Alcohol withdrawal and dopamine receptor sensitivtty after prolonged abstinence

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ALCOHOL WITRDRhW& AND DOP-R AFTER PROLOl’U3EDWE

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GERHARD A. WIESBECK’, EUGEN DAVIDS’, NORBERT WODARZ’, JOHANNES THOME’, GERT WEIJERS’, FRANZ JAKOB* and JOBST BOENING’ ‘Department of Psychiatry, Addiction Research Group and ‘Medical Policlinic, University of Wuerzburg, Germany

(Final form, July 996)

Abstract Wiesbeck, Gerhard A., Eugen Davids, Norbert H jdarz, Johannes Thome, Gert Weijers, Franz Jakob and Jobst Boening: Alcohol Withdrawal and Dopamine Receptb Sensitivitv after Prolonged Abstinence. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1996,2p. pp. 1171-l 180 I. Forty-four male inpatients suffering from moderate to severe alcohol dependence (DSMIII-R and ICD-10) as well as 14 healthy controls entered this study. Individuals were classified according to the severity of their withdrawal symptoms during detoxification i. e. group I) no withdrawal, group 2) autonomic hyperactivity, group 3) withdrawal delirium and group 4) controls. 2. During the 6th week of treatment, that is, when all patients were recovered, controlled abstinent, and several weeks away from the end of their withdrawal syndrome, dopamine receptor sensitivity was neuroendocrinologically assessed by stimulating human growth hormone (HGH) with apomorphine (APO). 3. In a repeated measures model ANOVA, the four groups differed significantly in their HGH release. However, when excluding the controls from the analysis and focusing on alcoholics only (group 1 - 3), the significant difference disappeared. Covariates such as age, weight, quantity of drinking and duration of dependence were not related to the dependent variable. 4. In conclusion, the first significant result (with controls) reflects a blunted HGH response in alcoholics. It confirms earlier reports. The second, non significant result with the alcohol dependents only, suggests that the scveri.rityof withdrawal is not reflected by the amount of HGH released. Therefore, in alcoholics, a reduced dopamine receptor function after six weeks of abstinence, as neuro-endocrinologicaliy assessed with apomorphine, seems to be related to alcohol dependence rather than to the severity of alcohol withdrawal. Keywords: alcohol dependence, sensitivity.

alcohol withdrawal, apomorphine,

dopamine receptor

Abbreviations: apomorphine (APO), analysis of variance (ANOVA), body mass index (BMI), cerebrospinal fluid (CSF), Diagnostic and Statistical Manual of Mental Disorders (DSM-IIIR), homovanillic acid (HVA), human growth hormone (HGH), International Classification of Diseases (ICD-lo), Muenchner Alkoholismus Test (MALT), Statistical Package for the Social Sciences (SPSS).

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Introduction

Acute alcohol withdrawal affects numerous neurotransmitter

systems in both animals

(Griffiths et al. 1974, Hunt and Majchrowicz 1974, Kahn and Saidder 1976) and humans (Kato et al. 1979, TabakotY et J. 1977). Especiahy during alcohol withdrawal delirium marked alterations of biogenic amines are well documented (Athen et al. 1977, 1978). Low concentrations of homovanilhc acid (HVA), the major metabolite of dopamine, in lumbar cerebrospinal fluid (CSF) suggest that dopaminergic neurotransmission is involved in the physiology of the acute alcohol withdrawal syndrome (Borg and Weinholdt 1982, Major et al. 1977). Fujimoto et al. (1983) for example, reported significantly reduced CSF HVA levels in 12 subjects with delirium when compared with controls while no HVA changes were observed in cases with no or only minor withdrawal symptoms. Importantly, the reduction of HVA seemed to be specific to the withdrawal syndrome and not solely retlective of severity of drinking (Major et al. 1977). However, while most studies focus on changes during acute withdrawal states there is a lack of data about the endurance of those changes during abstinence. For example, even three weeks after cessation of drinking, alcoholics with a delirium (but not alcoholics with solely vegetative

withdrawal

symptoms)

differed

significantly from controls in their plasma HVA concentrations (Sano et al. 1994). Data reported by Kato et al. (1979) revealed reduced HVA levels in alcohol dependents suffering from an acute

withdrawal

syndrome

as compared

against

controls.

