Changes in dopamine receptor responsivity during alcohol detoxification may predict relapse.

In the search for clinical and biological variables that may predict relapse of alcohol dependent patients after detoxification, we followed up for 1 year male patients that had undergone successful detoxification. The patients had been tested earlier during their usual alcohol consumption and immediately after detoxification for the responsivity of D2 dopamine receptors (as measured by the increases in prolactin plasma levels caused by intramuscular administration of 5 mg of the dopamine receptor blocker haloperidol). Of the 18 patients, eight had not consumed alcohol for more than 6 months, and ten had relapsed within 6 months. Comparison of the clinical and neuroendocrine data for the two subgroups revealed no significant differences in age, amount of alcohol consumed during alcohol abuse, score in the Beck Depression Inventory, score in the Brief Michigan Alcoholism Screening Test, or prolactin responses to haloperidol before detoxification. In patients who relapsed, the duration of alcoholism was marginally shorter (P=0.055). Patients who did not relapse had significantly higher (P=0.003) prolactin responses to haloperidol in the test performed after detoxification as compared with patients who did relapse, and their responses were similar to those of a group of healthy male subjects. The results show that the increase in dopamine receptor responsivity that occurs after detoxification is a favourable factor for non-relapse; it may reflect recovery from down-regulation of the dopaminergic reward system caused by alcohol consumption.     

Increased prolactin reserve in alcoholics

The prolactin response to oral metoclopramide (10 mg) was investigated in 53 chronic alcoholics (26 with alcoholic cirrhosis and 27 without evidence of liver disease) from two to seven days after alcohol suspension. The response appeared significantly higher in patients than in healthy controls and was not related to the presence of liver disease. This finding may depend on the deactivation of the dopaminergic activities secondary to alcohol suspension; alternatively, ethanol could have a direct action on prolactin secretion.     

Neuroendocrine serotonergic and dopaminergic responsivity in male schizophrenic patients during treatment with neuroleptics and after switch to risperidone

RATIONALE: The pharmacological profile of risperidone is that of an atypical neuroleptic regarding its serotonin 5-HT2A and dopamine D2 receptor blocking properties. Treatment with risperidone, though, results in considerably elevated plasma prolactin (PRL) levels which are not observed with other atypical neuroleptics, such as clozapine, indicating a differentiated action on receptors that are involved in PRL release, mainly dopaminergic and serotonergic. OBJECTIVE: To assess the responsivity of serotonergic and dopaminergic receptors during treatment with neuroleptics and after switch to risperidone, using neuroendocrine paradigms. METHODS: Two neuroendocrine challenge tests, measuring the PRL increases induced by acute administration of serotonergic (clomipramine, 25 mg i.v.) and dopaminergic (haloperidol, 5 mg i.m.) drugs were performed in 13 male schizophrenic patients during treatment with typical neuroleptics and, later, after 6 weeks of treatment with risperidone. The tests were also performed in a group of nine healthy male volunteers. PRL was estimated in blood samples taken every 15 min for 1 h for clomipramine and every 30 min for 2 h for haloperidol. Psychopathology was assessed using the Brief Psychiatric Rating Scale (BPRS). RESULTS: During treatment with neuroleptics (mean dose 1354 mg chlorpromazine equivalents, range 300-2400 mg), i.m. haloperidol caused significant elevations in plasma PRL, which were totally abolished after 6 weeks treatment with risperidone (mean dose 12.1 mg/day, range 8-16 mg/day), indicating complete D2 receptor blockade. In contrast, the PRL increases obtained after clomipramine administration during neuroleptic treatment were preserved after treatment with risperidone. Both PRL response patterns to clomipramine were similar to that of healthy controls. BPRS score was 50.2+/-9.3 points during neuroleptic treatment and was reduced after risperidone to 30.1+/-6.6 points, i.e., 40% in the mean. CONCLUSIONS: During treatment with typical neuroleptics, the PRL responses to clomipramine are normal, and they are preserved after switch to risperidone in doses that cause complete dopamine receptor blockade. Risperidone, a dopamine and 5-HT receptor blocker, does not affect 5-HT receptors that are involved in the PRL release by the 5-HT uptake blocker clomipramine, indicating a different behavior than other atypical neuroleptics such as clozapine or olanzapine, for which a reduction of the PRL release induced by serotonergic agents like fenfluramine or mCPP has been reported. A conclusive identification of the 5-HT receptor subtypes that are involved in this different action cannot be identified at present, but it should be taken into account that risperidone differs from clozapine, showing higher affinity for 5-HT2A than 5-HT2C receptors and lacking the marked affinity of clozapine to 5-HT1A receptors.     

