Alcohol urge and plasma β-endorphin change after alcohol challenge with naltrexone pretreatment in social drinkers

Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 663 – 670

Article

Alcohol urge and plasma b-endorphin change after alcohol challenge with naltrexone pretreatment in social drinkers Chul Na*, Young-Sik Lee Department of Neuropsychiatry, College of Medicine, Chung-Ang University Medical Center, Han-Gang Ro 3 Ga, 65-207, Yong-San Gu, Seoul 140-757, South Korea

Abstract The authors have investigated the effect of naltrexone (NTX) on lowering the urge of alcohol drinking and the action mechanism of NTX. Fifteen healthy male social drinkers voluntarily participated. The experimental method was a double-blind, placebo-controlled cross-over design. To eliminate NTX effect, 1 week washout cross-over interval was taken. Subjects ingested NTX, 50 mg/day, or placebo for 1 week. Then, the alcohol (0.5 ml/kg) challenge test was done in the evening. Blood samples were taken immediately before drinking, at 20 min and at 60 min after alcohol drinking. Plasma b-endorphin, plasma ACTH and serum cortisol levels were checked. Subjects completed self-report questionnaires such as the visual analog scales of drink urge and the alcohol sensation scales at regular intervals. In the case of NTX pretreatment, the subjects reported significantly ( P =.013) less urge to drink alcohol on the self-reporting urge scales, especially at postdrinking 20 min and 60 min than placebo pretreatment. After alcohol challenge, the subjects reported significantly more dizziness ( P =.015) in the case of NTX pretreatment, and reported less mood elevation trend, though not significant ( P =.052). Basal plasma b-endorphin levels were not different, but in the case of NTX pretreatment, the increasing degree of plasma b-endorphin during 20 min after alcohol challenge was significantly ( P =.039) higher than with placebo pretreatment. This results show that the NTX reduced the urge to drink alcohol with the mechanism of partially blocking the opioid positive reward system and partially mimicking the alcohol effect. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Alcohol challenge; b-Endorphin; Naltrexone; Social drinker

1. Introduction The opioid antagonist, naltrexone (NTX), is recently being used extensively in the treatment of alcoholism; however, its treatment mechanism has not been elucidated. Swift et al. (1994) reported that when alcohol [0.65 g/kg (female), 0.7 g/kg (male)] was challenged after pretreatment with 50 mg of NTX for 8 days, the stimulation effect due to alcohol was decreased but the sedation effect was increased. However, Doty and de Wit (1995) reported that the treatment with 25 –50 mg of NTX did not show effects on the subjective responses of drinking alcohol (0.5 g/kg) and Doty et al. (1997) reported that one time treatment of 25– 50 mg NTX did not lower acute response of alcohol (0.25 g/kg). Abbreviations: EDTA tube, ethylenediaminetetraacetate tube; HPA axis, hypothalamic – pituitary – adrenal axis; IRMA kit, Immuno-Radio-Metric Assay; NTX, naltrexone; POMC, pro-opiomelanocortin * Corresponding author. Tel.: +82-2-748-9572. E-mail address: [email protected] (C. Na).

We thought that these differences were due to the facts that various questionnaires filled out by the subjects were different, the amount of alcohol challenged was different and the period of NTX use was different. The study by Swift et al. (1994), which reported the lowered effect of urge to drink alcohol with the administration of NTX, used a moderate amount of alcohol, whereas the studies by Doty and de Wit (1995) and Doty et al. (1997) used less than the moderate amount of alcohol. The authors used a moderate amount of alcohol, 0.5 ml/kg, and obtained the same result that the urge to drink alcohol after NTX pretreatment decreased as those of Swift et al. (1994). Considering the study reporting that acetaldehyde also increased the secretion of b-endorphin in culture cells of the hypothalamus (Pastoric et al., 1994) and the time of acetaldehyde staying within the body is relatively longer in Asians in whom more people lack Type I aldehyde dehydrogenase compared to Westerners (Harada et al., 1981), the amount of alcohol, 0.5 ml/kg, may have been over the moderate amount. However, rather than the difference due

0278-5846/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S 0 2 7 8 - 5 8 4 6 ( 0 1 ) 0 0 3 1 5 - 3

