Serotonergic dysfunction in addiction: effects of alcohol, cigarette smoking and heroin on platelet 5-HT content

PSYCHIATRY RESEARCH ELSEVIER

Psychiatry Research 72 (1997) 177-185

Serotonergic dysfunction in addiction: effects of alcohol, cigarette smoking and heroin on platelet 5HT content Lutz G. Schmidt*, Peter Dufeu, Andreas Heinz, Silke Kuhn, Hans Rommelspacher Depament

of Psychiatq Universitiitsklinikum Benjamin Franklin, Free Universiry of Berlin, Eschenallee 3, 14050 Berlin, Germany

Received 19 February 1997; revised 21 July 1997; accepted 13 August 1997

Abstract The impact of ethanol, cigarette smoking and heroin on serotonin function was evaluated, first in alcoholics during chronic ethanol intoxication and in opiate addicts after long-term heroin consumption, and secondly in both patient groups after detoxification treatment (i.e. a short-term abstinence of 8 days). Our results showed that the 5-hydroxytryptamine (5-HT) content in platelets was: (1) increased in the subgroup of anti-social alcoholics; (2) transiently and differently altered in alcoholics compared to opiate addicts; and (3) lowered in drinking alcoholics and normal in alcoholics who were drinking as well as smoking (that may occur via MAO-B inhibition by smoke). The findings indicate that alterations of the peripheral and possibly the central serotonin system may occur as predisposing factors for alcoholism in individuals with anti-social traits; they may also have some impact on the progression of alcoholism due to its lowered function during chronic ethanol intoxication that is substantially modified by smoking. 0 1997 Elsevier Science Ireland Ltd. Keywords: Alcoholism;

*Corresponding

Drug abuse; Nicotine; Serotonin;

MAO; Thrombocytes

author. Tel.: + 49 3084458785; fax: + 49 3084458341; e-mail: [email protected]

01651781/97/$17.00 0 1997 Elsevier Science Ireland Ltd. All rights reserved. P11SOl65-1781(97)00102-9

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1. Introduction Evidence has accumulated that serotonin dysfunction is implicated in impulse control disorders that are often found in different types of psychopathological conditions, such as depression with suicidality, antisocial behavior linked with aggression, or obsessive-compulsive syndromes (Asberg et al., 1976; Linnoila et al., 1983; Coccaro et al., 1989; Insel et al., 1990). Studies of alcoholics also suggested that low brain serotonin function might be a pre-existing trait in a subgroup of patients, especially those with violent behavior (Virkkunen et al., 1996; Fils-Aime et al., 1996). Low serotonin function was supposed to act as a predisposing factor for the development of alcoholism in these individuals due to a transient increase of central serotonergic neurotransmission after an acute administration of ethanol (McBride et al., 1990). However, decreasing levels during chronic abuse of ethanol and after withdrawal are supposed to initiate a vicious cycle leading to aggravation of dependence (Ballenger et al., 1979). In most of these studies a serotonergic deficiency was concluded from reduced concentrations of its metabolite 5-hydroxy-indoleacetic acid (5-H&4) in CSF (Brown et al., 1982; Linnoila et al., 1983; Fils-Aime et al., 1996; Virkkunen et al., 1996) or by a blunted neuroendocrine response (e.g. of prolactin) to stimulation with 5-HT agonists (like 5-HTP, Lee and Meltzer, 19911, fenfluramine (Balldin et al., 1994; Coccaro et al., 1994) or m-CPP (Benkelfat et al., 1991). The efficacy of 5-HT uptake inhibitors in reducing alcohol intake in some alcoholic patients provided additional support for the notion that serotonin functioning might be deficient in a subgroup of individuals (Sellers et al., 1992). Because direct measures of brain 5-HT function are not readily accessible, 5-HT content has been studied in platelets or the whole blood (Kent et al., 1985; Boismare et al., 1987; Baccino et al., 1987; Bailly et al., 1990, 1993; Daoust et al., 1991; Ernouf et al., 1993). The blood platelet had been proposed as a model for the central nervous system neuron (LeMarquetand et al., 1994) with limitations in interpretation to be noticed as bone