Evaluation of apolipoprotein E (apoE) and lipoprotein profile in severe alcohol-dependent individuals

BACKGROUND: Chronic alcohol consumption down-regulates the expression of sialytransferase genes resulting in impaired sialylation of apolipoprotein E (apoE) and decreased association with HDL. There are a limited number of studies with contradictory data on the effect of alcohol dependence on human plasma apoE. The aim of the present work is to determine and compare the levels of apoE in relation to the other lipoproteins in alcohol-dependent individuals in order to evaluate the possible role of apoE in lipoprotein metabolism in conditions of severe alcohol dependence. PATIENTS AND METHODS: The sample of our study comprised 43 DSM-IV diagnosed alcohol-dependent/abusing subjects (33 males and 10 females), treated on an inpatient basis according to a standard detoxification protocol, and 27 healthy people (9 males and 18 females, as a control group). Serum concentration of hepatic enzymes (AST, ALT, gammaGT), as well as measures of cholesterol and lipoproteins were obtained at baseline and at discharge after a detoxification period of 4-5 weeks. RESULTS: Upon admission, all alcohol-dependent individuals had significantly higher hepatic enzyme levels, apoE and HDL values compared to controls. After completion of alcohol detoxification, all the above parameters returned to normal levels. Additionally, a significant correlation was observed between alcohol consumption during the previous year of alcohol abuse and the apoE values both upon admission to and on discharge from the detoxification program. CONCLUSION: The statistical correlation between apoE on admission and discharge with alcohol consumption during the previous year suggests that apoE is dependent on alcohol consumption and can serve as a sensitive marker of severe alcohol abuse.     

Neuroendocrine and behavioral responses to dopaminergic agonists in adolescents with alcohol abuse

Abstract Rationale. Dopaminergic systems are involved in the pathophysiology of alcohol use disorders, but there is little research investigating the role of these systems in adolescents. Objectives. In this study, we investigated dopaminergic systems in adolescents with alcohol abuse by determining neuroendocrine and behavioral responses to dopaminergic drug challenges. Methods. Twenty-six participants (11 with DSM IV alcohol abuse and 15 controls) were enrolled in the study. Neuroendocrine and behavioral response to the dopaminergic indirect agonist methylphenidate (10 mg) and the direct agonist pergolide (50 mcg), were examined. The primary response measures were spontaneous eye-blink rate, plasma prolactin (PRL), and growth hormone (GH). Additionally, participants completed a visual analog mood scale (VAMS). Results. The rate of increase in plasma GH level was blunted for adolescents with alcohol abuse compared to the control group, after methylphenidate administration [t=–2.75, P=0.0066, 95% confidence interval (CI) –0.3, –0.048]. The rate of decrease in PRL level after pergolide administration was greater in adolescents with alcohol abuse as compared to the control group (t=–3.05, P=0.0028, 95% CI –0.01923, –0.00409). Adolescents with alcohol abuse rated themselves as less "energized" in comparison to the control group after methylphenidate (rate difference=–0.4, P=0.0231). Conclusions. This preliminary study suggests that adolescents with alcohol abuse may have a differential response to dopaminergic agonists, as also reported for adults with alcohol use disorders. Further studies investigating gender differences, and other neurotransmitter systems are needed to understand the differential dopaminergic response in adolescents with alcohol use disorders. Electronic Publication     

Normal testosterone plasma levels in non-abstinent alcoholics

Testosterone (T), prolactin (PRL), and luteinizing hormone (LH) levels were estimated in plasma of 32 male chronic alcoholics during a period of their usual alcohol consumption and compared to the values of 32 age-matched controls. T levels were not different from normals, while both PRL and LH were significantly elevated. The subgroup of patients with severe liver injury (n = 11) showed elevated PRL (2P less than 0.001), but normal LH and T, while patients with normal hepatic function (n = 21) showed normal PRL levels, elevated LH, and a tendency to elevated T levels.     