664

C. Na, Y.-S. Lee / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 663–670

to the amount of alcohol, the bigger difference may be that the study by Doty et al. (1997) examined the response for alcohol after one treatment with NTX, whereas Swift et al. (1994) examined the responses after about 7 days of NTX treatment as in the present study. Several studies reported changes in the amount of alcohol ingestion according to the period of NTX treatment. As seen with the result of the study by Davidison and Amit (1997) showing that the alcohol consumption habit did not decrease at 24 h after stopping the administration of NTX, although the habit decreased 4 h after in animal experiments, the effect of NTX is time-limited, not achieving the long-term elimination of alcohol consumption habit. Also, Altshuler et al. (1980) reported that when NTX was administered in the rhesus monkeys that were given at least 1.0 g/kg/day, the results showed that self-alcohol consumption increased during the first 5 days but decreased afterwards. The results of these studies are related with the results of the study by Yoburn and Inturrisi (1988) reporting that the analgesic effect decreased with 8-day administration of NTX, although no effect was seen with 1-day administration. Thus, it could be said that the urge to drink would decrease with the administration of NTX for at least several days in social drinkers. Until recently, three hypotheses have been proposed as the treatment mechanism of NTX. The first hypothesis is the hypothesis of ‘‘blocking the positive reinforce system’’ (Froehlich and Li, 1993; O’Brien et al., 1996), which proposes that alcohol consumption increases endogenous opioid, which in turn works as the positive reward system to increase drinking habit, explaining that NTX suppresses the increase of the level of endogenous opioid to eventually block the effect of positive reinforcement system of alcohol. The second one is the hypothesis of ‘‘mimicking alcohol effect,’’ which proposes that NTX works as the alcohol-like substance or alcohol-substitutive substance. Swift et al. (1994) reported that when people were pretreated with NTX, the positive reinforcement effect due to alcohol is decreased, whereas the calming effect is rather increased, making people subjectively feel as if they drank a lot despite a small amount of alcohol consumption. Also, Volavka et al. (1979) reported that NTX equally increases the concentrations of plasma b-endorphin, ACTH and cortisol as alcohol does. The third one is the ‘‘aversion hypothesis’’ where physical and psychological discomforts resulting from NTX are the factors that decrease drinking habit, not the decreasing urge of drinking alcohol specifically (Doty et al., 1997). De Wit et al. (1999) also reported that NTX reduced ethanol consumption as well as placebo beverage in healthy volunteers, so they suggested that NTX may reduce alcohol consumption by a nonspecific mechanism. Thus, in order to elucidate the treatment mechanism of NTX, subjective psycho-physio-biological changes related with NTX need to be investigated in the same subjects; however, most studies until now have focused on evaluating only one aspect.

Among endogenous opioids, b-endorphin plays an important role in reward and reinforcement. In order to measure the concentration of b-endorphin produced in the hypothalamus or pituitary gland, it is desirable to measure the concentration in the cerebrospinal fluid, but since it was difficult to get the consent from the subjects, the authors measured the concentration of plasma b-endorphin. Also, we selected social drinkers for the subjects instead of alcoholics due to the ethical issue of needing to perform alcohol challenge test and the presence of confounding factors, such as depression, that usually accompany alcoholism (Reiger et al., 1990). Depression itself could affect the results of neuroendocrine system. Whether the effect of decreasing urge to drink by NTX is also present in social drinkers is debatable. Although Davidison et al. (1996) reported that NTX also decreases the total amount of drinking by reducing the urge to drink even in social drinkers, Doty et al. (1997) reported that NTX could not affect the urge to drink in social drinkers. These contrary results may have been due to various factors such as drinking amount, study period, study condition, measuring instrument of alcohol urge, NTX pretreatment period and NTX amount administered. The present study was a double-blind, cross-over, placebo-controlled design. The subjective physical responses to alcohol and the degree of urge to drink alcohol were measured through a self-reporting questionnaire, and at the same time, we measured the concentrations of plasma b-endorphin, ACTH and cortisol. By comprehensively reviewing the results, we tried to elucidate whether NTX treatment could effectively lower the urge of alcohol drinking and to investigate the action mechanism of NTX.

2. Materials and methods 2.1. Study subjects Fifteen healthy social drinkers who were medical practitioners and nonsmokers understood the purpose of the study and volunteered for this study. All of them scored under 12 points in the Korean version of Michigan Alcoholism Screening Test (Selzer, 1971) and had no physical and psychiatric disease, including substance dependence, by DSM-IV (APA, 1994) through an interview evaluation by two psychiatrists. We defined these people as social drinkers. The average age of those subjects was 31.8 ± 3.4 years(26– 35 years); the average amount of drink per month in these subjects was 3.6 ± 2.7 bottles of Soju. Soju is a clear distilled liquor that tastes like vodka, made with tapioca with an alcohol content of 25%. Two subjects had familial problems related with alcohol. 2.2. Study design In order to evaluate the pure effect of NTX, the present study was done in the manner of placebo control, double

C. Na, Y.-S. Lee / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 663–670 Table 1 Three-point side effect profile during NTX pretreatment and placebo pretreatment (mean ± S.D.)