marrow function and platelet production is affected by chronic ethanol toxicity (Alling et al., 1986). Most studies showed lower 5-HT content in platelets in drinking alcoholics (Rolf et al., 1978; Bailly et al., 1990, 1993), a finding that could possibly result from lowered 5-HT synthesis, decreased platelet uptake or increased platelet release. In attempting to disentangle predisposing (or trait) factors from (state or) disease related characteristics, tobacco smoking was often neglected as a confounding variable (Tabakoff et al., 1988; Bailly et al., 1990, 1993; Gerra et al., 1995). Due to important metabolic effects of tobacco smoking on the breakdown of dopamine and, to some extent, of serotonin (Weyler et al., 1990; Fowler et al., 1996), this study was designed to evaluate the impact of alcohol and cigarette smoking on serotonin content in platelets of alcohol and drug abusers. In addition, MAO-B activity was also determined as this marker was suggested to be implicated in serotonin turnover and low values had been reported in subgroups of alcoholism (van Knorring et al., 1985; Sullivan et al., 1990; Anthenelli et al., 1995). As MAO-B affinity was shown to be unchanged in alcoholics (Tabakoff et al., 1988; Rausch et al., 1991; Rommelspacher et al., 1994), this marker was not evaluated. The background of this study was the assumption that long term alterations of serotonin metabolism, if induced by chronic alcohol or heroin abuse, might be important conditions underlying the maintenance or relapse of addictive behaviors. 2. Methods 2.1. Subjects The control group consisted of 56 healthy probands, 40 males and 16 females averaging 44.2 f 9.1 years of age. Thirty-four were (cigarette-inhaling) smokers and 22 were nonsmokers. The subjects had no history of substance abuse or dependence and no first degree relatives known to be alcoholics. Before the start of the study, subjects underwent an internal medical and psychiatric examination. No indications of liver, renal or metabolic disorders were apparent either

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upon physical examination or after laboratory tests had been conducted. All subjects had abstained from alcoholic beverages for at least 24 h. The patient group included 83 alcoholics (60 males and 23 females, 60 of whom were also cigarette-inhaling smokers) and 22 opiate addicts (17 males and five females, all of whom were also smokers). Patients met criteria of the alcohol or opiate dependence syndrome according to ICD10. Demographic and family history information and data of the substance abuse module of the CID1 interview (CIDI-SAM, Robins et al., 1988) had been obtained during previous contact of the patients with our outpatient clinic. The nutritional status of patients and probands was not assessed. The first blood sample was drawn by venipuncture into a heparin containing vacutainer tube after admission to our detoxification unit (when the patients were still intoxicated by chronic alcohol or heroin abuse). In cases where medica-

tion was necessary to treat withdrawal symptoms, alcoholics received clomethiazole (a synthetic thiazol derivative that is similar to thiamine) with an elimination time of 3-5 h when the CIWA withdrawal scale (Sullivan et al., 1989) exceeded scores of 12. Opiate addicts received doxepin or trimipramine for treating opiate withdrawal symptoms when requested by the patients. After 8 days of abstinence, a second blood sample was drawn in 7.5 alcohol and 15 heroin addicts, as some patients developed non-compliance with the protocol. The patient characteristics are compiled in Table 1. After the patients had been completely detoxified, they were re-assessed for lifetime co-morbidity on the basis of all obtainable information using a checklist with ICD-10 criteria (‘best estimate diagnosis’). Diagnostic designations were made by experienced clinicians prior to, and without knowledge of biological variables. As the number of heroin addicts was too small for sub-

Table 1 Sample characteristics Alcoholics n = 83 Age (years) Sex (male/female) Age of onset of alcohol dependence since loss of control (years) Daily ethanol consumption’ (g of pure ethanol per day) % with alcoholism in first degree relatives Age of onset of heroin dependence since regular consumption (years) Heroin consumption’ (g day-’ ) % of smokers Number of cigarettes (in smoke&/day rGlutamyltransferaseb (U 1-r) Number of days with drugs for withdrawal treatment Clomethiazole (mg day- ’ > for alcohol withdrawal treatment Anti-depressants (doxepin or trimipramine mg day-‘) for opiate withdrawal treatment n.a., not available. aDuring the month prior to the study. bDay of admission. Numbers in table are mean values f SD.

43.7 * 8.6 61/22 32.8 + 8.4

Opiate addicts n = 22 30.3 f 5.5 17/5 n.a.

257.7 + 176.7

95.6 f 89.1

48.1 n.a.

64.0 24.6 f 5.1

n.a. 72.5 33.6 f 17.8 113.2 rt 172.0 1.3 f 1.8

0.8 f 100 30.0 f 17.0 f 5.5 f

0.5

708.8 * 481.8

n.a.

n.a.

