naloxone and Alcoholism

Although far from conclusive, evidence implicating the endogenous opioid system in the development and maintenance of alcoholism is growing. Currently available data suggest that ethanol increases opioid neurotransmission and that this activation is part of the mechanism responsible for its reinforcing effects. Findings from preclinical research indicate that ethanol consumption and ethanol-induced dopamine (DA) release are both reduced by opioid antagonists. Individual differences in endogenous opioid activity have been linked to inherited risks for alcoholism in studies comparing ethanol-preferring and nonpreferring rats, as well as in studies using targeted gene mutation (knockout) strategies. To a large extent, findings from human studies have paralleled those from the preclinical work. Persons who differ in family history of alcoholism have been shown to also differ in basal beta-endorphin activity, beta-endorphin response to alcohol, and subjective and HPA axis hormonal response to opioid antagonists. Findings from clinical trials indicate that opioid antagonists may reduce ethanol consumption in alcoholics, particularly in persons who have resumed drinking. Nevertheless, many questions remain unanswered about the use of opioid antagonists in alcoholism treatment and about the exact role of the opioid system in ethanol preference and reward. The progression of knowledge in this field suggests that many of these questions are imminently answerable, as our ability to characterize relationships between opioid activity and human behavior continues to develop. This paper summarizes both the progress that has been made and the gaps that remain in our understanding of the interactions between the endogenous opioid system and risk for alcoholism.

Topics: Alcohol Drinking; Alcoholism; Animals; Endorphins; Humans; Hypothalamo-Hypophyseal System; Naloxone; Narcotic Antagonists; Pituitary-Adrenal System; Receptors, Opioid; Reward; Risk Factors; Stress, Physiological; Synaptic Transmission

Results from studies of pharmacotherapies for primary alcoholism are reviewed, including selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (e.g. fluoxetine), opiate antagonists (e.g. naltrexone) and dopamine agonists (e.g. bromocriptine). Because there is considerable comorbidity between alcohol dependence, anxiety, and affective disorders, results from studies of medications used to treat these psychiatric disorders are also reviewed, including the 5-HT agonist buspirone and the noradrenergic agent desipramine. The neurobehavioural model of alcohol dependence implies that combinations of medications may lead to more effective treatment; thus, identifying subtypes of alcoholic patients will be important in determining which therapies or combinations of therapy will be most effective in treating alcohol dependence. For example, in an ongoing study, we are attempting to subtype an alcoholic population for treatment selection by measuring endogenous opioid activity. Because endogenous opioids are involved in analgesia, we exposed male and female subjects with alcoholism [some of whom had post-traumatic stress disorder (PTSD)] to cold-induced pain and measured their response before and after administration of naloxone or placebo. The naloxone injection reduced pain response. In addition, women who have PTSD are much more sensitive to stress, which may be related to levels of brain opioid activity.

Topics: Adult; Alcohol Deterrents; Alcoholism; Animals; Arousal; Brain; Dopamine Agonists; Double-Blind Method; Female; Humans; Male; Naloxone; Narcotic Antagonists; Neurotransmitter Agents; Pain Threshold; Psychotropic Drugs; Receptors, Neurotransmitter; Selective Serotonin Reuptake Inhibitors

Although the isoquinoline hypothesis has stimulated and even tantalized the scientific inquiry of a small number of investigators, it has been an area of widespread controversy. For the most part, until recently, alcohol researchers would ascribe very little importance to the role played by insoquinolines in alcohol actions or in the disease state known as alcoholism. To most, there was adequate evidence that these condensation amines had potent pharmacologic properties but little was known about their biochemical and behavioral interaction with ethanol or opiates. As pointed out here, there is an increasing amount of evidence that indicates the putative role of isoquinolines as regulators of alcohol dependence. There is even evidence that suggests a possible "link" to opiates. If this turns out to be the case, then it is rational to consider the possibility that when one imbibes alcohol a central opiate-like substance is, in essence, produced. It would appear that the sum total of evidence to date supports the notion that there are common territories between the two highly addictive classes of drugs--alcohol and opiates. Although still not definite, future studies may well confirm the intermediacy of the TIQ compounds.

Topics: Alcoholism; Alkaloids; Animals; Calcium Chloride; Drug Interactions; Ethanol; Humans; Isoquinolines; Mice; Motor Activity; Naloxone; Rats; Sleep; Substance Withdrawal Syndrome; Substance-Related Disorders

Neither the predictive value of early continuous abstinence in alcohol use disorder (AUD) or the point at which this effect may emerge has been evaluated. This analysis of the Combined Pharmacotherapies and Behavioral Interventions (COMBINE) clinical trial evaluated whether abstinence early in treatment was a predictor of longer term abstinence.. Participants who stated a goal of total abstinence (N = 954) were dichotomized into Early Abstainer vs. Nonabstainers and were compared on a variety of drinking outcome measures that are frequently used in clinical trial evaluations of alcohol treatment strategies, as a function of duration of early continuous abstinence.. Significant differences existed for every outcome. Early Abstinence was significantly associated with fewer drinks per drinking day, number of drinking and number of heavy drinking days, and longer time to first drinking and first heavy drinking day. Effects were evident within the first week. The magnitude of all effects increased as the duration of early abstinence (1-4 weeks) increased, though the size of increase varied across the outcomes.. These data provide evidence that drinking at the beginning of alcohol treatment is significantly and robustly associated with drinking throughout and at the end of a clinical trial treatment for AUD. Early drinking may be a useful early index to identify whether patients are responding positively to a treatment strategy, and provides a useful method for tailoring treatment to patients that is consistent with a personalized medicine approach.

Topics: Acamprosate; Adult; Alcohol Abstinence; Alcohol Deterrents; Alcoholism; Behavior Therapy; Double-Blind Method; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Taurine; Time Factors; Treatment Outcome

The present analysis describes the longitudinal change in buprenorphine treatment outcome. It also examines several participant characteristics to predict response to buprenorphine.. Participants (n=501, age>15 years) received buprenorphine/naloxone treatment for 4 weeks, and then were randomly assigned to undergo dose tapering over either 7 days or 28 days. An empirical model was developed to describe the longitudinal changes in treatment outcome. Several patient characteristics were also examined as possible factors influencing treatment outcome.. We have developed a model that captures the general behavior of the longitudinal change in the probability of having an opioid-negative urine sample following buprenorphine treatment. The model captures both the initial increase (i. e., initial response) and the subsequent decrease (i. e., relapse to opioid) in the likelihood of providing an opioid-negative urine sample. Characteristics associated with successful buprenorphine treatment outcome include: having a negative urine test for drugs, having alcohol problems [assessed using alcohol domain of addiction severity index (ASI-alcohol)] at screening, being older, and receiving low cumulative buprenorphine dose. However, ASI-alcohol values were generally low which make the application of the proposed alcohol effect for patients with more severe alcohol problems questionable.. A novel approach for analyzing buprenorphine treatment outcome is presented in this manuscript. This approach describes the longitudinal change in the probability of providing an opioid-free urine sample instead of considering opioid use outcome at a single time point. Additionally, this model successfully describes relapse to opioid. Finally, several patient characteristics are identified as predictors of treatment outcome.

Topics: Adolescent; Adult; Age Factors; Aged; Alcoholism; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Dose-Response Relationship, Drug; Drug Combinations; Female; Humans; Longitudinal Studies; Male; Middle Aged; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Severity of Illness Index; Substance Abuse Detection; Treatment Outcome; Young Adult

Animal and clinical studies implicated opioid dysfunction in the pathogenesis of alcohol abuse and dependence. The π-opioid antagonist naltrexone reduces craving, eventually modulated by hypothalamic-pituitary-adrenal axis. Altered cortisol response to opioid receptor blockade not only in alcohol dependent persons, but also in persons with a family history of alcohol dependency was reported.. Twenty patients with alcohol dependence who had undergone detoxification were recruited. Naloxone (3.2 mg/70 kg body weight) having a very similar receptor profile to naltrexone and placebo were administered in cross-over fashion on two separate days 48 h apart. Mood and craving was assessed with well-established instruments (Alcohol Craving Questionnaire (ACQ), Profile of Mood Scale (POMS)). Both patients and raters were blind to all treatments. Twelve patients were first treated with naloxone, eight were first treated with placebo.. No significant differences were found between the placebo and naloxone groups according to ACQ and POMS. Cortisol levels were significantly higher in naloxone group.. We could not replicate the result, that blocking of the endogenous opioid system leads to reduced craving in alcohol-dependent individuals, while increase of cortisol after naloxone challenge is the expected biological effect of opioid receptor blockade on the hypothalamic-pituitary-adrenal (HPA) axis.