Headache Anxiety Dizziness Nervousness Fatigue Increased energy Insomnia Day somnolence Depressed mood Suicide idea Nausea Vomiting Abdominal pain Decreased appetite Diarrhea Constipation Dry mouth Arthralgia Muscle ache Increased sexual desire Increased erection time Delayed ejaculation Tearfulness Nasal stiffness Skin rash Febrile sense

NTX

Placebo

0.8 ± 0.7 0.3 ± 0.6 0.8 ± 0.9 0.6 ± 0.7 1.3 ± 0.7 0 0.5 ± 0.6 1.2 ± 0.7 0.2 ± 0.4 0 0.7 ± 0.7 0.3 ± 0.6 0.4 ± 0.6 0.7 ± 0.7 0.1 ± 0.4 0.1 ± 0.5 0.3 ± 0.5 0.1 ± 0.3 0.3 ± 0.5 0 0 0 0 0 0 0.3 ± 0.6

0.2 ± 0.6 0.1 ± 0.3 0.1 ± 0.3 0.1 ± 0.3 0.6 ± 0.6 0 0.2 ± 0.4 0.3 ± 0.5 0.1 ± 0.3 0 0.1 ± 0.4 0.1 ± 0.3 0.2 ± 0.4 0.1 ± 0.4 0.1 ± 0.3 0 0.1 ± 0.3 0 0.1 ± 0.3 0 0 0 0 0.1 ± 0.3 0.1 ± 0.3 0.1 ± 0.3

Z

P 1.964 1.414 2.428 2.271 1.960 0.000 1.508 2.739 1.000 0.000 1.999 1.633 1.342 1.999 0.577 1.000 1.732 1.000 1.342 0.000 0.000 0.000 0.000 1.000 1.000 1.134

.050 .157 .015* .023* .049* 1.0 .132 .006** .317 1.0 .046* .102 .180 .046* .564 .317 .083 .317 .180 1.0 1.0 1.0 1.0 .317 .317 .257

* P < .05. ** P < .01.

blind and cross-over test. The subjects were asked to take either placebo (a formula that looked like NTX with no effective ingredient of NTX) or NTX (50 mg/day) at 9 am every day for a week for the first week; nothing happened during the second week that was reserved for the drug washout period. Finally, at the third week, placebo was administered for a week for those who took NTX at the first week and NTX administered for a week for those who took placebo at the first week. On the last day of the first and third weeks at 6:30 pm, the subjects were asked to come in empty stomach. The authors then performed alcohol challenge test and sampled blood, and the subjects were asked to fill out the questionnaire. During the testing period, the subjects were asked to stay off from alcohol, cigarette and coffee. 2.3. Study condition Since social drinkers usually drink during the evening period, the test time was set at 7 pm. The study was done in

665

conditions and environment similar to actual social drinking settings. Movements of the subjects during the test period were not restricted; the subjects were provided with newspapers and magazines so they could read freely and free talking was allowed in relaxation state but they were not allowed to work. In order to create the drinking environment similar to actual drinking environment, those subjects in the NTX pretreatment period and placebo pretreatment period participated in the experiments while watching a video frequently shown in karaoke bars. The content of the video is that someone is drinking Soju joyfully while listening to comfortable music. 2.4. Study method After inserting an indwelling catheter with a heparin cap on the forearm of the subjects who arrived at the study site at 6:30 pm, they were asked to complete the questionnaire on the side effects of NTX and on the degree of urge to drink for 30 min and then were asked to rest. After taking the first blood sample at 7 pm, the subjects were asked to drink 0.5 ml/kg Soju (with an alcohol content of 25%) in several sips to be able to finish it in 10 min, starting at 7:10 pm. The amount of Soju used was 0.5 ml/kg, which was sufficiently more than enough to show subjective effects to social drinkers and show the priming effect in alcoholics (Chutuape et al., 1994; Volpicelli et al., 1995), but would not induce severe acute physical or psychological responses. The second blood sample was taken 20 min after drinking, and the third was done 60 min after drinking. Twenty milliliters of blood was taken for each sampling. After taking blood samples, the subjects were asked to fill out the questions on Alcohol Sensation Scale and Analog Scales of Alcohol Urge (Davidison et al., 1996). 2.5. Measurement of the blood samples The blood samples taken were placed divided into an ethylenediaminetetraacetate tube (EDTA tube; b-endorphin, ACTH) and a glass tube (cortisol, GPT, GPT), and centrifuged immediately at 4C. The centrifuged plasma and serum were kept at 75C until use. The measurements of b-endorphin, ACTH and cortisol were done according to the instruction of the kit from DiaSorin (Stillwater, MN, USA).

Table 2 Alcohol drinking urge score after NTX pretreatment and placebo pretreatment (mean ± S.D.) NTX Urge

Baseline 1.0 ± 1.0

Placebo 20 min later 1.5 ± 1.5*

60 min later 1.3 ± 1.1*

Baseline 1.5 ± 1.2

Drug effect 20 min later 2.6 ± 1.2*

Post hoc analysis of drug effect. * Significant difference between NTX pretreatment and placebo pretreatment (at each time), P < .05.