Interestingly,

reexamination during the fourth week still revealed no significant recovery of dopaminergic function. Findings like these raise the question whether alterations in brain dopamine activity may outlast the clinical withdrawal symptoms and persist even atIer several weeks of abstinence.

There are other indicators which support the h,ypothesis that dopaminergic neuromediation remains impaired in alcohol dependents even a long time after detoxification. Balldin and coworkers (1993) assessed D2 dopamine receptor tinction by stimulating human growth hormone (HGH) secretion with the dopamine receptor agonist apomorphine (APO). Alcohol dependents revealed a signiticantly lower HGH response than controls - indicating a reduced dopamine receptor function not only after heavy alcohol intake (Balldin et al. 1985) but, more importantly, even after several years of abstinence (Balldin et al. 1993). Again the question could be asked whether a long term impairment of dopaminergic neurotransmission might be

Alcohol wtthdrawal and dopamtne receptor sensittvtty

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associated with the severity of alcohol withdrawal during detoxification. However, there are no studies yet which give attention to this question. Therefore, postsynaptic dopamine receptor sensitivity, as neuroendocrinologically assessed with apomorphine, was determined in 44 alcohol dependent men and in 12 healthy controls. The purpose of the present paper was to assess dopamine receptor Iunction in different groups of alcohol dependents during their sixth week of abstinence classified according to the severity of their alcohol withdrawal syndrome during detoxification.

Methods

Subjects Forty-four male alcohol dependent subjects and 14 healthy male controls entered this study aiter informed consent was obtained. All alcoholics suffered from moderate to severe primary alcohol dependence which was diagnosed according to the criteria of ICD-IO (World Health Organization

1992) and DSM-III-R

(American Psychiatric Association

1987). Alcohol

consumption was calculated as the average amount of drinks per day (1 drink = 7g of alcohol) during the last six months prior to admission. Controls and alcohol dependent subjects were grouped according to their diagnosis and the severity of the alcohol withdrawal state during the first week of inpatient treatment by two experienced psychiatrists: l

Group 1 (n = 13): Alcohol dependent individuals who had experienced no alcohol withdrawal symptoms during their detoxification.

l

Group 2 (n = 19): Alcohol dependent individuals who had suffered from vegetative symptoms atter cessation of alcohol use (i.e. tachycardia, increased hand tremor, sleep disturbances, sweating).

l

Group 3 (n = 12): Alcohol dependent individuais who had gone through an alcohol withdrawal delirium after cessation of drinking which had been composed of vegetative symptoms in combination with psychomotor agitation, anxiety, hallucinations and a lowered level of consciousness.

l

Group 4 (n = 14): Healthy controls without any history of dependence and with light social drinking habits.

Alcohol dependents who had experienced a grand mal seizure during alcohol withdrawal did not enter this study.

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Wiesbeck et aL

Neuroendocrine Test Procedure Dopamine receptor sensitivity assessed with apomorphine (APO) served as the parameter for dopaminergic function in this study. APO is a selective dopamine receptor agonist which exerts its activity at postsynaptic D-l-like

and D2-!ike dopamine receptor binding sites

(DiChiara and Gessa 1978, Sourkes and La1 1975). It stimulates human growth hormone (HGH) via hypothalamic D-2 dopaminc receptors &al et al. 1973, Meister et al. 1985). This neuroendocrine test is well established in psychiatcz in general (La1 1988), as well as specifically, in alcohol research to assess dopamine receptor sensitivity in dependent individuals (Annuziato et al. 1983, Heinz et al. 1995, Wiesbeck et al. 1995). The test was performed during the patients’ sixth week of treatment. At this time all individuals were alcohol and drug free for at least five weeks and liver function tests were back to normal. Patients with hepatic failure didn’t enter this study. AtIer informed consent, the test took place under standardized conditions: always at 8.30 in the morning, in a quiet room, with subjects fasted overnight, and with an subcutaneous injection of APO in subemetic and weight related dosage (0.01 mg APO per kg body weight). Subjects remained recumbent throughout the testing procedure. APO was well tolerated. Some subjects experienced a slight fatigue but nobody fell asleep and there was no nausea or vomiting neither in alcoholics nor in controls. Blood was collected at five different time points: immediately before the injection of APO (tr = 0 min), 30 (tz), 60 (tx), 90 (t4) and 120 (ts) minutes thereafter. Blood samples were centritiged