Topics: Adult; Alcoholism; Cross-Over Studies; Cues; Double-Blind Method; Humans; Hydrocortisone; Male; Middle Aged; Naloxone; Narcotic Antagonists; Placebos; Treatment Outcome; Young Adult

Having opioid dependence and HIV infection are associated with poor HIV-related treatment outcomes.. HIV-infected, opioid-dependent subjects (N = 295) recruited from 10 clinical sites initiated buprenorphine/naloxone (BUP/NX) and were assessed at baseline and quarterly for 12 months. Primary outcomes included receiving antiretroviral therapy (ART), HIV-1 RNA suppression, and mean changes in CD4 lymphocyte count. Analyses were stratified for the 119 subjects not on ART at baseline. Generalized estimating equations were deployed to examine time-dependent correlates for each outcome.. At baseline, subjects on ART (N = 176) were more likely than those not on ART (N = 119) to be older, heterosexual, have lower alcohol addiction severity scores, and lower HIV-1 RNA levels; they were less likely to be homeless and report sexual risk behaviors. Subjects initiating BUP/NX (N = 295) were significantly more likely to initiate or remain on ART and improve CD4 counts over time compared with baseline; however, these improvements were not significantly improved by longer retention on BUP/NX. Retention on BUP/NX for three or more quarters was, however, significantly associated with increased likelihood of initiating ART (β = 1.34 [1.18, 1.53]) and achieve viral suppression (β = 1.25 [1.10, 1.42]) for the 64 of 119 (54%) subjects not on ART at baseline compared with the 55 subjects not retained on BUP/NX. In longitudinal analyses, being on ART was positively associated with increasing time of observation from baseline and higher mental health quality of life scores (β = 1.25 [1.06, 1.46]) and negatively associated with being homo- or bisexual (β = 0.55 [0.35, 0.97]), homeless (β = 0.58 [0.34, 0.98]), and increasing levels of alcohol addiction severity (β = 0.17 [0.03, 0.88]). The strongest correlate of achieving viral suppression was being on ART (β = 10.27 [5.79, 18.23]). Female gender (β = 1.91 [1.07, 3.41]), Hispanic ethnicity (β = 2.82 [1.44, 5.49]), and increased general health quality of life (β = 1.02 [1.00,1.04]) were also independently correlated with viral suppression. Improvements in CD4 lymphocyte count were significantly associated with being on ART and increased over time.. Initiating BUP/NX in HIV clinical care settings is feasible and correlated with initiation of ART and improved CD4 lymphocyte counts. Longer retention on BPN/NX was not associated with improved prescription of ART, viral suppression, or CD4 lymphocyte counts for the overall sample in which the majority was already prescribed ART at baseline. Among those retained on BUP/NX, HIV treatment outcomes did not worsen and were sustained. Increasing time on BUP/NX, however, was especially important for improving HIV treatment outcomes for those not on ART at baseline, the group at highest risk for clinical deterioration. Retaining subjects on BUP/NX is an important goal for sustaining HIV treatment outcomes for those on ART and improving them for those who are not. Comorbid substance use disorders (especially alcohol), mental health problems, and quality-of-life indicators independently contributed to HIV treatment outcomes among HIV-infected persons with opioid dependence, suggesting the need for multidisciplinary treatment strategies for this population.

Topics: Alcoholism; Anti-HIV Agents; Buprenorphine; Buprenorphine, Naloxone Drug Combination; CD4 Lymphocyte Count; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Risk Factors; RNA, Viral; Treatment Outcome

The rate of substance-use disorders in patients with mental illnesses within the psychotic spectrum, such as schizophrenia, schizoaffective disorder, and bipolar disorder, is higher than the rate observed in the general population and is associated with significant morbidity and mortality. Although there are currently 3 medications approved by the Food and Drug Administration for the treatment of alcohol dependence, no medications have been approved for the specific treatment of dually diagnosed patients. A small but growing body of literature supports the use of 2 of these medications, disulfiram and naltrexone, in dually diagnosed individuals. This article outlines a review of the literature about the use of disulfiram and naltrexone for alcoholism and in patients with comorbid mental illness. In addition, results are presented of a 12-week randomized clinical trial of disulfiram and naltrexone alone and in combination for individuals with Axis I disorders and alcohol dependence who were also receiving intensive psychosocial treatment. Individuals with a psychotic spectrum disorder, including schizophrenia, schizoaffective disorder, and bipolar disorder, had worse alcohol outcomes than those without a psychotic spectrum disorder. Individuals with a psychotic spectrum disorder had better alcohol-use outcomes on an active medication compared with placebo, but there was no clear advantage of disulfiram or naltrexone or of the combination. Retention rates and medication compliance in the study were high and exceeded 80%. Pharmacotherapeutic strategies should take into account the advantages and disadvantages of each medication. Future directions of pharmacotherapeutic options are also discussed.

Topics: Adult; Alcohol Deterrents; Alcoholism; Bipolar Disorder; Combined Modality Therapy; Comorbidity; Diagnosis, Dual (Psychiatry); Disulfiram; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Motivation; Naloxone; Narcotic Antagonists; Psychotic Disorders; Schizophrenia; Treatment Outcome; Veterans

Pituitary and adrenal responsiveness is suppressed in abstinent alcohol-dependent individuals. To clarify the specific organizational disruption in hypothalamic-pituitary-adrenal functioning during early abstinence, the authors separately assessed each level of the stress-response axis. In this second of a two-part study, ovine corticotropin-releasing factor (oCRH) was used to stimulate the pituitary corticotrophs, and naloxone was used to activate the axis at the hypothalamic level. In addition, pulsatile characteristics of corticotropin and cortisol were assessed over a 12-hr period (0800 to 2000 hr).. Eleven abstinent alcohol-dependent men and 10 healthy comparison participants were assessed. All participants were between the ages of 30 and 50 years, and alcohol-dependent patients were abstinent from 4 to 6 weeks. Basal concentrations of corticotropin and cortisol were obtained every 10 min from 0800 to 2000 hr and subjected to pulsatile analysis. Plasma corticotropin and cortisol concentrations were then obtained every 5 to 10 min after low-dose, intravenously administered doses of oCRH (0.4 microg/kg) or naloxone (0.125 mg/kg). Medications were administered at 2000 hr and the two challenge studies were separated by 48 hr.. Pulsatile analysis revealed that the mean corticotropin amplitude was increased in alcohol-dependent patients relative to controls (p <0.05). Other pulsatile characteristics of corticotropin and all cortisol pulsatile measures were not significantly different between the two groups. The integrated cortisol response to oCRH was significantly lower in alcohol-dependent patients compared with controls (p <0.01), but the integrated corticotropin response was not significantly different. In contrast, neither the corticotropin nor the cortisol response to naloxone was significantly different between groups.. Adrenocorticoid hyposensitivity persists after oCRH infusion for at least 1 month after cessation of drinking, whereas hyporesponsiveness of the pituitary corticotrophs to CRH seems to resolve with continued abstinence. The authors suggest that adrenocortical hyporesponsiveness during prolonged abstinence may impact relapse risk.

Topics: Adrenocorticotropic Hormone; Adult; Alcoholism; Animals; Corticotropin-Releasing Hormone; Demography; Endorphins; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pituitary-Adrenal System; Sheep; Temperance

Because abnormalities in opioid neurotransmission appear to underlie some of the inherited risk for alcoholism, we examined the effects of naloxone, an opioid antagonist, on corticotropin and cortisol responses in nonalcoholic subjects differentiated by paternal history of alcoholism.. Placebo-controlled, balanced, within-subject design involving 2 test days over a period of 3 to 7 days. Thirty-six subjects (67% male; 53% paternal-history-positive; mean age = 25.0 years) were screened to exclude substance abuse or dependence. Subjects received intravenous naloxone 125 microg/kg or placebo, with sessions in random order. Plasma corticotropin and cortisol were measured for up to 120 min post infusion.. Corticotropin responses at baseline and following naloxone did not differ by paternal history of alcoholism; however, paternal-history-positive subjects exhibited greater cortisol concentrations at baseline, and at 15 and 30 min after naloxone administration. Paternal-history-positive subjects also had an earlier and greater peak cortisol response to naloxone and a nonsignificant trend for a greater area under the cortisol time curve than paternal-history-negative subjects.. These findings suggest that individuals with greater vulnerability to alcoholism may have altered Hypothalamic-pituitary axis (HPA) dynamics, a finding that is consistent with a growing body of data on the role of opioidergic neurotransmission in the inherited risk of alcoholism.