60 min later 2.3 ± 1.4*

F 8.18

P .013

666

C. Na, Y.-S. Lee / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 663–670

Table 3 Alcohol Sensation Scale score during NTX pretreatment and placebo pretreatment (mean ± S.D.) NTX

Facial flushing Palpitation Dizziness Headache Nausea Feel sleepy Abdominal discomfort Dry mouth Weakness Anxious Irritable Depressed Relaxed Elated Happy Romantic mood Talkative

Placebo

Drug effect

20 min later

60 min later

20 min later

60 min later

F

P

3.0 ± 2.1 2.2 ± 1.8 2.3 ± 1.7 2.2 ± 1.9 1.7 ± 1.6 2.6 ± 1.7 2.3 ± 1.8

3.2 ± 1.9 2.2 ± 1.6 2.3 ± 1.7 2.1 ± 1.6 1.5 ± 1.4 2.6 ± 1.6 1.8 ± 1.5

3.0 ± 2.0 2.3 ± 1.6 2.0 ± 1.7 1.6 ± 1.6 1.3 ± 1.5 1.9 ± 1.6 1.9 ± 1.3

2.4 ± 2.1 1.7 ± 1.6 1.2 ± 1.2 1.5 ± 1.4 1.2 ± 1.1 2.0 ± 1.5 1.5 ± 1.1

2.30 0.89 7.68 3.50 1.36 2.70 1.51

.152 .361 .015* .082 .263 .123 .240

1.9 ± 1.7 2.9 ± 1.5 0.7 ± 0.8 0.9 ± 1.0 1.2 ± 1.6 2.5 ± 1.7 1.7 ± 1.5 2.5 ± 1.7 1.9 ± 1.4

2.1 ± 1.2 2.6 ± 1.6 1.1 ± 1.0 1.1 ± 1.0 0.9 ± 0.9 2.3 ± 1.3 1.5 ± 1.2 1.7 ± 1.2 1.4 ± 1.3

1.1 ± 1.1 2.1 ± 1.5 1.0 ± 1.4 0.7 ± 1.1 0.8 ± 1.0 3.6 ± 1.6 2.8 ± 1.6 2.5 ± 1.4 2.1 ± 1.3

1.5 ± 1.1 1.7 ± 1.2 0.7 ± 1.2 0.7 ± 1.1 0.5 ± 0.8 2.3 ± 1.6 1.8 ± 1.4 1.9 ± 1.7 2.0 ± 1.8

2.93 3.34 0.06 1.00 2.09 1.64 4.40 0.04 1.58

.109 .089 .815 .334 .171 .221 .055 .845 .229

2.5 ± 1.6 2.0 ± 1.2 2.7 ± 1.6 2.5 ± 1.8 0.89

.361

* Significant difference between NTX pretreatment (60 min later) and placebo pretreatment (60 min later), P < .05.

2.6. Components of the questionnaire 2.6.1. Side effects check list The self-reporting questionnaire listing the existing side effects of NTX developed by O’Malley (1998) was composed of a three-point scale for each item.

2.7. Data analysis In order to compare the differences in adverse effects during the NTX-pretreated period and placebo-pretreated period, we used the nonparametric method. Compared to the baseline urge to before drinking, repeated ANOVA was used to verify the difference in the urge with 20 and 60 min after alcohol consumption. Repeated ANOVA was used to verify the difference in alcohol sensation 20 and 60 min after alcohol consumption between the two periods. It also was used to verify the differences in the changes in the b-endorphin, ACTH and cortisol levels at 20 and 60 min after alcohol consumption by comparing with the baseline b-endorphin, ACTH and cortisol levels before drinking during the two periods. The changes in the b-endorphin, ACTH and cortisol levels due to drinking, the increased rate 20 min after drinking [(measured value 20 min after drinking measured value immediately before drinking (baseline))/measured value immediately before drinking (baseline)] and the increased rate 60 min after drinking [(measured value 60 min after drinking measured value immediately before drinking (baseline))/measured value immediately before drinking (baseline)] were calculated based on the levels before drinking. Then, paired t test was used to compare whether the difference was present between the NTXpretreated period and placebo-pretreated period.

3. Results 3.1. Side effects of NTX

2.6.2. Analog scales of urge This self-reporting type of Analog Scales of Alcohol Urge employed by Davidison et al. (1996) was designed with items that were measured with seven-point scale from none (0) to very strong urge (6). 2.6.3. Alcohol sensation scale In order to measure psychological and physical responses experienced after drinking, we used the Korean version of Alcohol Sensation Scale developed by Lee (1989), which was designed with 17 items with a sevenpoint scale measuring acute physical responses (nine items), psychological discomfort (three items) and pleasure (five items).