152.6 f 53.2

11.1 10.6 3.1

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L.G. Schmidt et al. /Psychiatry Research 72 (1997) 177-185

group stratification, the alcoholic patients were only divided into the following groups: an uncomplicated group (no co-morbidity, it = 411, patients with anxious/depressive disorders (n = 151, antisocial personality disorder (n = 5) and other personality disorders (other co-morbidity, 12= 22). The relation of these co-morbidities with biological variables was statistically evaluated for the admission condition (when patients had been chronically intoxicated with alcohol or heroin), but not after detoxification (when eight patients had left the hospital prematurely, leaving subgroups too small for statistical analysis). The study was approved by the ethics committee of the Rudolf Virchow Klinikum of the Free University of Berlin. All subjects had given informed consent after full understanding of the study protocol. 2.2. Biochemical measurements Platelet 5-HT level was determined by HPLC compiled with a fluorescence detector. None of the patients had been on a special diet. Blood samples were collected after an overnight fast in a plastic tube containing EDTA and then immediately centrifuged for 15 min at 200 X g and 4°C to obtain platelet rich plasma (PRP). After a platelet count, 1 ml PRP was centrifuged for 10 min at 2000 x g (Varifuge, Heraeus, FRG). The supematant was discarded and the pellet suspended in 1 ml of a mixture containing 4% perchloric acid, 0.05% EDTA and 0.1% NaS,O,. The mixture was sonicated on ice and subsequently centrifuged for 10 min at 2000 x g and 4°C. The resulting supernatant was filtered (0.45 pm Millipore glass fibre filters) by centrifugation for 5 min at 2000 x g and 4°C (Abi-med tubes, Langenfeld, FRG). The eluate was frozen until use at - 80°C. The sample was thawed and centrifuged at 2000 x g and 3 min. An aliquot of the supernatant (100 ~1) was applied to a Hewlett Packard system, type 1090, a fluorescence detector, type 1046A and a Chem Station (Hewlett Packard, Palo Alto, CA.) equipped with a 5-pm C,, reversed phase column, 250 mm (Inertsil ODS2, VDS Optilab, Berlin FRG). The elution buffer consisted of 50 mM potassium phosphate buffer

(pH 5.0) and 12% methanol, flow rate 1 ml min-‘, isocratic conditions. The fluorescence detector was set at 230 nm excitation and emission at 338 nm. The intra-assay coefficient of variation was 2.7%. Results are expressed in ng/109 platelets. The MAO-B activity was determined by a fluorometric assay as described previously (Rommelspacher et al., 1994). The results were calculated in nmol of 4-hydroxy-quinoline formed/min per mg of protein with the aid of internal 4-hydroxy-quinoline (product) standards and after protein determination according to Bradford (1976) with bovine serum albumin as standard. 2.3. Statistics Comparisons were made by one-way analyses of variance (ANOVA); differences between subgroups were evaluated by the multiple range test using the Student-Newman-Keuls-procedure with ranges for the 0.05 level. The MANOVA procedure was applied for testing two-factor statistical designs. Pearson coefficients were calculated for testing correlations between variables. 3. Results Alcoholics (chronically intoxicated with ethanol) had lower platelet 5-HT levels than control subjects, and opiate addicts (chronically intoxicated with heroin) had higher values (83 alcoholics: 367.0 + 474.9 ng/109 platelets; 22 heroin addicts: 796.8 + 496; 56 control subjects: 518.0 + 317.6; ANOVA: F = 9.04; d.f. = 2,158; P = 0.0002; the multiple range test of Student-NewmanKeuls indicated that the differences between normal subjects and both patient groups were significant at the 0.05 level; see Fig. 1). After shortterm abstinence, the values had increased in alcoholics (n = 75: 480.0 k 536.4) and decreased in heroin addicts (n = 15: 563.5 &-409.8) and were no longer significantly different from control subjects. Intra-individual correlation was significant in alcoholics (r = 0.82; P = 0.000) as well as in opiate addicts (r = 0.57; P = 0.04). Among alcoholics, 5-HT content was significantly higher in smokers compared to nonsmokers during chronic ethanol consumption (i.e.

L. G. Schmidt et al. / P~hiatry Research 72 (I 997) 177-185

181

platelet S-HT (ng/lOg ) 1000

alcoholics opiate addicts

800

Fig. 1. Platelet 5-HT levels in alcoholics and opiate addicts during chonic intoxication and after short-term abstinence (8 days later) compared to control subjects.