Topics: Adrenocorticotropic Hormone; Adult; Alcoholism; Analysis of Variance; Female; Genetic Predisposition to Disease; Humans; Hydrocortisone; Infusions, Intravenous; Male; Naloxone; Narcotic Antagonists

This study was designed to confirm our previous findings that nonalcoholic offspring from families with alcohol-dependent individuals have greater hypothalamic-pituitary-adrenal axis activation induced by opioid blockade compared with nonalcoholic subjects without a family history of alcohol dependence.. Sixty-four nonalcoholic subjects aged 18 to 25 years were enrolled in the protocol. Twenty-seven subjects were offspring from families with alcohol dependence and were designated as family history-positive subjects (FHP). Thirty-seven subjects were biological offspring of non-alcohol-dependent parents and were designated as family history-negative subjects (FHN). Subjects received naloxone hydrochloride (0, 50, 125, 375, and 500 microg/kg) in double-blind, randomized order; adrenocorticotropin (ACTH) and cortisol were monitored over 120 min.. No hormone differences at baseline or during placebo administration were identified between FHP and FHN subjects. FHP subjects had greater ACTH and cortisol response to opioid receptor blockade induced by naloxone hydrochloride compared with FHN subjects.. These observations confirm previous findings that differences in ACTH and cortisol dynamics between FHP and FHN subjects can be unmasked by opioid receptor blockade.

Topics: Adolescent; Adrenal Glands; Adrenocorticotropic Hormone; Adult; Alcoholism; Double-Blind Method; Female; Humans; Hydrocortisone; Hypothalamus; Male; Naloxone; Narcotic Antagonists; Pituitary Gland; Placebos

The endogenous opioid system is part of a neural circuitry functionally related to alcohol-seeking behaviors. A family history of alcoholism is the strongest predictor of future development of alcohol dependence. This study was designed to evaluate ACTH responses to opioid receptor blockade as a function of family history for alcohol dependence. The nonselective opioid antagonist naloxone stimulates ACTH secretion by blocking opioidergic input on paraventricular corticotropin-releasing factor neurons, thereby providing a methodology for comparing hypothalamic opioid tone between study groups. Sixty nonalcoholic subjects, aged 18-25 yr, were enrolled in a protocol to measure the ACTH response to naloxone. Thirty-two subjects were offspring from families with a high density of alcohol dependence and were designated as family history-positive subjects. Twenty-eight subjects were offspring of nonalcohol-dependent parents and were designated family history-negative subjects. Subjects received naloxone (125 microg/kg) or placebo (0.9% saline) in double blind, randomized order. Plasma ACTH was monitored. Family history-positive men had increased ACTH response to naloxone compared to 1) family history-positive women, 2) family history-negative men, and 3) family history-negative women. Despite differences in plasma ACTH levels after naloxone administration, plasma naloxone concentrations did not differ between study groups. This finding suggests that nonalcoholic male offspring of alcohol-dependent men have altered endogenous opioid activity directed at hypothalamic corticotropin-releasing factor neurons.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Alcoholism; Corticotropin-Releasing Hormone; Double-Blind Method; Female; Humans; Hypothalamo-Hypophyseal System; Male; Naloxone; Narcotic Antagonists; Pituitary-Adrenal System

This study was designed to assess whether nonalcoholic offspring from families with a high density of alcohol-dependent individuals have altered hypothalamic-pituitary-adrenal (HPA) axis dynamics compared with nonalcoholic subjects without a family history of alcohol dependence.. Seventy-eight nonalcoholic subjects aged 18 to 25 were enrolled in the protocol. Thirty-nine subjects were offspring from families with a high density of alcohol dependence and were designated as family history-positive (FHP) subjects. Thirty-nine subjects were biological offspring of nonalcohol-dependent parents and were designated as family history-negative (FHN) subjects. Subjects received naloxone hydrochloride (0 and 125 microg/kg) and cosyntropin (0, 0.25 microg, and 250 microg) in double-blind, randomized order and cortisol was monitored. A subset of subjects (11 FHP, 11 FHN) was admitted to the General Clinical Research Center to measure serum cortisol levels every 30 min for 24 hr.. FHP subjects had an increased cortisol response to opioid receptor blockade induced by naloxone. However, no group differences in cortisol were uncovered during administration of cosyntropin or during monitoring of the cortisol circadian profile.. These observations suggest that differences in the cortisol dynamics between FHP and FHN subjects are unmasked by opioid receptor blockade directed at the hypothalamus, but not when cortisol levels are directly provoked at the level of the adrenal gland. In addition, unprovoked cortisol secretion monitored over a 24-hr interval cannot distinguish FHP from FHN subjects.

Topics: Adolescent; Adult; Alcoholism; Biomarkers; Circadian Rhythm; Cosyntropin; Double-Blind Method; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Naloxone; Narcotic Antagonists; Pituitary-Adrenal System

This study was designed to assess whether nonalcoholic offspring from families with a high density of alcohol-dependent individuals have altered endogenous central nervous system opioid activity. Naloxone hydrochloride stimulates plasma cortisol by blocking opioidergic input on the corticotropin-releasing factor neuron, thereby providing a noninvasive method for measuring hypothalamic opioid tone.. Forty-eight nonalcoholic subjects aged 18 to 25 years were enrolled in a protocol to measure endogenous opioid activity by inducing opioid receptor blockade with the receptor antagonist, naloxone. Twenty-six subjects were offspring from families with a high density of alcohol dependence and were designated as family history-positive subjects. Twenty-two subjects were biological offspring of nonalcohol-dependent parents and designated as family history-negative subjects. Subjects received naloxone hydrochloride (0, 125, and 375 microg/kg) in double-blind, randomized order. Serum cortisol levels were monitored.. Family history-negative subjects had a graded cortisol response to each dose of naloxone. In contrast, family history-positive subjects achieved a maximal cortisol response to the 125-microg/kg dose of naloxone hydrochloride with no further increase in cortisol levels observed following the 375-microg/kg dose. Family history-negative subjects had a diminished cortisol response to the 125-microg/kg dose compared with the family history-positive subjects. Plasma naloxone concentrations did not differ between family history groups.. Individuals from families with a high density of alcohol dependence are more sensitive to naloxone compared with offspring of nonalcohol-dependent parents. This implies that individuals with a family history of alcohol dependence have diminished endogenous hypothalamic opioid activity.

Topics: Adolescent; Adult; Alcoholism; Corticotropin-Releasing Hormone; Dose-Response Relationship, Drug; Double-Blind Method; Family; Female; Humans; Hydrocortisone; Hypothalamus; Male; Naloxone; Opioid Peptides; Receptors, Opioid

The role of vasopressin (AVP) as a stress hormone in man is still a matter of controversy. Thus, the response of plasma AVP, among other hormones, to either intravenously injected human corticotropin releasing factor (hCRF, in the absence or presence of the opioid antagonist naloxone) or a combined 5-minute stress test was compared in healthy men (n = 10) and short-term abstinent alcoholics (n = 11), a group with recognized abnormalities of humoral stress parameters. Stimuli were applied blindly and in random order, one per day, in a 3-day experimental block. A second block using the same standardized protocol was carried out 12 weeks later. Alcoholics entered block I 8 days after the last ethanol ingestion. Up to block II, they were strictly controlled for abstinence. On each experimental day, subjects remained supine from 0700h until 1500h. Stimuli were applied alternatively at 1030h each day. Fourteen blood samples were drawn per day with simultaneous fluid substitution. There were no significant changes in plasma AVP as an acute response to any of the stimuli in either group or block. However, unexpectedly, controls had significantly higher basal AVP levels throughout block I as compared with block II without concomitant changes in plasma osmolality or blood pressure. Further analysis of the data revealed that the dramatically increased AVP levels of the five younger control subjects accounted for this difference. In fact, AVP levels in the five older healthy subjects and in all alcoholics remained low throughout the two blocks. Our data suggest that plasma AVP is continuously elevated in healthy young men upon anticipation of novelty. In contrast, healthy men of the older age group and early abstinent alcoholics seem to lack such a sustained AVP response.

Topics: Adult; Alcoholism; Arginine Vasopressin; Arousal; Circadian Rhythm; Corticotropin-Releasing Hormone; Double-Blind Method; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Reference Values; Temperance; Water-Electrolyte Balance

Results from studies of pharmacotherapies for primary alcoholism are reviewed, including selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (e.g. fluoxetine), opiate antagonists (e.g. naltrexone) and dopamine agonists (e.g. bromocriptine). Because there is considerable comorbidity between alcohol dependence, anxiety, and affective disorders, results from studies of medications used to treat these psychiatric disorders are also reviewed, including the 5-HT agonist buspirone and the noradrenergic agent desipramine. The neurobehavioural model of alcohol dependence implies that combinations of medications may lead to more effective treatment; thus, identifying subtypes of alcoholic patients will be important in determining which therapies or combinations of therapy will be most effective in treating alcohol dependence. For example, in an ongoing study, we are attempting to subtype an alcoholic population for treatment selection by measuring endogenous opioid activity. Because endogenous opioids are involved in analgesia, we exposed male and female subjects with alcoholism [some of whom had post-traumatic stress disorder (PTSD)] to cold-induced pain and measured their response before and after administration of naloxone or placebo. The naloxone injection reduced pain response. In addition, women who have PTSD are much more sensitive to stress, which may be related to levels of brain opioid activity.