The score distribution of NTX side effects is shown in Table 1. At the time of NTX pretreatment, the items such as tiredness, headache, dizziness, being sensitive, day somnolence, nausea and decreased appetite were significantly higher than at the time of placebo pretreatment ( P < .05). 3.2. Urge to drink alcohol Changes in urge to drink immediately before drinking, 20 and 60 min, and after drinking were shown in Table 2. The urge to drink with NTX pretreatment was significantly lower than that with placebo pretreatment. Although this difference was not shown before drinking, the difference

Table 4 b-endorphin, ACTH and cortisol levels after alcohol challenge during NTX pretreatment and placebo pretreatment (mean ± S.D.) NTX

b-endorphin ACTH Cortisol

Placebo

Drug effect

Baseline

20 min later

60 min later

Baseline

20 min later

60 min later

F

3.94 ± 2.28 21.31 ± 5.28 6.91 ± 2.51

5.51 ± 4.79* 18.63 ± 3.75 5.47 ± 2.06

4.54 ± 2.17* 17.71 ± 4.02 4.87 ± 2.19

4.00 ± 1.91 23.92 ± 6.12 8.80 ± 4.88

3.04 ± 1.46* 18.65 ± 4.77 7.41 ± 4.53

3.35 ± 2.10* 19.05 ± 3.37 5.87 ± 3.75

4.76 1.75 2.58

Plasma b-endorphin: mean ± S.D. (pmol/l); plasma ACTH: mean ± S.D. (pg/ml); serum cortisol: mean ± S.D. (mg/dl). * Significant difference between NTX pretreatment and placebo pretreatment (at each time, P < .05).

.047 .207 .131

C. Na, Y.-S. Lee / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 663–670

667

Table 5 The changing degree of b-endorphin, ACTH and cortisol levels after alcohol exposure NTX D1 b-endorphin ACTH Cortisol

0.98 ± 1.75 0.11 ± 0.18 0.21 ± 0.14

D1

Placebo D2

D1 0.81 ± 2.1 0.12 ± 0.30 0.28 ± 0.23

D2 0.17 ± 0.46 0.21 ± 0.10 0.11 ± 0.31

D2

t 0.01 ± 0.94 0.17 ± 0.20 0.31 ± 0.18

2.28 2.41 1.14

P

t

P

.039 * .030 * .273

1.375 0.744 0.407

.191 .469 .690

Plasma b-endorphin: mean ± S.D. (pmol/l); plasma ACTH: mean ± S.D. (pg/ml); serum cortisol: mean ± S.D. (mg/dl). D1: (20 min later baseline)/baseline; D2: (60 min later baseline)/baseline. * P < .05.

was significant 20 and 60 min after drinking ( F = 8.18, P < .05; Table 2). 3.3. Alcohol sensation scale The responses to drink that measured psychological and physical changes at 20 and 60 min after drinking are shown in Table 3. More dizziness was felt with NTX pretreatment; this difference was not significant at 20 min after drinking but was significantly high at 60 min after drinking ( F = 7.68, P < .05). Although statistical significance was not present ( F = 4.40, P =.055), the degree of relatedness was lower with NTX pretreatment compared to placebo pretreatment. No difference was seen in other items and subfactor scores. 3.4. Concentrations of plasma b-endorphin, ACTH and cortisol Changes in the concentrations immediately before drinking, 20 and 60 min after drinking are shown in Table 4. Compared to placebo pretreatment, the concentration of plasma b-endorphin was significantly higher at the time of NTX pretreatment ( F = 4.76, P =.047). The concentrations of plasma ACTH and cortisol did not show significant differences. The significant increasing rate of the plasma b-endorphin concentration at 20 min after drinking was shown at the time of NTX pretreatment (t = 2.28, P =.039), but a rather decreasing tendency was shown at the time of placebo pretreatment (Table 5). Basal plasma ACTH level and basal serum cortisol level were not significantly different between the two pretreatment conditions. After alcohol challenge, only the decreasing degree of plasma ACTH levels at 20 min was significantly (t = 2.41, P =.030) lowered with the NTX pretreatment compared to placebo pretreatment (Table 5).

4. Discussion The present study showed that the subjective experiences such as headache, dizziness, being sensitive, day somnolence, nausea and decreased appetite were present during the 1-week NTX pretreatment period. Compared to the multicenter study by Croop et al. (1997) on alcohol-

dependent patients who complained of nausea (9.8%) and headache (6.6%) from the treatment with NTX, the results of our study showed significantly more side effects of day somnolence, tiredness and dizziness. The side effects from NTX may be different for Asians and Westerners; considering the study by Wilkin and Hazelrigg (1987) reporting that abdominal discomfort and nausea were present significantly more in Asians although there was no difference in the flushing of the face between the two peoples, further studies are needed on the right amount of NTX for treatment. Especially, the result that the side effects of drug overdose such as day somnolence, tiredness and dizziness with the treatment of 50 mg of NTX were more prevalent in the present study suggests that Asians need relatively smaller amount of NTX compared to Westerners. King et al. (1997) reported that more side effects (headache, nausea, anxiety and impotence) could be experienced as the concentration of the metabolite of NTX, 6b-naltrexol, was higher in urine, but we could not check NTX concentrations in the present study. Compared to placebo pretreatment, the present study showed that the concentration of plasma b-endorphin did not show a significant difference before drinking with NTX pretreatment, but increased significantly at 20 min after drinking. In the case of plasma cortisol and adrenocorticotropic hormone, no significant difference was seen between NTX pretreatment and placebo pretreatment. These results were different from the result that alcohol increases adrenocorticotropic hormone concentration by stimulating the hypothalamic –pituitary –adrenal axis (HPA axis) of the pituitary gland in the experimental study (River et al., 1983) and the result that alcohol increased corticotrophin-releasing factor mRNA (River et al., 1990), but were similar with the results that a small amount of alcohol rather suppresses the HPA axis (Rasmussen et al., 1998) and that the level of cortisol increases after acute administration of alcohol (Gianoulakis et al., 1989) but rather decreased (Gianoulakis et al., 1996) when a stabilizing period was given before the introduction of alcohol. Ciero (1981) reported that the increased response of cortisol was usually present with a very high level of alcohol administration through an extensive literature study. Also, at the time of placebo pretreatment, the result of the rather decreasing tendency in the concentrations of b-endorphin, ACTH and cortisol after drinking could be the effect of the periodical