Effect of alcohol detoxification on serum S-100B levels of alcohol-dependent individuals

BACKGROUND: Chronic alcohol consumption has been associated with both liver dysregulation and neurotoxic effects in the central nervous system of human beings and experimental animals. Serum levels of S100B protein have been extensively studied in several conditions of neural tissue injury but not in alcohol abuse. The aim of this study was to evaluate the serum levels of S100B in alcohol-dependent individuals and to further investigate the effect of alcohol detoxification on the levels of S100B. PATIENTS AND METHODS: Our study included 20 alcohol dependent/abusing subjects, diagnosed based on the DSM-IV criteria and treated on an inpatient basis according to a standard detoxification protocol. The serum concentration of hepatic enzymes (ASAT, ALAT, gammaGT), as well as measurements of anxiety, depression and global functioning were obtained at baseline and at weekly intervals over the period of 4-5 weeks, while S100B levels were measured on admission and discharge. RESULTS: Upon admission, hepatic enzyme levels were found increased compared to normal levels and correlated positively with the degree of alcohol consumption of the last year. Interestingly, the ALAT levels correlated positively with S100B levels upon admission. After completion of alcohol detoxification, the hepatic enzyme levels returned to normal. The S100 B levels decreased in 10 patients with a moderate alcohol-consumption over the last year, but increased in 10 patients with high alcohol consumption over the last year. Additionally, a significant correlation was found between the levels of S100B and the global functioning scale at the end of detoxification treatment. CONCLUSION: S100B protein levels are affected differently in alcohol-dependent individuals with either mild or high alcohol consumption during the period of up to one year before assessment. A good correlation between the release pattern of S100B and global functioning scale was found. Although this is a preliminary study, the present data suggest a possible use of S100B protein measurements in detecting alcohol-dependent individuals with high alcohol consumption and in further monitoring the alcohol detoxification treatment.     

Plasma homovanillic acid: a significant association with alcoholism is independent of a functional polymorphism of the human catechol-O-methyltransferase gene.

The central dopamine system seems to influence addictive disorders. Plasma homovanillic acid (HVA) is an indicator of central dopaminergic activity. In this study the hypothesis that plasma HVA is associated with alcoholism or with delirium tremens (DT) during alcohol withdrawal was tested. A functional genetic polymorphism of the enzyme catechol-O-methyltransferase (COMT) that participates in converting dopamine into its final metabolite HVA was investigated for an association with alcoholism or DT during alcohol withdrawal. In addition, a relation between the functional polymorphism of COMT and plasma HVA concentrations was studied. Plasma HVA concentrations and COMT genotypes were determined in 142 German alcoholics and 101 German healthy controls. Alcoholic patients were examined after a minimum of 3 weeks after cessation of drinking. Mean plasma HVA concentrations were significantly lower in alcoholic patients compared to healthy controls. A group of alcoholics with a history of DT during alcohol withdrawal (n=62) did not differ significantly in plasma HVA concentrations from alcoholics with a history of only mild withdrawal symptoms (n=67). The functional polymorphism of the human COMT gene was neither significantly associated with the diagnosis of alcoholism or DT during alcohol withdrawal nor with plasma HVA concentrations.     

Pharmacogenetic insights to monoaminergic dysfunction in alcohol dependence

Rationale Alcohol dependence is characterized by the development of tolerance, withdrawal symptoms, and craving for alcohol. Chronic alcohol consumption causes neuroadaptive changes in the central dopaminergic and serotonergic system, which are partially reversible after detoxification. The severity and time-course of recovery of these neuroadaptive changes may depend on the genetic constitution of monoamine transporters and receptors and contribute to the relapse risk of alcoholics.Objectives To assess the interaction between the genetic constitution and the in vivo availability of dopamine and serotonin transporters and receptors, chronic alcohol intake, alcohol craving and withdrawal.Methods Review of brain imaging studies that assess the genotype and availability of dopamine and serotonin transporters in detoxified alcoholics and healthy control subjects.Results Chronic alcohol intake induced neuroadaptive reductions in striatal dopamine transporter (DAT) availability, which were reversible during early abstinence. A polymorphism of the DAT gene (SLC6A3) was associated with the in vivo transporter availability and with the severity of alcohol withdrawal. Neurotoxic reductions in 5-HTT protein expression were limited to homozygous carriers of the long allele in the 5-HTT gene (SCL6A4) regulatory region and correlated with negative mood states.Conclusion Genetic constitution interacts with the in vivo availability of central dopamine and serotonin transporters during alcohol detoxification and may affect the severity of alcohol withdrawal and clinical depression.     