489.9 f 586.4 ng/lO’ in 47 smokers with values available for both conditions vs. 240.3 f 181.1 ng/lO’ in 19 non-smokers), as well as after short-term (alcohol) abstinence (591.5 & 623.5 ng/lO’ vs. 247.1 A-174.0 ng/lO’; MANOVA group factor: F = 4.80; d.f. = 64,2; P = 0.032; no significant time effect or interaction, see Fig. 2). However, we could not show for healthy controls that 5-HT levels were different in smokers (538.3 + 350.1 ng/lO’) compared to non-smokers (502.9 &-295.8; n.s.>. MAO-B activity was lower in smokers compared to non-smokers during chronic ethanol intoxication [V,,, (with 200 mM ethanol in vitro) = 2.42 + 0.77 nmol mm-’ per mg of protein vs. 3.31 + 1.32 nmol min-’ per mg of protein; t = 2.20; d.f. = 22.56; P = 0.041 and also after short-term abstinence (3.15 + 1.18 nmol mine1 per mg of protein vs. 4.21 f 1.62 nmol min-’ per mg of protein; t = 2.45; d.f. = 22.81; P = 0.03). Comparing alcoholic subgroups with different co-morbidities during chronic ethanol consumption, 5-HT levels were highest in antisocial alcoholics (n = 5: 1201.8 f 1015.3 ng/lO’) and significantly different (ANOVA: F = 4.44; d.f. = 4,80; P = 0.0027) from those observed in alcoholics with

no co-morbidity (n = 41: 289.3 & 372.7 ng/lO’), anxious/depressed alcoholics (n = 15: 332.0 f 290.8 ng/lO’) or alcoholics with other co-morbidities (n = 22; 346.2 + 429.6 ng/lO’) and from normal subjects (using the Student-NewmanKeuls procedure with ranges for the 0.05 level); all other alcoholics did not differ from normal subjects (Fig. 3). 4. Discussion Four findings of the study have to be discussed. First, we could confirm earlier results showing lower platelet 5-HT content in drinking alcoholics (Rolf et al., 1978; Bailly et al., 1990, 1993) compared to control subjects (that had not been normalized after short-term abstinence). In general, low 5-HT levels might be the result of lowered 5-HT synthesis, decreased platelet uptake or increased platelet release. This means that if lower platelet 5-HT content suggests lower neuronal 5-HT levels in the CNS, this could either imply increased 5-HT release and utilization or decreased CNS serotonergic functioning through decreased 5-I-IT synthesis. In alcoholics, other

L.G. Schmidt et al. /Psychiatry Research 72 (1997) 177-185

182

platelet SHT Oxl~los1

m ....... ........................ ............... _. ............. .......... ............. .......................... _._. ._. ...... ._._._ ..........

200

.................. ................ ...._..........‘.

lo(-)

....... ...._.................... .._............_. ....................... ............ ............. .._._. ............................... ...._......_ ..................... ._........... .... ........

non-smoking alcoholics

0

chronic intoxication

short-term abstinence

Fig. 2. Platelet 5-HT levels in smoking alcoholics compared to non-smoking alcoholics during chronic (ethanol) intoxication and after short-term abstinence.

blood measures had been studied in more detail. Plasma tryptophan availability most often turned out to be decreased, possibly due to an increase in tryptophan oxygenase/pyrrolase (BuydensBranchey et al., 1989). An increased affinity of 5-HT for its carrier or an increased capacity of the carrier (Kent et al., 1985; Boismare et al., 1987; Baccino et al., 1987; Daoust et al., 1991; Ernouf et al., 1993) was found, suggesting a decreased availability of 5-HT in the synapse. A diminished ability of 5-HT to stimulate 5-HT2/5HTlc receptor-mediated formation of inositol phosphates in platelets was also shown for chronic intoxication and the early alcohol withdrawal phase (Simonsson and Alling, 1988). Supposing that observed alterations in platelets may correspond to various alterations of the central 5-HT system (Mann et al., 1992a), these findings would suggest reduced serotonergic functioning in chronic alcoholism. However, the relevance of platelet 5-HT content to brain 5-HT function has not yet been established and, accordingly, extrapolation to brain 5-HT function remains speculative at this time.