Topics: Adult; Alcohol Deterrents; Alcoholism; Animals; Arousal; Brain; Dopamine Agonists; Double-Blind Method; Female; Humans; Male; Naloxone; Narcotic Antagonists; Neurotransmitter Agents; Pain Threshold; Psychotropic Drugs; Receptors, Neurotransmitter; Selective Serotonin Reuptake Inhibitors

Biological markers of alcohol consumption have been used in both clinical and research settings to aid in the identification of relapse drinking. Although carbohydrate-deficient transferrin (CDT) has been shown to be a sensitive and specific marker for the identification of heavy drinkers, little data are available as to its utility as a marker for relapse drinking during treatment, particularly in comparison with the more widely used serum gamma-glutamyltransferase (GGT). CDT and GGT were measured in 35 male alcoholics before entering, and every 4 weeks during, a 12-week outpatient treatment trial combining pharmacotherapy and cognitive behavioral therapy. CDT and GGT were again measured 14 weeks after completion of treatment. During the 12-week treatment period, CDT showed a significant difference in those individuals who abstained from drinking (30% decrease), compared with those who relapsed (10% increase). GGT decreased on average in all individuals, and the change from treatment entry did not differ significantly across the drinking outcome groups. The change in CDT, but not GGT, from study entry to termination, significantly correlated with total alcohol consumption during the trial. At the 14-week posttreatment, follow-up evaluation CDT showed about a 60% elevation and GGT showed a 30% elevation, on average, from study entry values in those individuals who had relapse drinking by self and/or collateral report. The change in both markers differed between those individuals who remained abstinent or relapsed during the poststudy period. In general, the change in CDT from pretreatment levels seemed more sensitive to drinking status during treatment and follow-up than GGT. This indicates that CDT may be more sensitive marker for evaluating drinking status during both clinical and research treatment trials.

Topics: Adult; Alcoholism; Ambulatory Care; Biomarkers; Cognitive Behavioral Therapy; Combined Modality Therapy; Double-Blind Method; Follow-Up Studies; gamma-Glutamyltransferase; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Recurrence; Transferrin; Treatment Outcome

The morphine dose 10(-7) M had practically no effect on adenylate cyclase (AC) activity in lymphocytes of healthy controls (n = 20). The same dose of morphine had a pronounced stimulating effect on the AC activity in lymphocytes of alcoholics in withdrawal (n = 16). In the group of opiate addicts in withdrawal (n = 9) morphine had also a stimulating effect, which differed significantly from controls (33.7 +/- 13.8; P. 0.02). The range of fluctuation of morphine influence on AC activity during the first week of hospitalization was 162.9 +/- 33.0% in alcoholics and 30.4 +/- 4.6% in opiate addicts (P 0.01).

Topics: Adenylyl Cyclases; Alcoholism; Humans; Lymphocytes; Morphine; Naloxone; Opioid-Related Disorders; Time Factors

This study employed naloxone, an opiate antagonist, to explore whether a learned opioid response, mediated by drinking experience, accounts for ethanol and placebo analgesia. Cold pressor pain was evaluated before and after ethanol (0.5 g/kg), placebo, and no-alcohol control treatments (administered in randomized order) and again after double-blind administration (6 mg/kg) of naloxone to 11 men and saline to 9. A triple interaction of treatments, antagonist conditions, and drinking experience indicated that naloxone as compared to saline diminished ethanol and placebo analgesia among experienced drinkers but had opposite effects among the same men in the control treatment. Six men, who reported that the injection of naloxone had an effect on pain, had higher drinking experience scores than the five men who reported naloxone had no effect. The similar pattern of response to both the alcohol and the placebo treatments suggests that the opioid system response to alcohol is learned.

Topics: Adult; Alcohol Drinking; Alcoholism; Arousal; Brain; Endorphins; Humans; Male; Naloxone; Nociceptors; Pain Measurement; Receptors, Opioid

We examined the effects of the serotonin antagonist pizotifene (4 mg daily for 3 days orally), and the opiate antagonist naloxone-HCI (0.8 mg intravenously) on the TRH-induced thyrotropin (TSH), growth hormone (GH), and prolactin (PRL) response in female psychiatric inpatients with adjustment disorder or alcohol abuse. All the patients were free from interfering endocrine and metabolic illness and had not received major psychotropic medication before the investigation. Pizotifene caused a small but significant decrease of the TRH-induced TSH response in 8 patients, two of them changed their responses from normal (i.e. above 5 mU/l) to blunted. Neither GH nor PRL changed significantly after pizotifene. Naloxone-HCI, 30 min before the TRH challenge, did not produce any significant change in the TSH, GH or PRL responses, nor did it cause any significant change in the plasma level of these hormones by itself. The hormonal responses to TRH remained unaltered in ten other patients who had repeated tests without any drug treatment between the two occasions. The results suggest that serotonin deficiency may play a role in the blunted TSH response to TRH, while opiate mechanisms do not appear to have a primary influence on these endocrine effects of TRH.

Topics: Adjustment Disorders; Adult; Alcoholism; Female; Growth Hormone; Humans; Middle Aged; Naloxone; Pizotyline; Prolactin; Thiophenes; Thyrotropin; Thyrotropin-Releasing Hormone

The phenomenon of alcohol analgesia and tolerance can facilitate misuse and lead to the development of alcohol use disorder (AUD). Numerous alcohol-induced behaviors are genetically influenced; however, it is unknown if alcohol analgesia has a genetic contribution. Rodent studies have shown that alcohol responses differ vastly between two widely studied inbred strains of mice, C57BL/6 J (B6) and DBA/2 J (D2). Here, we used B6 and D2 mice as an initial behavioral genetic analysis of acute alcohol-induced antinociception.. The antinociceptive effect of orally-administered alcohol was characterized using the hot plate test in B6 and D2 mice of both sexes. Using the opioid receptor antagonist naloxone, the involvement of the opioid system was assessed. Locomotor activity and blood alcohol concentrations were also measured. Ovariectomized mice were used to evaluate the influence of ovarian sex hormones on alcohol-induced antinociception.. Alcohol induced an antinociceptive effect in B6 and D2 male mice in a time- and dose-dependent manner. In addition, D2 male mice were more sensitive to the antinociceptive effect of alcohol than B6 male mice. However, locomotion is not impeded by the tested doses of alcohol in B6 mice. Female D2 and B6 mice failed to show significant antinociceptive effects in alcohol dose-response studies. In addition, alcohol-induced antinociception was still not evident in ovariectomized female mice. Male mice of both strains developed tolerance to this effect after repeated administration of alcohol. Strain differences were found in blood alcohol concentration. Finally, no difference was found in the blockade of alcohol antinociception by 2 mg/kg naloxone.. Our results indicate that the antinociceptive effects of alcohol in the hot plate test are influenced by strain and sex. These findings support further genetic analysis of alcohol-induced antinociception to identify operative mechanisms and better assess the contribution of this phenotype to AUD.

Topics: Alcoholism; Analgesics, Opioid; Animals; Blood Alcohol Content; Ethanol; Female; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Naloxone; Narcotic Antagonists; Pain

Topics: Alcoholism; Cocaine-Related Disorders; Dopamine; Drug Overdose; Heroin Dependence; History, 20th Century; History, 21st Century; Humans; Marijuana Abuse; Methadone; Methamphetamine; Naloxone; National Institutes of Health (U.S.); Neurosciences; Opioid-Related Disorders; Positron-Emission Tomography; Prefrontal Cortex; Psychiatry; Reward; Socioeconomic Factors; United States

Persons in addiction treatment are likely to experience and/or witness drug overdoses following treatment and thus could benefit from overdose education and naloxone distribution (OEND) programs. Diverting individuals from the criminal justice system to addiction treatment represents one treatment engagement pathway, yet OEND needs among these individuals have not been fully described.. We characterized justice involvement patterns among 514 people who use opioids (PWUO) participating in a criminal justice diversion addiction treatment program during 2014-2016 using a gender-stratified latent class analysis. We described prevalence and correlates of naloxone knowledge using quasi-Poisson regression models with robust standard errors.. Only 56% of participants correctly identified naloxone as an opioid overdose treatment despite that 68% had experienced an overdose and 79% had witnessed another person overdose. We identified two latent justice involvement classes: low involvement (20.3% of men, 46.5% of women), characterized by older age at first arrest, more past-year arrests, and less time incarcerated; and high involvement (79.7% of men, 53.5% of women), characterized by younger age at first arrest and more lifetime arrests and time incarcerated. Justice involvement was not associated with naloxone knowledge. Male participants who had personally overdosed more commonly identified naloxone as an overdose treatment after adjustment for age, race, education level, housing status, heroin use, and injection drug use (prevalence ratio [95% confidence interval]: men 1.5 [1.1-2.0]).. All PWUO in criminal justice diversion programs could benefit from OEND given the high propensity to experience and witness overdoses and low naloxone knowledge across justice involvement backgrounds and genders.