and HGH plasma levels were determined at the same day using a Synchron

Enzyme Linked Immuno Sorbent Assay (SYNELISA, Elias, Freiburg, Germany). Intraassay coefficients of variation were 5 9 - 8.9%. Interassay coefficients of variation were 7.6 - 8.8%. The lower limit of detection was 0. i nghl; 95% of unstinrulated normal values in unselected patients (n = 530) are between 0 - 29 r&ml. Baseline levels below it ngiml were considered to be normal. Data Analyses Data were subjected to a two factorial analysis of variance repeated measure model (ANOVA) with APO induced HGH release as the dependent variable, and “group” and “time” as factors (“time” as the repeated measure). All calculations were done with SPSS.

Alcohol withdrawal and dopamtne receptor sensitMty

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Results Table 1 illustrates the characterizing data of the three withdrawal groups (1 - 3) and of controls (group 4). Alcohol dependent subjects were comparable in sex, age, drink quantity and severity of dependence as reflected by the Muenchner Aliioholismus Test (Feuerlein et al. 1977). There was a slight difference in weight and duration of dependence with group 3 subjects being lighter and suffering from alcohol dependence for a shorter period of time than members of group 1 and group 2. However, within the alcohol dependents, these differences were not statistically significant, neither for weight (FoJ,, = 0.94; p = 0.4) nor for duration of dependence (Fo.JI, = 3.09; p = 0.06). Nevertheless, in the statistical analysis, possibly confounding variables such as age, weight, body mass index, quantity of drinking and duration of dependencies were taken into account as covariates. Table 1 Characterizing Data of Alcohol Dependent Subjects (Group 1 to 3) and Contro!s (Group 4)

Sex Age (years) Weight (kg) Body Mass Index (kglm*) Drink Quantity (g/day) MALT Score

Groua No Alcohol Withdrawal n= 13 m 39.3 (* 7.49) 79.6 (+-9.74) 24.5 (k 2.32) 248.9 (+ 154.293 32.4 (.? 6.56) 17.4 (k 7.46)

Groua Autonomic. Hyperactivity n= 19 m 41.4 (& 7 17) 76.9 (+ 8.23) 24 5 (+ 2.68) 285 I (+ lil i0) 32 6 !+ 7 55) 17?? (rt 9.10)

Duration of Dependence (years) Numbers reflect means and (It:standard deviations)

WZl Delirium n= 12 4Y7 (+ 9.13) 74.7 (* 9.39) 24.1 (+ 2.64) 243.1 (168.60) 35 3 (f 5 99) 11.1 (* 5.49)

%!Ei! n= 14 3Yl (& 11.51) 77.1 (* 8.74) 24.0 (+ 2.59) 13.8 (? 6.20)

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G.A. Wiesbeck et al Table 2 Amount of Growth Hormone Released (in q&l) at 5 Different Time Points Across the 4 Croups

Time Points of Withdrawal 1Typeractirity Dehrium HGH n= 19 Determination n= 13 n=12 tl= Omin 0.5 (Ilr .46\ 0.3 (* .22) O?(+ 1.27) __._.--...-..._‘L_ ...__.._____L_ t2 = 30 min 5.3 (It 6.94) 4.8 (* 5.82) 10.3 (& 9.85) t3 = 60 min 7.5 (i6.41 j 9.1 (k 6.90) 7.0 (& 5.01) t4 = 90 min 2.2 (& 2.45) 2.7 (* 3.02) 3.1 (k 4.57) t5 = 120min 0.9 (Itl.40) 0.8 (t8lj 0.9@ 1.15) Numbers reflect means and (* standard deviations)

n= 14 0.3 (* 62) 9.9(f9.17) 13.7 (* 8.71) 4.9 (It 4.72) 1.6 (* 1.72)

The amount of growth hormone released across the four groups is shown in Table 2. In the firs: step, these data were analyzed by a 4 (group) by 5 (time) ANOVA design with “time” as the repeated measure. This revealed no main effect for “group”, a main effect for ‘lime” which was highly significant, and another significant main et&t

for group-by-time

interaction.. .Table 3.