Second, it was shown in our study that the metabolism of serotonin was affected by cigarette smoking in alcoholics. Our data showing that serotonin levels are normalized in smoking and drinking alcoholics, but not in active alcoholics who refrain from smoking, are consistent with observations that cigarette smoking reduces MAO-B function in smokers (Oreland et al., 1982). Unfortunately we could not demonstrate a smoking effect on 5-HT content in healthy control subjects possibly due to the fact that our control subjects were not as heavy smokers as most of our alcoholics; in opiate addicts we were not able to look for smoking effects, as all subjects were smokers. These observations have led us to infer that (heavy) smoking might have some compensating effects on the serotonin system in drinking alcoholics - a finding that was shown to be accompanied by MAO-B inhibition in our patients and also other patients (Anthenelli et al., 1995). However, stimulation of dopamine release by nicotine and a synergistic enhancement of dopamine by MAO-B inhibition due to cigarette smoking might overrule this normalizing effect

LG. Sch~t

et al. ,/P~~

Research 72 (1997) 177-185

183

1200 1000 800

Fig. 3. Platelet 5-ESTieveis in alcoholics (all smokers, during chronic ethanol intoxication) according to different co-morbidities and s&oking control subjects.

and could explain strong reinforcing properties of cigarette smoking leading the alcoholic not to terminate, but to maintain his addictive behavior. It remains to be elucidated how normalization of low serotonin is mediated by MAO-B inhibition (Weyler et al., 1990) as the molecular mechanism behind the neuropharmacological action of cigarette smoking is not yet known (Fowler et al., 1996). Thirdly, anti-sociali~ was shown in this study to be linked with increased MIT content in the platelets. We suppose that this finding {though observed in only five anti-social patients) relates to a trait beyond chronic alcohol and smoking effects, as all patients had not differed in their drinking and smoking status at the time of hospital admission. Clearly, it would have been desirable to have studied the patients again while they were neither drinking nor smoking. Unfortunately, it is nearly impossible to motivate such patients for ~vestigations in drug-free states. Despite these methodological caveats, it is interesting to note that earlier results obtained by Bailly et al., 1990, 1993 had pointed in the same direc-

tion indicating higher 5-HT levels in platelets of patients with lifetime impulse control disorders. The finding of high MIT platelet levels in patients with impulsive, aggressive or violent behaviors could correspond to results showing reduced concentrations of cerebrospinal fluid 5-hydrovindolacetic acid (CSF 5-HL4A; Brown et al., 1982; Linnoila et al., 1983; Fils-Aime et al., 1996; Virkkunen et al., 1996). This particular condition can be found in subjects (often type II alcoholics) characterized by novel~/sensation seeking traits or impulsive/aggressive behavior and reduced MAO-B function (Buchsbaum et al., 1976; von Knorring et al., 1984, 1985; Lidberg et al., 1985; Sullivan et al., 1990; Rommelspacher et al., 1994; Anthenelli et al., 1995). However, the particular relationship between high 5-HT levels and reduced MAO-B function again remains to be elucidated. Finally, though we do not have a valid explanation for high platelet levels of 5-HT in opiate addicts under chronic heroin consumption, the increase of 5-I-IT seemed to be an over-ruling effect as the removal of heroin was the only

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L.G. Schmidt et al. /Psychiatry Research 72 (1997) 177-185

changing variable while the smoking and comorbid status of the patients were unchanged after one week of detoxification treatment. However, the data of Gerra et al. (1995) and Brambilla et al. (1988) and our own post-detoxification data do not point to a chronic impairment of the serotonergic system in heroin addicts as a condition etiopathogenetically related to the maintenance or relapse in opiate addiction. In conclusion, despite several confounding factors that have to be considered in this field [e.g. nutritional/seasonal influence on 5-W (Mann et al., 1992b) that are possibly not preserved in alcoholics (Roy et al., 1995), 5-HT degradation more related to MAO-A than to MAO-B (Lenders et al., 1996)] our data give further evidence that: (a) dysfunction of the serotonin system may be related to predisposing traits of the subgroup of anti-social alcoholics; (b) the serotonin system is differentially altered in alcoholics and opiate addicts; and (c) smoking might compensate serotonin deficiencies in alcoholics due to alterations in the metabolic pathways that, however, might be overruled by its direct reinforcing effects on reward systems and thus leading to a progression of addictive behaviors. Acknowledgements This study was supported 916/7-2).

by DFG (AZ: He

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