Gonadal axis hormones in male schizophrenic patients during treatment with haloperidol and after switch to risperidone

Rationale: The atypical neuroleptic risperidone, in addition to its dopamine receptor blocking activity, has a high affinity for serotonergic receptors. Since both dopaminergic and serotonergic neuronal activities participate in regulation of the pituitary – gonadal axis (PGA), it is expected that a switch from treatment with haloperidol to treatment with risperidone should influence plasma levels of PGA hormones. Objective: To study the effects of a drug with dopamine and serotonin receptor blocking activity on PGA hormones in patients who were on treatment with a dopamine receptor blocker. Methods: Plasma levels of testosterone, luteinizing harmone (LH) and follicle stimulating harmone (FSH), as well as prolactin and cortisol, were measured in 16 male schizophrenic patients during treatment with haloperidol (mean dose 23.3 mg daily, SD = 16.9) and 6 weeks later after switching to treatment with risperidone (mean dose 11.8 mg daily, SD = 2.9). Psychopathology was assessed by BPRS. Results: After switching to risperidone, total BPRS score and the scores in its subscales for positive, negative, and general symptoms were all significantly reduced in the order of 35–45%. Prolactin levels were significantly increased from 39.5 ± 22.3 to 58.9 ± 28.5 ng/ml (F = 4.61, P = 0.04), while cortisol, testosterone, LH, and FSH remained unchanged. No significant correlations between prolactin increases and reduction in BPRS or in its subscale scores were found. Conclusions: The results show that blocking of both dopamine and serotonin receptors does not influence the pituitary – gonadal axis but considerably increases prolactin release. Received: 29 June 1998/Final version: 23 October 1998     

Alcohol and drug problems in Czechoslovakia

The authors describe the current drug and alcohol scene in Czechoslovakia, with references to historical developments. Drug abuse is divided into nine groups: from drugs most frequently abused (opiates and speed) to illegally cultivated hemp (hashish and marijuana). In 1985 there were 9,900 registered drug addicts and 720 are added to this number annually. There are approximately 15 nonregistered drug addicts for every registered one. In the consumption of alcoholic beverages, Czechoslovakia holds 13th place in the world (average annual per capita consumption is in the vicinity of 9.5 litres of 100% alcohol). In 1985 there were 239,385 registered alcoholics (of this number, 18,746 were women). In conclusion the authors describe the Czechoslovak system of treatment of addictions: detoxification departments, outpatient treatment, and institutional care, as well as treatment for prisoners and forced treatment. They also mention the effectiveness of these treatment programs.     

Discriminative stimulus properties of pizotifen maleate (BC105): a putative serotonin antagonist

The neurochemical specificity of physiological, biochemical, and psychological responses to dextroamphetamine was tested by pretreating volunteers with haloperidol (0.014 mg/kg IM), proparonol (0.1 mg/kg IV), thymoxamine (0.1 mg/kg IV), or placebo prior to 0.3 mg/kg IV amphetamine. Healthy volunteers (N=12) participated in the studies, but not all volunteers received each drug combination. Haloperidol prevented dextroamphetamine-induced behavioral excitation, but did not significantly affect plasma norepinephrine or pressor responses, whereas propranolol inhibited norepinephrine and pressor responses without influencing excitation or other behavioral responses. Thymoxamine did not affect any of the responses measured. None of the agents significantly affected plasma cortisol or growth hormone responses. The prolactin rise following dextroamphetamine was potentiated by haloperidol. The results are consistent with the hypothesis that behavioral excitation after dextroamphetamine occurs through a dopaminergic mechanism, and pressor responses through a noradrenergic mechanism.     