Topics: Adult; Alcoholism; Clinical Competence; Correlation of Data; Criminal Law; Cross-Sectional Studies; Drug Overdose; Female; Humans; Male; Middle Aged; Naloxone; Narcotic-Related Disorders; Sex Factors; Survival Rate; United States

BACKGROUND The aim of this research was to investigate the treatment effect of naloxone combined with hemodialysis on acute severe alcoholism. MATERIAL AND METHODS We included 36 patients treated with naloxone combined with hemodialysis in Group I and 34 patients treated with naloxone without hemodialysis in Group II. The Glasgow coma scale (GCS) score, the consciousness recovery time, alanine amino transferase (ALT) level, and complications were analyzed. RESULTS Mean GCS score in Group I was higher than that in Group II, with a significant difference (P<0.05). The consciousness recovery time in Groups I and II were 3.0±0.8 h and 6.9±2.1 h, respectively, with a significant difference (P<0.05). After naloxone treatment and hemodialysis, the ALT level in Group I was lower than that in Group II (P<0.05). Moreover, the incidence of hepatic and renal function damages in Group I was smaller than that in Group II (P<0.05). Only 1 patient in Group I developed pneumonia, which was fewer than that in Group II, with a significant difference (P<0.05). CONCLUSIONS Naloxone combined with hemodialysis effectively reduces the central inhibition of alcohol, shortens consciousness recovery time, improves respiratory and cardiovascular function, decreases hepatic and renal function damages, and reduces the incidence of complications.

Topics: Acute Disease; Adult; Alcoholism; Consciousness; Female; Glasgow Coma Scale; Humans; Male; Naloxone; Renal Dialysis

In the exam room, providers can identify--and often treat--patients who need help with a substance use disorder.

Topics: Alcoholism; Buprenorphine; Drug Combinations; Humans; Illicit Drugs; Interdisciplinary Communication; Intersectoral Collaboration; Mass Screening; Minnesota; Naloxone; Naltrexone; Opioid-Related Disorders; Prescription Drugs; Primary Health Care; Referral and Consultation; Substance-Related Disorders

Toll-like receptor 4 (TLR4) is a critical component of innate immune signaling and has been implicated in alcohol responses in preclinical and clinical models. Members of the Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune) consortium tested the hypothesis that TLR4 mediates excessive ethanol drinking using the following models: (1) Tlr4 knock-out (KO) rats, (2) selective knockdown of Tlr4 mRNA in mouse nucleus accumbens (NAc), and (3) injection of the TLR4 antagonist (+)-naloxone in mice. Lipopolysaccharide (LPS) decreased food/water intake and body weight in ethanol-naive and ethanol-trained wild-type (WT), but not Tlr4 KO rats. There were no consistent genotypic differences in two-bottle choice chronic ethanol intake or operant self-administration in rats before or after dependence. In mice, (+)-naloxone did not decrease drinking-in-the-dark and only modestly inhibited dependence-driven consumption at the highest dose. Tlr4 knockdown in mouse NAc did not decrease drinking in the two-bottle choice continuous or intermittent access tests. However, the latency to ethanol-induced loss of righting reflex increased and the duration decreased in KO versus WT rats. In rat central amygdala neurons, deletion of Tlr4 altered GABA. Toll-like receptor 4 (TLR4) is a key mediator of innate immune signaling and has been implicated in alcohol responses in animal models and human alcoholics. Members of the Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune) consortium participated in the first comprehensive study across multiple laboratories to test the hypothesis that TLR4 regulates excessive alcohol consumption in different species and different models of chronic, dependence-driven, and binge-like drinking. Although TLR4 was not a critical determinant of excessive drinking, it was important in the acute sedative effects of alcohol. Current research efforts are directed at determining which neuroimmune pathways mediate excessive alcohol drinking and these findings will help to prioritize relevant pathways and potential therapeutic targets.

Topics: Alcohol Drinking; Alcoholism; Animals; Body Weight; Conditioning, Operant; Female; Gene Knockout Techniques; Lipopolysaccharides; Male; Mice; Mice, Knockout; Naloxone; Narcotic Antagonists; Nucleus Accumbens; Rats; Receptors, GABA-A; Toll-Like Receptor 4

Acetaldehyde is the main metabolite of ethanol ingested through alcoholic beverages. Traditionally considered aversive is presently being viewed as an activating agent of the mesolimbic dopamine system but underlying mechanisms are only partially known.. Through in vivo electrophysiology experiments in rats we have studied the role of endogenous opioids in acetaldehyde-induced increments in dopamine activity.. Here we show that acetaldehyde-induced increase in firing rate, burst firing and spikes/burst of antidromically-identified ventro-tegmental area nucleus accumbens-projecting neurons are abolished by pretreatment with the opiate unselective antagonist naltrexone (0.4 mg/kg/ip). Similar effects are obtained after administration of naloxone (0.1 mg/kg/iv). These results indicate that endogenous opiate system(s) participate in acetaldehyde-induced increments in dopaminergic neuronal activity.. These data may explain the reduction in acetaldehyde-induced dopamine release in the nucleus accumbens after blockade of opiate receptors. Considering the paucity of efficacious therapies in alcoholism, and recent developments in ethanol-derived acetaldehyde effects, further experiments are warranted to further elucidate its role as a biomarker potentially useful to develop new strategies in the search for effective compounds aimed at reducing excessive alcohol intake, abuse and ultimately alcoholism.

Topics: Acetaldehyde; Alcoholism; Animals; Dopamine; Dopaminergic Neurons; Dose-Response Relationship, Drug; Male; Naloxone; Naltrexone; Narcotic Antagonists; Nucleus Accumbens; Rats; Rats, Wistar; Ventral Tegmental Area

The opioid system of the central nervous system plays an essential role in the regulation of the rewarding effects of alcohol. Alcohol affects mu-opioid receptor (MOR) function. Enhanced MOR function inhibits the GABAergic inhibition of the nucleus accumbens (Nac), which leads to a release of dopamine in the Nac. Of the few pharmaceutical treatments for alcoholism, the MOR antagonists naltrexone and nalmefene benefit most a subset of alcoholics who are characterized with early onset and impulsivity. Our aim was to investigate possible differences in the binding density of [³H]naloxone, a MOR competitive antagonist, between Cloninger type 1 anxiety-prone and harm-avoidant alcoholics, Cloninger type 2 impulsive and antisocial alcoholics, and healthy controls in brain areas that are essential for reward, learning, impulse-control, and mood regulation.. We used postmortem whole-hemisphere autoradiography with [³H]naloxone, as a binding ligand. A subsequent autoradiography was performed with [³H]DAMGO, a selective MOR agonist.. Cloninger type 1 alcoholics displayed decreased [³H]naloxone binding density in all studied brain areas. This trend reached statistical significance in the dentate gyrus, where type 1 alcoholics' [³H]naloxone binding density was significantly decreased (p = 0.019) when compared to controls. A similar trend of decreased binding in type 1 alcoholics was observed in the [³H]DAMGO study.. Our finding suggest that Cloninger type 1 anxiety-prone alcoholics may have an altered [³H]naloxone binding in brain areas related to reward, impulse-control, mood, and learning. The finding lends support to the idea of Cloninger type 1 anxiety-prone alcoholics responding weaker to the opioidergic pharmaceuticals of the treatment of alcoholism than Cloninger type 2 impulsive alcoholics.

