups of alcoholics. Although the animal literature on the effects of alcohol on central serotonin levels is conflicting, there is evidence that alcohol functions in a reserpine-like manner to release serotonin,* as well as intriguing evidence that the alcohol preference of the genetic strain of rats that prefer alcohol to water is dependent on low central serotonin levels.27,55"58 Our data, if supported by future work, would be consistent with a hypothesis that the pathophysiology of alcoholism might involve preexisting low brain serotonin levels that are increased transiently by alcohol consumption, but that brain serotonin levels grad¬ ually undergo increments of further depletion as a conse¬ quence of repeated drinking. This alcohol-produced deple¬ tion would aggravate the postulated preexisting serotonin deficit, setting up a "vicious cycle" in which the alcoholic repeatedly seeks to pharmacologically modify a central indoleamine defect. The actual mechanism by which acute or chronic alcohol ingestion altered central serotonin levels (eg, direct effect on brain, secondary to peripheral effects on amino acids, etc) is not critical to this hypothesis. To explore further these preliminary findings, CSF studies are underway that employ pretreatment with probenecid; this drug causes 5HIAA and HVA to accumuneurons, the exact nature of this

*References 19, 28-30, 35, 36, 42, 54.

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late in CSF by inhibiting their removal from the brain-CSF pool into the blood, perhaps providing a better reflection of central serotonin turnover than is possible with baseline levels alone.15 References

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and

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Alcohol and central serotonin metabolism in man.

Alcohol and Central Serotonin Metabolism in Man James C. Ballenger, MD; Frederick K. Goodwin, MD; Leslie F. Major, MD; Gerald \s=b\ Animal studi...
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