Haloperidol and prolactin concentrations in Asians and Caucasians

Serum haloperidol and prolactin concentrations were measured in 34 normal male volunteers (12 Caucasians, 11 American-born Asians, and 11 foreign-born Asians) over a 7-hour period after haloperidol administration (0.5 mg given intramuscularly or 1.0 mg given orally). The results were similar between the two Asian groups but significantly different between Caucasians and Asians. After controlling for body surface area, Caucasians still had lower serum haloperidol concentrations and less prominent prolactin responses than did Asians. Furthermore, the ethnic difference in prolactin responses could not be fully accounted for by the differences in serum haloperidol concentrations between the two ethnic groups. These results indicate that both pharmacokinetic factors, including absorption and hepatic first-pass metabolism, and pharmacodynamic factors (dopamine receptor-mediated responses) contribute to the difference in responses between Caucasians and Asians.     

Alcohol dehydrogenase: an autoantibody target in patients with alcoholic liver disease

The link between alcohol consumption and liver disease is not direct and several factors including autoimmunity to hepatocyte components have been implicated. We have previously identified alcohol dehydrogenase (ADH) as an autoantigen in autoimmune liver disease and in a proportion of patients with alcoholic liver disease. The aim of the present study is to investigate the association between the presence of anti-ADH antibodies, alcohol consumption and severity of liver damage in alcoholic patients. The presence of antibodies to human ADH beta2 and horse ADH was investigated in 108 patients with documented history of alcohol consumption and alcohol related liver disease, 86 being active alcohol abusers and 22 on sustained alcohol withdrawal, 39 with non-alcohol related disease and 22 normal subjects. Antibodies to either ADH form were more frequently detected in active alcohol abusers (55/86, 64%) than in patients on sustained alcohol withdrawal longer than 6 months (1/8, 13 %, P < 0.005), HBV infection (2/8, 25 %, P=0.03), non-alcohol related disease (9/29, 23 %, P < 0.0001) and in normal controls (3/22, 14 %, P < 0.0001); were more frequent in patients with cirrhosis than in those with steatosis (26/34, 76 % vs 34/64, 53 %, P=0.02); and were associated with elevated levels of ALT (anti-ADH beta2, P < 0.05), immunoglobulin A (P < 0.05) and gamma-glutamyl transpeptidase (P=0.01). Anti-ADH antibody positive serum samples were able to inhibit the enzymatic activity of ADH. These findings suggest that anti-ADH antibodies may be triggered by alcohol consumption and act as a disease activity marker in alcoholic liver disease.     

Dopamine challenge tests as an indicator of psychological traits

After discussing some introductory considerations about the value of challenge tests in general for discriminating personality dimensions which are considered extrapolations of psychopathological diseases, the present paper outlines the matter of responsivity to agonistic and antagonistic dopaminergic drugs or drugs of different mechanisms of action in the dopaminergic system, and elucidates that different hormones elicited by dopaminergic substances (prolactin, growth hormone) may indicate personality related differences in susceptibility of different brain areas. A further point was to demonstrate not only the well known relationship of dopaminergic hyperactivity with reward seeking and motivational factors associated with extraversion and novelty seeking, but also the relationship of dopaminergic hypofunction with the personality dimension of depression which had already been reported in studies on animals and psychiatric patients. A final point was to demonstrate that besides size of hormone responses additional parameters like time of response onset and initial prolactin increase can be used as biochemical indicators for identifying certain personality types, like highly depressive neurotic persons characterized by lower and later dopamine responses as compared to low depressives, and extraverted sensation-seeking types responding by an initial prolactin peak as opposed to low sensation seekers.     

Prolactin and TSH responses to TRH and to haloreridol in schizophrenic patients before and after treatment

The prolactin (PRL) and the TSH responses to thyrotropin releasing hormone (TRH, 0.4 mg i.v.) and to haloperidol (5 mg i.m.) were studied in 11 male schizophrenic patients in a drug-free state and after treatment with haloperidol, 60 mg daily. The PRL responses observed after i.m. haloperidol in the drug-free state, on average 35.4 ng/ml, were abolished after treatment, indicating complete receptor blockade, while the PRL responses to TRH were preserved, although moderately reduced (from 19.4 to 14.8 ng/ml on average). The TSH responses to TRH were unaltered by the treatment (means 8.25 and 7.74 mIU/1). The results show that the TSH and partially the PRL releasing actions of TRH are not mediated via receptors that are effectively blocked by haloperidol.     