Topics: Adolescent; Adult; Aged; Alcoholics; Alcoholism; Anxiety; Autopsy; Autoradiography; Dentate Gyrus; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Protein Binding; Tritium; Young Adult

The extent of damage in New York City following Hurricane Sandy in October 2012 was unprecedented. Bellevue Hospital Center (BHC), a tertiary public hospital, was evacuated and temporarily closed as a result of hurricane-related damages. BHC's large primary care office-based buprenorphine clinic was relocated to an affiliate public hospital for three weeks. The extent of environmental damage and ensuing service disruption effects on rates of illicit drug, tobacco, and alcohol misuse, buprenorphine medication supply disruptions, or direct resource losses among office-based buprenorphine patients is to date unknown.. A quantitative and qualitative semi-structured survey was administered to patients in BHC's primary care buprenorphine program starting one month after the hurricane. Survey domains included: housing and employment disruptions; social and economic support; treatment outcomes (buprenorphine adherence and ability to get care), and tobacco, alcohol, and drug use. Open-ended questions probed general patient experiences related to the storm, coping strategies, and associated disruptions.. There were 132 patients enrolled in the clinic at the time of the storm; of those, 91 patients were recruited to the survey, and 89 completed (98% of those invited). Illicit opioid misuse was rare, with 7 respondents reporting increased heroin or illicit prescription opioid use following Sandy. Roughly half of respondents reported disruption of their buprenorphine-naloxone medication supply post-event, and self-lowering of daily doses to prolong supply was common. Additional buprenorphine was obtained through unscheduled telephone or written refills from relocated Bellevue providers, informally from friends and family, and, more rarely, from drug dealers.. The findings highlight the relative adaptability of public sector office-based buprenorphine treatment during and after a significant natural disaster. Only minimal increases in self-reported substance use were reported despite many disruptions to regular buprenorphine supplies and previous daily doses. Informal supplies of substitute buprenorphine from family and friends was common. Remote telephone refill support and a temporary back-up location that provided written prescription refills and medication dispensing for uninsured patients enabled some patients to maintain an adequate medication supply. Such adaptive strategies to ensure medication maintenance continuity pre/post natural disasters likely minimize poor treatment outcomes.

Topics: Alcoholism; Appointments and Schedules; Buprenorphine; Cross-Sectional Studies; Cyclonic Storms; Disasters; Female; Health Facility Closure; Health Services Accessibility; Health Surveys; Hospitals, Public; Humans; Illicit Drugs; Male; Naloxone; New York City; Opioid-Related Disorders; Primary Health Care; Qualitative Research; Self Care; Smoking; Smoking Prevention; Substance Abuse Treatment Centers; Treatment Outcome

Evaluation of State Opioid Substitution Treatment OST (methadone and buprenorphine/naloxone- Addnok-N) program in Georgia and optimization of the routine measurement instrument. Patients were recruited from 4 Tbilisi and 5 regional State Programs in May-October 2013. 2 structured self-questionnaires (one - anonymous for sensitive questions) were developed for patients to assess demographics, retention in treatment, mean drug dose, HIV and Hepatitis C and B status, illicit drug and alcohol use, social activities, crime involvement, health status, HIV risk behavior, treatment compliance and satisfaction. 608 patients (7 females) were surveyed (512 - on Methadone, 96 - on buprenorphine/naloxone). 337 (1 female) patients completed an anonymous questionnaire. Mean age - 39.43±8.7 (21-65 years). 10 (1.64%) respondents were HIV positive; 448 (73.68%) - HCV+ and 24 (3.95%) - HBV+; average methadone dose - 39.27±22.2mg; buprenorphine/naloxone - 7.4±3.6 mg; 64 (40%) of employed began working while in program; 365 (60%) have been in treatment for less than 1 year, and 146 (24%) - for 1-3 years vs. 258 (51%) out of 506 patients surveyed in 2011. 494 (81.2%) reported improvement of social status and 508 (83.5%) - of health status. 305 (90.5%) out of 337 reported no- and 30 (8.9%) - reduction of criminal activity. 467 (76.81%) patients attended individual and 200 (32.9%)-group psychotherapy sessions with various frequencies. The common adverse events: sleep disturbances - 48.84%; weakness - 50.82%; mood disturbances - 42.44%, and heaviness - 36.35%. 257 (46%) reported using of alcohol; 16 - opioids; 29 - sedative/hypnotics; 8 - marijuana and 1 - ATS past 30 days; 55 - drug injection and 11 - sharing of any injection equipment past 6 months. State OST program is effective in Georgia in terms of reduction of illegal drug use, injection risk behavior and criminal activity, and on the other hand - improving of social activity and general health. Treatment retention is less as compared with 2011 survey.

Topics: Adult; Aged; Alcoholism; Buprenorphine; Female; Georgia (Republic); Government Programs; Hepatitis B; Hepatitis C; HIV Infections; Humans; Male; Methadone; Middle Aged; Naloxone; Opiate Substitution Treatment; Patient Compliance; Patient Satisfaction; Surveys and Questionnaires; Young Adult

Hypothalamic-pituitary-adrenal (HPA) axis responses following naloxone administration have been assumed to provide a measure of opioid receptor activity. Employing positron emission tomography (PET) using the mu opioid receptor (MOR) selective ligand [(11)C] carfentanil (CFN), we demonstrated that cortisol responses to naloxone administration were negatively correlated with MOR availability. In this study, we examined whether naloxone-induced cortisol and adrenocorticotropin (ACTH) responses in 15 healthy control and 20 recently detoxified alcohol-dependent subjects correlated with delta opioid receptor (DOR) availability in 15 brain regions using the DOR-selective ligand [(11)C] methyl-naltrindole (MeNTL) and PET imaging. The day after the scan, cortisol responses to cumulative doses of naloxone were determined. Peak cortisol and ACTH levels and area under the cortisol and ACTH curve did not differ by group. There were negative relationships between cortisol area under curve to naloxone and [(11)C] MeNTL-binding potential (BP(ND)) in the ventral striatum, anterior cingulate, fusiform cortices, temporal cortex, putamen and a trend in the hypothalamus of healthy control subjects. However, in alcohol-dependent subjects, cortisol responses did not correlate with [(11)C]MeNTL BP(ND) in any brain region. Plasma ACTH levels did not correlate with [(11)C]MeNTL BP(ND) in either group. The study demonstrates that naloxone provides information about individual differences in DOR availability in several mesolimbic structures. The data also show that the HPA axis is intimately connected with mesolimbic stress pathways through opioidergic neurotransmission in healthy subjects but this relationship is disrupted during early abstinence in alcohol-dependent subjects.

Topics: Adrenocorticotropic Hormone; Adult; Alcoholism; Area Under Curve; Case-Control Studies; Dose-Response Relationship, Drug; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Ligands; Limbic System; Linear Models; Male; Middle Aged; Naloxone; Naltrexone; Narcotic Antagonists; Pituitary-Adrenal System; Positron-Emission Tomography; Receptors, Opioid, delta; Stress, Psychological; Young Adult

The mu opioid receptor system is altered in alcohol dependent (AD) subjects. Cortisol responses to opioid receptor antagonists are assumed to impart information about opioid receptor activity. In the present study we examined naloxone-induced cortisol responses in 18 healthy control (HC) and 25 recently detoxified AD subjects and then correlated the cortisol response with mu opioid receptor availability across 15 brain regions using positron emission tomography (PET) and the mu opioid receptor selective ligand [(11)C] Carfentanil (CFN). On average the AD subjects required twice the dose of naloxone to induce a peak cortisol response compared to the HC subjects. Using the rising slope of the cortisol curve (placebo to peak) as a metric we then went on to examine the relationship between cortisol responses to naloxone and [(11)C]CFN BP(ND). There were significant negative relationships between cortisol and [(11)C]CFN binding potential (BP(ND)) in multiple brain regions of HC subjects. However, cortisol responses did not correlate with [(11)C]CFN BP(ND) across any brain region in AD subjects. In summary, naloxone imparts information about individual differences in mu opioid receptor availability throughout the mesolimbic system in healthy individuals. However pathways governing the relationship between naloxone-induced cortisol and mu opioid receptor availability are disrupted during early abstinence in AD subjects.