668

C. Na, Y.-S. Lee / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 663–670

change of hormone. Ekman et al. (1994) reported that when alcohol was administered in social drinkers at evening time, the concentration of ACTH showed the decreasing tendency according to normal periodical change and showed also the increasing tendency, and this change was not significantly different between the group with alcohol administration and control group. However, since the effect of periodical change cannot be evaluated with the measurement only in 1 h, more studies are needed in the future to investigate the balanced relationship between the effect of periodical change of hormone and the effect of drinking by lengthening the measurement time. Although we cannot control various factors that are necessarily involved in hormone studies in various conditions, we conducted the cross-over experiment where variables found similar in social drinking situation were created and the same conditions were repeated in the same subjects. In order to have the experimental conditions close to social drinking situation, we selected the alcohol consumption amount to be 0.5 ml/kg (about 1/3 bottle of Soju) and tried to eliminate stress accompanying blood taking and acute stress from the experimental condition itself by giving the subjects 30-min relaxation period after the insertion of an indwelling catheter. Also, most of the existing studies measuring hormonal changes in social drinkers or alcoholdependent patients were done in morning time, but we took blood samples at evening time when drinking is done in actual social situations rather than morning time. Bronstein et al. (1993) reported that the concentration of pro-opiomelanocortin (POMC) mRNA increased in the hypothalamus after an 8-day treatment with NTX in rat, and based on the study (Bronstein and Akil, 1990) that the concentration decreased with the pretreatment with morphine, we assumed that the secretion and production of b-endorphin are effected by a kind of feedback mechanism. The result of the present study showed no significant difference at the time of NTX pretreatment and of placebo pretreatment before drinking, but the changing rate based on the concentration before drinking showed a significant difference at 20 min after priming drinking with NTX pretreatment but no significant difference at 60 min after drinking, leading us to make the hypothesis that no difference was seen in the changing rate of b-endorphin at 60 min after drinking with NTX pretreatment compared with placebo pretreatment although the amount of b-endorphin production increase in the pituitary gland with NTX pretreatment due to negative feedback mechanism and the releasing amount of b-endorphin increase with the administration of alcohol depleted stored b-endorphin with time. The action mechanism of NTX based on our results was as follows. Among the side effects experienced with NTX pretreatment, only dizziness was significantly higher among the responses to alcohol administration than placebo pretreatment. This result cannot support the hypothesis by Doty et al. (1997) that NTX itself induces uncomfortable psycho-

logical and physical responses, resulting in the decreased consumption of alcohol. Although no statistically significant difference was seen in acute physical response and positive psychological effect after drinking, the item of mood elevation was rather low with NTX pretreatment, whereas the degree of drowsiness tended to be higher with NTX pretreatment. These results of the present study could partially support the results of the study by Swift et al. (1994) claiming that even a small amount of drink can increase the sedative effect of alcohol as in the case of heavy drinking with NTX pretreatment and decrease the stimulation effect, decreasing the drinking habit. With NTX pretreatment, the urge to drink was significantly low, and although this difference was not significant before drinking, significantly low result was seen after priming drink. This effect of decreasing alcohol craving by NTX supported the hypothesis (Froehlich and Li, 1993; O’Brien et al., 1996) that in a series of the response cycle of the administration of alcohol increasing the level of endogenous opioid and the increased opioid again working on the positive reward system to eventually increase and maintain drinking habit, NTX blocks the effect of opioid to eventually block the positive reinforcement effect of alcohol. However, compared to placebo pretreatment, the result that the concentration of b-endorphin rather increased with NTX pretreatment at 20 min after drinking supported the hypothesis of NTX ‘‘mimicking alcohol effect’’ as alcohol increasing the level of b-endorphin. Thus, with NTX pretreatment, although drinking response of heavy drinking was not shown with the same amount of alcohol, the significant increase of the concentration of b-endorphin was seen as in the case of heavy drinking. Thus, the hypothesis of NTX ‘‘mimicking alcohol effect’’ and the hypothesis of ‘‘blocking effect of positive reinforcement system’’ were mixed in the results of the present study. We interpreted this result that when NTX blocked the action site of b-endorphin, the production and stored amount of b-endorphin increased in the pituitary gland by the negative feedback mechanism at the production site, followed by the production of a large amount of b-endorphin with a small amount of drink to show a higher concentration of serum concentration, but NTX blocked the action site of b-endorphin in the positive reinforcement system, decreasing the urge to drink according to priming drinking. The present study on social drinkers itself had a few limitations. For example, Gianoulakis et al. (1996) reported that in the experiment of inducing drinking after NTX pretreatment, the level of plasma b-endorphin was increased in the high-risk social drinker group that had the family history of alcoholism, but b-endorphin did not increase in the low-risk social drinker group. Another limitation of the present study was not being able to check active/inactive form of b-endorphin. Jaffe et al. (1994) reported that the ratio of b-endorphin31(active form)/b-endorphin-27 plus b-endorphin-26(inact-