Drinking,Alcoholism, and Sexual Behavior in a Cohort of Gay Men

The relationships between usual alcohol consumption, alcoholism, and sexual behavior were examined using data derived from a sample of 604 New York City gay men who had been interviewed annually in 1985, 1986, 1987, and who did not have a diagnosis of AIDS. Alcohol consumption was measured as the product of usual quantity and frequency of drinking over the year prior to each interview. Diagnoses of alcohol abuse and dependence during the years of 1986 and 1987 were assessed using the National Institute of Mental Health (NIMH) Diagnostic Interview Schedule (DIS). Sexual behaviors varied in their risk on transmission of Human Immunodeficiency Virus (HIV), (the cause of Acquired Immunodeficiency Syndrome [AIDS]), and included insertive and receptive oral-genital sex and unprotected insertive and receptive anal intercourse. Significant associates were found between usual alcohol consumption and oral sex in 1985 and 1986, but not in 1987. Those identified as alcoholic also reported significantly more episodes of receptive oral sex in 1987. No other significant associations were found. This pattern of results did not change when lover status and age were controlled for as covariates. These results are discussed in light of their implications for future work on the issue of drinking and sexual risk taking.     

Serum prolactin correlates with depressed mood during alcohol withdrawal

Alterations in central dopamine function have been identified in depression and in alcohol withdrawal. Attempts to determine the magnitude and direction of the central dopamine alteration in alcohol withdrawal have produced conflicting results. In this study serum prolactin (PRL) was used as an indicator of central dopamine activity since dopamine is the most important factor in the control of prolactin secretion from the pituitary. Increased serum PRL levels were found during alcohol withdrawal and they correlated significantly with high scores on the Hamilton Depression Rating Scale (HDRS). No significant correlations were identified with The Brief Psychiatric Rating Scale (BPRS), the 'Mini-Mental State' of Folstein (MMS), The Beck Depression Inventory (BDI) or The Modified Gross Alcohol Withdrawal Selective Severity Assessment Scale (GAWSSA). The authors concluded that the transient depressive symptomatology typically found in detoxifying alcoholic patients may be, in part, the result of a central hypodopaminergic state.     

A randomized trial of two behavioral interventions to improve outcomes following inpatient detoxification for alcohol dependence

Participants (n=150), undergoing inpatient alcohol detoxification, were randomized into 3 groups: treatment as usual (TAU), motivation enhancement therapy (MET), or peer-delivered 12-step facilitation (P-TSF). The main outcome was the initiation of any type of subsequent rehabilitation service (i.e., professional treatment or self-help) within 30 and 90 days of discharge. At the 30-day follow-up interview, there was no significant difference among the groups in the rate of initiation of any type of subsequent care (82%, 74%, and 82%, respectively, p=0.617); however, the MET group had significantly more patients initiate subsequent inpatient treatment by the 90-day follow-up interview compared to the P-TSF group (31% and 61%, respectively, p=0.007) and a greater proportion of MET participants completed subsequent inpatient treatment compared to both the TAU and P-TSF groups. There were no differences in drinking-related outcomes. MET during inpatient detoxification may help patients initiate subsequent inpatient rehabilitation treatment.     

Initiating acamprosate within-detoxification versus post-detoxification in the treatment of alcohol dependence

ObjectivesThis trial compared the efficacy of acamprosate, started at the beginning of detoxification, to acamprosate started at the completion of detoxification, in the treatment of alcohol dependence.MethodsThis biphasic clinical trial consisted of a randomized, double-blind, placebo-controlled Detoxification Phase (DP), followed by a 10-week open-label Rehabilitation Phase (RP). Forty alcohol dependent patients were randomly assigned to receive either 1998 mg of acamprosate daily, or matching placebo, during the DP (5–14 days). After completing detoxification, all patients received open label acamprosate (1998 mg daily) in the RP. Outcome measures during the DP included: treatment retention, alcohol withdrawal, alcohol consumption, and oxazepam used. Outcome measures during the RP included: treatment retention and alcohol consumption.ResultsThere were no significant outcome differences between acamprosate and placebo-treated patients during the DP. Patients given acamprosate, compared to placebo, during the DP drank more alcohol in the RP.ConclusionsStarting acamprosate at the beginning of detoxification did not improve DP outcomes. Starting acamprosate after detoxification was completed was associated with better drinking outcomes during subsequent alcohol rehabilitation treatment.