Topics: Adult; Alcoholism; Carbon Radioisotopes; Female; Fentanyl; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pituitary-Adrenal System; Positron-Emission Tomography; Receptors, Opioid, mu

Topics: Alcohol Deterrents; Alcohol-Related Disorders; Alcoholism; Humans; Mental Disorders; Naloxone; Patient Compliance; Practice Guidelines as Topic; Psychotherapy; Thiamine; Vitamin B Complex

Naltrexone, a compound with high affinity for the mu opioid receptor (MOP-R) reduces alcohol consumption. SoRI-9409 is a derivative of naltrexone that has highest affinity at delta opioid receptors (DOP-Rs). We have investigated the effects of SoRI-9409 on ethanol consumption to determine the consequences of altering the naltrexone compound to a form with increased efficacy at DOP-Rs.. Effects of the opioid receptor antagonists, SoRI-9409 (0-30 mg/kg, IP), naltrexone (0-30 mg/kg, IP), or naltrindole (0-10 mg/kg, IP) on ethanol consumption was measured in high- and low-ethanol-consuming rats with two different drinking paradigms. SoRI-9409-, naltrexone-, and naltrindole-mediated inhibition of DOP-R-stimulated [(35)S]GTP gamma S binding was measured in brain membranes prepared from high-ethanol-consuming rats. The effects of SoRI-9409 on morphine-mediated analgesia, conditioned place preference, and anxiety were also examined.. In high- but not low-ethanol-consuming animals, SoRI-9409 is threefold more effective and selective at reducing ethanol consumption when compared with naltrexone or naltrindole for up to 24 hours. SoRI-9409 administered daily for 28 days continuously reduced ethanol consumption, and when the administration of SoRI-9409 was terminated, the amount of ethanol consumed remained lower compared with vehicle-treated animals. Furthermore, SoRI-9409 inhibits DOP-R-stimulated [(35)S]GTP gamma S binding in brain membranes of high-ethanol-consuming rats.. SoRI-9409 causes selective and long-lasting reductions of ethanol consumption. This suggests that compounds that have high affinity for DOP-Rs such as SoRI-9409 might be promising candidates for development as a novel therapeutic for the treatment of alcoholism.

Topics: Alcohol Drinking; Alcoholism; Animals; Behavior, Animal; Brain; Choice Behavior; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Food Preferences; Guanosine 5'-O-(3-Thiotriphosphate); Male; Morphine Derivatives; Naloxone; Narcotic Antagonists; Narcotics; Protein Binding; Rats; Rats, Long-Evans; Receptors, Opioid, delta; Sucrose

For opioid-dependent patients, the need for detoxification has been a barrier to entry into long-term residential treatment. This report describes a retrospective observational cohort study with the first 38 opioid-dependent patients entering First Step, a 14-day buprenorphine-naloxone (Suboxone) detoxification regimen integrated into a long-term residential therapeutic community (TC) program. Eighty-nine percent (34 of 38) of First Step patients completed a 14-day buprenorphine taper protocol, 50% (19 of 38) completed an initial 3- to 4-week stay, and 39% (15 of 38) completed at least 3 months of residential treatment at the TC. Retention did not differ significantly in a demographically matched concurrently admitted control group without impending opioid withdrawal, in which 65% (24 of 37) completed an initial 3- to 4-week stay (p = .20) and 57% (21 of 37) completed at least 3 months of treatment (p = .14). Withdrawal symptoms were mild, and there were no instances of precipitated withdrawal. The findings suggest the potential for buprenorphine to serve as a bridge, improving the viability of long-term residential treatment for managing opioid dependence.

Topics: Adult; Alcoholism; Buprenorphine; Clinical Trials as Topic; Cocaine-Related Disorders; Female; Heroin Dependence; Humans; Long-Term Care; Male; Middle Aged; Naloxone; Narcotic Antagonists; Narcotics; Neurologic Examination; New York City; Opioid-Related Disorders; Patient Dropouts; Residential Treatment; Retrospective Studies; Substance Withdrawal Syndrome; Therapeutic Community

Ethanol stimulates the dopaminergic mesoaccumbal pathway, which is thought to play a role in ethanol reinforcement. Mu (mu)-opioid (MOP) receptors modulate accumbal dopamine activity, but it is not clear whether MOP receptors are involved in the mechanism of ethanol-stimulated accumbal dopamine release.. We investigated the role that MOP receptors play in ethanol (2.0 g/kg)-stimulated accumbal dopamine release by using MOP receptor knockout mice (C57BL/6J-129SvEv and congenic C57BL/6J genotypes) along with blockade of MOP receptors with a mu1 selective antagonist (naloxonazine).. Both gene deletion and pharmacological antagonism of the MOP receptor decreased ethanol-stimulated accumbal dopamine release compared with controls with female mice showing a larger effect in the C57BL/6J-129SvEv genotype. However, both male and female mice showed reduced ethanol-stimulated dopamine release in the congenic MOP receptor knockout mice (C57BL/6J). No differences in the time course of dialysate ethanol concentration were found in any of the experiments.. The data demonstrate the existence of a novel interaction between genotype and sex in the regulation of ethanol-stimulated mesolimbic dopamine release by the MOP receptor. This implies that a more complete understanding of the epistatic influences on the MOP receptor and mesolimbic dopamine function may provide more effective pharmacotherapeutic interventions in the treatment of alcoholism.

Topics: Alcohol Drinking; Alcoholism; Animals; Basal Ganglia; Disease Models, Animal; Dopamine; Epistasis, Genetic; Ethanol; Genotype; Humans; Mice; Mice, Congenic; Mice, Inbred C57BL; Mice, Knockout; Microdialysis; Naloxone; Nucleus Accumbens; Receptors, Opioid, mu; Reinforcement, Psychology; Sex Characteristics

Oral naltrexone, an opioid antagonist, reduces relapse and heavy drinking in alcohol-dependent patients. However, oral delivery is associated with poor compliance and adverse events. To enhance treatment outcome and reduce side effects, injectable extended-release naltrexone formulations have been developed. Currently, there are no studies available directly comparing oral and injectable formulations of naltrexone in alcohol-dependent patients. This paper reviews the efficacy and adverse events of oral versus injectable extended-release naltrexone. Therefore, data were extracted from two recently published reviews about oral naltrexone in the treatment of alcohol dependence. Pooled outcomes were compared with reported outcomes of recent studies on injectable extended-release naltrexone. Injectable naltrexone seems to be effective in the management of alcohol dependence. Although inconclusive, the available results indicate that the expected advantages of injectable naltrexone over oral naltrexone still have to be proven. Randomized studies with direct comparisons of oral and injectable naltrexone are urgently needed.

Topics: Administration, Oral; Alcoholism; Delayed-Action Preparations; Humans; Injections, Intramuscular; Naloxone; Narcotic Antagonists; Secondary Prevention; Treatment Outcome

In recent human studies, the anticonvulsant drug topiramate (TPM) has shown efficacy in treating alcohol craving and mood disorders. However, preclinical evidence supporting such effects is surprisingly sparse. Three experiments were conducted here to assess possible anticraving and antidepressant effects of TPM using animal models.. In Experiment 1, rats were given 23 weeks ad libitum access to food, water, and either beer (4.44% ethanol v/v) or "near-beer" (a calorie-matched nonalcoholic beer, 0.44% ethanol) in their home cages. They were then restricted to daily 1 hour operant sessions in which they licked for water and either beer or near-beer under a progressive ratio schedule of reinforcement in a lickometer apparatus. The acute effects of TPM on the motivation to consume beer or near-beer were then assessed. The effects of naloxone were also assessed (as a positive control) after TPM testing. In Experiment 2, rats were given 11 weeks of ad libitum home-cage access to food, water, and beer. They then received repeated daily injections of TPM and effects on beer consumption under ad libitum home cage access conditions were monitored. In Experiment 3, the effects of TPM were assessed in the modified Porsolt forced swim test, emergence test, and elevated plus-maze (EPM) using alcohol naïve rats.. Topiramate (10, 20, and 40 mg/kg) significantly reduced the motivation to lick for beer, although the maximal effect was moderate in comparison with naloxone (10 mg/kg). However, naloxone, unlike TPM, also reduced responding for near-beer suggesting an alcohol-specific effect of TPM. In Experiment 2, TPM (40 and 80 mg/kg) tended to transiently reduce alcohol consumption in the home cage under ad libitum access but this effect disappeared with repeated administration of the drug. TPM (10 to 80 mg/kg, given twice over 4 hours before test) produced a robust dose-dependent decrease in immobility and increase in active coping strategies in the forced swim test similar to that seen with desipramine (2 x 20 mg/kg). There were modest anxiolytic effects of TPM on the EPM and emergence tests.. With acute administration, TPM is moderately effective and relatively selective in reducing the drive to consume alcohol in Wistar rats. This anti-alcohol effect is modest in comparison with naloxone and appears to dissipate under conditions of chronic treatment and ad libitum alcohol access. A marked antidepressant-like effect in the forced swim test and partial anxiolytic effects in other animal models suggests that TPM may be a beneficial treatment for affective disorders. These preliminary results suggest further research is warranted to resolve the mechanisms involved in TPM modulation of both mood and alcohol consumption.