C. Na, Y.-S. Lee / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 663–670

ive form) was increased compared to that of the control group at the time of NTX pretreatment in hypothalamus sections for 7 days and Bronstein et al. (1990) reported that the inactive form of b-endorphin increased with the treatment of morphine on the third day. The composition of b-endorphin that increases with alcohol administration after NTX pretreatment may be different from the composition of b-endorphin that is produced after the administration of only alcohol. Thus, in order to elucidate the accurate action mechanism of NTX, further studies comparing social drinkers according to the presence of family history of alcoholism, comparing drinking pattern of alcoholic patients and measuring the active– inactive composition analysis of b-endorphin are needed. Although the urge and craving for a drug have a very close relationship with each other to the point that they cannot be differentiated, the craving can be the desire for the drug, and the urge can be the internal pressure or mobilization to act on the craving. To measure this multidimensional construct in the subject, a short questionnaire with multiple items would be appropriate; however, we used the urge scale with single items used by Davidison et al. (1996) since we had to continue the experiments while maintaining the drinking environment. We think that further studies are needed to confirm various urges/cravings in subjects by improving the study conditions and varying the urge scale.

5. Conclusions The present results strongly suggest that NTX also reduced the urge to drink alcohol in social drinkers. The NTX-pretreated subjects showed a decrease in alcohol craving within 20 min after drinking alcohol while showing an immediate increase in the b-endorphin level. We think that these results were due to the alcohol-mimicking effect due to the drastic increase in the b-endorphin level. We concluded that the decreased craving was due to the blocking effect of the opioid receptor at the same time. The action mechanism of NTX may be that NTX partially blocks the opioid positive reward system and partially mimics the alcohol effect.

References Altshuler, H.L., Phillips, P.E., Feinhandler, D.A., 1980. Alteration of ethanol self-administration by naltrexone. Life Sci. 26, 679 – 688. American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, fourth ed. American Psychiatric Association, (Washington, DC). Bronstein, D.M., Akil, H., 1990. In vitro release of hypothalamic betaendorphin by argine vasopressin, corticotrophin-releasing hormone and 5-hydroxytryptophane: evidence for release of opioid active and inactive beta E forms. Neuropeptides 16, 33 – 40. Bronstein, D.M., Przewlocki, R., Akil, H., 1990. Effects of morphine treat-