ANOVA Table for Alcohol Dependent Subjects and Controls (Group 14)

source GrOUp Time Group x Time

Degrees of Freedom 3 4 12

Although the group-by-time &era&n

F 1.87 51.79 2.04

Sigdicance of F .I5 < .OOl ,022

wa3 sign&am, tile @cct t‘ppearedto be carried by

group 4 (controls) solely. Thid became obvious tit a sewr:d step ;&en o:;iy the data of alcohol dependents (group 1 - 3) were analyzed by a 3 (group) by 5 (time) ANOVA design. After excluding the non dependent controls, only the main effect for “time”’ remained sign&ant. There was neither a main effect for “group”, interaction.. .Table 4.

nor, importantly,

a group-by-time

Alcohol withdrawal and dopamine receptor sensitivity

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Table 4 ANOVA Table for the Alcohol Dependent Subjects (Croup 1-3) Source GrOUtI

Time Croup x Time

Degrees of Freedom 2

F 1 45

31.37 4 ----_----____________.---._-1.38 8

Signiticance of F 25

< ,001 .21

Additionally, analyses of covaria~~ccw2re WI with “age”, %eight”, “drink quantity”, and “duration of dependence” as the covariates. However, none of these covariates was signiticantly related to the dependent variable.

Discussion Dopaminergic neurotransmission is affected by acute alcohol withdrawal (Kato et al. 1979, Tabakoff et al. 1977). Parameters which reflect central presynaptic dopamine activity, like HVA levels in CSF, for example, suggest that even after several weeks of abstinence dopaminergic function is not tilly recovered in patients who had suffered from an alcohol withdrawal delirium (Sano et al. 1994, Kato et al. 1979). In the present study postsynaptic dopamine receptor sensitivity was neuroendocrinologically

assessed with apomorphine in

alcohol dependents grouped according to the severity of their alcohol withdrawal syndrome during detoxification.

The present study showed a significant effect for group-by-time interaction when all individuals (group l-4) were included in the statistical analyses reflecting that the four groups differed over the time in their postsynaptic dopamine receptor sensitivity.

However, this

effect was due to the difference between alcchol dependents and controls, but not to the severity of the withdrawal syndrome among dcohohcs. This could be demonstrated by focusing on alcohol dependents solely. After excluding the non dependent controls from the statistical analysis, the significant difference mentioned above vanished. Alcoholics without withdrawal, alcoholics with vegetative symptoms solely, or alcoholics suffering from a withdrawal delirium did not differ in their postsynaptic dopamine receptor sensitivity as neuroendocrinologicahy assessed. Therefore, the significant difference mentioned above was related to alcohol dependence and not to alcohol withdrawal. It was the consequence of a reduced dopamine receptor tbnction atter long term severe alcohol intake, which is well

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documented in both animals and humans (Balldin et al. 1985, 1993, Lucchi et al. 1988, Rommelspacher et al. 1992, Sylvalathi et al. 1988). So far, the present analysis confirms these results. The main goal of this study, however, was to examine whether the severity of alcohol withdrawal still affects dopamine fimction even after several weeks of abstinence. In conclusion, the results of this study suggest no.

We conclude that in alcohol dependent subjects a reduced dopamine receptor tinction, as neuroendocrinologicaIly

assessed with apomorphine after six weeks of abstinence, is not

related to the severity of alcohol withdrawal during detoxification.

Acknowledgment This study was supported by grant OlEB94 19 from the German Bundesministerium tier Bildung und Technologie.

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Alcohol withdrawal and dopamine receptor sensitivity

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Inquiries and reprint requests should be addressed to: Dr. Gerhard A. Wiesbeck University of Wuerzburg Department of Psychiatry Fuechsleinstr. 15 97080 Wuerzburg Germany Phone: FAX:

093 l/203-1 093 l/203-425