669

ment on pro-opiomelanocortin systems in rat brain. Brain Res. 519, 102 – 111. Bronstein, D.M., Day, N.C., Gustein, H.B., Trujillo, K.A., Akil, H., 1993. Pre- and posttranslational regulation of beta-endorphin biosynthesis in the CNS: effects of chronic naltrexone treatment. J. Neurochem. 60, 40 – 49. Chutuape, M.A.D., Mitchell, S.H., de Wit, H., 1994. Ethanol preloads increase ethanol preference under concurrent random-ratio schedules in social drinkers. Exp. Clin. Psychopharmacol. 2, 310 – 318. Ciero, T.J., 1981. Neuroendocrinological effects of alcohol. Annu. Rev. Med. 32, 123 – 142. Croop, R.S., Faulkner, E.B., Labriola, D.F., 1997. The safety profile of naltrexone in the treatment of alcoholism. Results from a multicenter usage study. The Naltrexone Usage Study Group. Arch. Gen. Psychiatry 54, 1130 – 1135. Davidison, D., Amit, Z., 1997. Effects of ethanol drinking and naltrexone on the subsequent drinking in rats. Alcohol 14, 581 – 584. Davidison, D., Swift, R., Fitz, E., 1996. Naltrexone increases the latency to drink alcohol in social drinkers. Alcohol.: Clin. Exp. Res. 20, 732 – 739. de Wit, H., Svenson, J., York, A., 1999. Non-specific effect of naltrexone on ethanol consumption in social drinkers. Psychopharmacology (Berlin) 146, 33 – 41. Doty, P., de Wit, H., 1995. Effects of naltrexone pretreatment on the subjective and performance effects of ethanol in social drinkers. Behav. Pharmacol. 6, 386 – 394. Doty, P., Kirk, J.M., Cramblett, M.J., de Wit, H., 1997. Behavioral responses to ethanol in light and moderate social drinkers following naltrexone pretreatment. Drug Alcohol Depend. 47, 109 – 116. Ekman, A.C., Vakkuri, O., Vuolteenaho, O., LeppSluoto, J., 1994. Delayed pro-opiomelanocortin activation after ethanol intake in man. Alcohol.: Clin. Exp. Res. 18, 1226 – 1229. Froehlich, J.C., Li, T.K., 1993. Opioid peptides. In: Galanter, M. (Ed.), Recent Development in Alcoholism Ten Years of Progress, vol. 11. Plenum, New York, pp. 187 – 205. Gianoulakis, C., Beliveau, D., Angelogiani, P., Meaney, M., Thavundayil, J., Tawar, V., Dumas, M., 1989. Different pituitary beta-endorphin and adrenal cortisol response to ethanol in individuals with high and low risk for future development of alcoholism. Life Sci. 45, 1097 – 1109. Gianoulakis, C., Krishnan, B., Thavundayil, J., 1996. Enhanced sensitivity of pituitary to ethanol in subjects at high risk of alcoholism. Arch. Gen. Psychiatry 53, 250 – 257. Harada, S., Agarwal, D.P., Goedde, H.W., 1981. Aldehyde dehydrogenase deficiency as cause of facial flushing reaction to alcohol in Japanese. Lancet 129, 982. Jaffe, S.B., Sobieszczk, S., Wardlaw, S.L., 1994. Effects of opioid antagonism on the beta-endorphin processing and proopiomelanocortin-peptide release in the hypothalamus. Brain Res. 648, 24 – 31. King, A.C., Volpicelli, J.R., Gunduz, M., O’Brien, C.P., Kreek, M.J., 1997. Naltrexone biotransformation and incidence of subjective side effects: a preliminary study. Alcohol.: Clin. Exp. Res. 21, 906 – 909. Lee, T.J., 1989. The study on the relationship between aldehyde dehydrogenase I isoenzyme variance and alcohol sensitivity, drinking habit, and alcoholism in Korean males (unpublished). O’Brien, C.P., Volpicelli, L.A., Volpicelli, J.R., 1996. Naltrexone in the treatment of alcoholism: a clinical review. Alcohol 13, 35 – 39. O’Malley, S., Substance Abuse and Mental Health Services Administration, 1998. Naltrexone and Alcoholism Treatment, Treatment Improvement Protocol 28. Rockwell, Rockville, MD, pp. 51 – 54. Pastoric, M., Boyadjieva, N., Sarkar, D.K., 1994. Comparison of the effects of alcohol and acetaldehyde on proopiomelanocortin mRNA levels and b-endorphin secretion from hypothalamic neurons in primary cultures. Mol. Cell. Neurosci. 5, 580 – 586. Rasmussen, D.D., Bryant, C.A., Boldt, B.M., Colasurdo, E.A., Levin, N., Wilkinson, C.W., 1998. Acute alcohol effects on opiomelanocortinergic regulation. Alcohol.: Clin. Exp. Res. 22, 789 – 801.

670

C. Na, Y.-S. Lee / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 663–670

Reiger, D.A., Farmer, M.E., Rae, D.S., Locke, B.Z., Keith, S.J., Judd, L.L., Goodwin, F.K., 1990. Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) study. JAMA, J. Am. Med. Assoc. 264, 2511 – 2518. River, C., Bruhn, T., Vale, W., 1983. Effect of ethanol on the hypothalamic – pituitary – adrenal axis in the rat: role of corticotrophin-releasing factor. J. Pharmacol. Exp. Ther. 229, 127 – 131. River, C., Imaki, T., Vale, W., 1990. Prolonged exposure to alcohol: effect on CRF mRNA levels, and CRF- and stress-induced ACTH secretion on the rats. Brain Res. 520, 1 – 5. Selzer, M., 1971. The Michigan Alcoholism Screening Test: the quest for a new diagnostic instrument. Am. J. Psychiatry 127, 1653 – 1658. Swift, R.M., Whelihan, W., Kuznetsov, O., Buongiorno, G., Hsuing, H.,

1994. Naltrexone-induced alterations in human ethanol intoxication. Am. J. Psychiatry 151, 1463 – 1467. Volavka, J., Mallya, A., Bauman, J., Cho, D., 1979. Hormonal and other effect of naltrexone in normal men. Adv. Exp. Med. Biol. 116, 291 – 305. Volpicelli, J.R., Watson, N.T., King, A.C., Sherman, C.E., O’Brien, C.P., 1995. Effects of naltrexone on alcohol high in alcoholics. Am. J. Psychiatry 152, 613 – 615. Wilkin, J.K., Hazelrigg, E.J., 1987. Effect of naltrexone in the ethanolprovoked flushing in Oriental and white subjects. Clin. Pharmacol. Ther. 42, 582 – 587. Yoburn, B.C., Inturrisi, C.E., 1988. Modification of the response to opioid and nonopioid drugs by chronic opioid antagonist treatment. Life Sci. 42, 1689 – 1696.