Topics: Alcohol Drinking; Alcoholism; Animals; Antidepressive Agents; Anxiety; Behavior, Animal; Depression; Fructose; Male; Maze Learning; Motivation; Naloxone; Narcotic Antagonists; Rats; Rats, Wistar; Swimming; Topiramate

To study the changes in the expression and phosphorylation of cAMP response element binding protein (CREB) in the rat nucleus accumbens after chronic ethanol intake and its withdrawal.. Ethanol was given in drinking water at the concentration of 6 % (v/v), for one month. Changes in the levels of CREB and phospho-CREB (p-CREB) protein in the nucleus accumbens were measured by immunohistochemistry methods.. Ethanol given to rats in drinking water decreased the level of p-CREB protein in the nucleus accumbens (-75 %) at the time of exposure to ethanol. The decrement of p-CREB protein in the nucleus accumbens remained at 24 h (-35 %) and 72 h (-28 %) of ethanol withdrawal, which recovered toward control level after 7 d of ethanol withdrawal. However, chronic ethanol, as well as ethanol withdrawal failed to produce any significant alteration in the level of CREB protein in the nucleus accumbens. Naloxone (alone) treatment of rats had no effect on the levels of CREB and p-CREB protein in the nucleus accumbens. However, when naloxone was administered concurrently with ethanol treatment, it antagonized the down-regulation of p-CREB protein in the nucleus accumbens (142 %) of rats exposed to ethanol.. A long-term intake of ethanol solution down-regulates the phosphorylation of CREB in the nucleus accumbens, and those changes can be reversed by naloxone, which may be one kind of the molecular mechanisms associated with ethanol dependence.

Topics: Alcoholism; Animals; Cyclic AMP Response Element-Binding Protein; Ethanol; Male; Naloxone; Nucleus Accumbens; Phosphorylation; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

Effect of naloxon on the activity of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in the blood serum and content of catecholamines (CA) in the brain structures (hypothalamus, midbrain, new cortex) and blood of rats under alcoholic dependence were studied. Participation of opiate structures of receptors in formation of alcoholic dependence is shown.

Topics: Alcohol Dehydrogenase; Alcoholism; Aldehyde Dehydrogenase; Animals; Brain Chemistry; Catecholamines; Naloxone; Narcotic Antagonists; Opioid Peptides; Rats; Receptors, Opioid

Opiate antagonists are promising pharmacotherapeutic agents for the treatment of alcohol dependence, reducing craving and relapse rates in weaned alcoholics. However, preclinical findings indicate that they can also increase ethanol consumption and preference in animals with a strong liking for ethanol, depending on the dose and treatment regimen.. The present study examined the effects of chronic, intermittent and acute opiate antagonist treatment on the alcohol deprivation effect (ADE) in long-term ethanol- experienced rats, which is an animal model of craving and relapse.. Long-term ethanol-experienced rats were either implanted with mini-osmotic pumps delivering 0, 0.5 or 1 mg/kg per hour naloxone (chronic treatment) or received intermittent naltrexone injections (2x5 mg/kg per day SC). Effects of chronic and intermittent treatment on the ADE were studied in a four-bottle home cage drinking paradigm. In a second experiment, long-term ethanol-experienced rats trained in an operant ethanol self-administration paradigm received acute naltrexone treatment (0, 0.1, 1 or 10 mg/kg SC) before a 23-h session either during basal drinking or during the ADE.. Chronic naloxone treatment increased ethanol preference during the ADE. Intermittent naltrexone treatment at a dose comparable to the lower dose of chronic treatment moderately attenuated the ADE. Acute naltrexone treatment selectively reduced lever pressing for ethanol both during the ADE and during basal drinking only at the lowest dose, whereas higher doses also suppressed water intake. The ethanol-specific suppressant effect on the ADE was long lasting. Concerning basal drinking, however, naltrexone had a long lasting reductive effect only on lever pressing for water.. A low dose of naltrexone and an intermittent treatment regimen seem to be necessary to maintain a specific reduction in ethanol intake in individuals with a high motivation to consume ethanol. These findings are consistent with the notion that, at low doses, opiate antagonists reduce the reward value of reinforcers.

Topics: Alcoholism; Animals; Ethanol; Male; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Wistar; Self Administration

Previous studies have suggested that alcohol-reinforcing effects are mediated by the endogenous opioid system, which, in turn, stimulates mesolimbic dopaminergic neurotransmission. In addition, evidence obtained in both humans and rats indicates that genetic factors may influence alcohol-drinking behavior. In the present study, we examined several components of the opioid system in selected brain regions of rats bred selectively for their innate alcohol preference (Sardinian preferring = sP) or alcohol aversion (Sardinian nonpreferring = sNP).. To evaluate whether differences observed were consequent to alcohol intake, sP rats were divided into two subgroups, ethanol-naive sP (sP) and ethanol-experienced sP (sPexp). Opioid receptors were labeled, using [3H]naloxone (mu, delta, and kappa receptors), [D-Ala2,N-Me-Phe4,Gly,ol5]enkephalin ([3H]DAMGO; mu receptors), and [D-Ala2,D-Leu5]enkephalin ([3H]DADLE; delta receptors), by means of quantitative autoradiography. Enkephalin and dynorphin mRNA contents were measured by in situ hybridization by using 25- and 47-base oligonucleotide probes with sequences complementary to mRNA encoding rat enkephalin or dynorphin.. Our results revealed a significant reduction of opioid receptors in caudate-putamen nucleus and in the shell portion of the nucleus accumbens in sP compared with sNP rats. Alcohol intake partially reversed this reduction in the caudate-putamen nucleus. In addition, enkephalin mRNA expression was found to be decreased in the ventral part of caudate-putamen nucleus and increased in the cerebral cortex of sP rats compared with sNP rats; no significant differences were found in dynorphin mRNA expression in any of the brain areas examined.. Differences observed between the two lines of rats may implicate that genetic modifications in the opioid system are possibly responsible for the innate preference of sP rats toward alcohol intake. At the same time, it cannot be excluded that other functions might also be affected to some degree.

Topics: Alcoholism; Animals; Basal Ganglia; Brain Mapping; Breeding; Enkephalins; Genetic Markers; Male; Naloxone; Narcotic Antagonists; Opioid Peptides; Rats; Receptors, Opioid; RNA, Messenger

Endogenous opioid peptides appear to be involved in acute behavioral effects induced by single doses of ethanol. However, its role in repeated ethanol exposure has not been studied. In the present study ethanol was given to rats at the doses of 2 and 4 g/kg by a stomach gauge for 15 days, and its effects on spontaneous motility, open-field activity, and active avoidance behavior recorded on the 3rd, the 6th and the 15th days. Then the effect of naloxone (0.5 and 2 mg/kg by intraperitoneal route) was tested against a challenge ethanol dose, administrated by oral route, on the 16th day. Control animals received tap water and saline instead of ethanol or naloxone, respectively. Both doses of ethanol induced a decrease in spontaneous motility that was antagonized by naloxone. Open-field ambulations were increased by the high dose of ethanol, low-dose lacking effect; naloxone did not modify these ethanol effects. The low dose of ethanol shortened latency time in shuttlebox, the high dose causing escape and freezing responses; none of these effects were modified by naloxone. Therefore, endogenous opioid peptides appear to play a limited role in the chronic effects of ethanol in rats; particularly its effects in tests inducing an increase in the level of anxiety were resistant to naloxone.

Topics: Alcoholism; Animals; Behavior, Animal; Central Nervous System Depressants; Ethanol; gamma-Aminobutyric Acid; Male; Motor Activity; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley

Human beta-endorphin-like immunoactivity was measured in highly trained athletes (n = 10), alcoholics in the early phase of abstinence (n=9) and normal controls (n=15) using the Nichols Allegro immunoradiometric assay. The assay was examined for cross reactivity against related peptides, beta-lipotropin and human N-acetyl beta-endorphin. Venous blood sampling was carried out in the morning at 0900 and 1100 hours in a fasting state. Using two-way analysis of variance there was a significant effect of subject group on beta-endorphin concentration (p=0.029). Post-hoc analysis using the Bonferroni t-test showed that the source of the difference was the alcoholic group having significantly lower beta-endorphin immunoreactivity (p < 0.05). There was no difference between the controls and the athletes. There was a positive correlation between plasma beta-endorphin level at 1100 hours and the subsequent ACTH incremental response to naloxone in the group as a whole (r=0.48, p=0.004). The assay showed 100% cross reactivity with beta-lipotropin and 73% cross reactivity with N-acetyl-beta-endorphin. We conclude that alcoholics have reduced levels of beta-endorphin-like immunoactivity. While beta-endorphin is known not to cross the blood-brain barrier, levels of plasma beta-endorphin-like immunoactivity may indirectly reflect central opioid activity.

Topics: Adrenocorticotropic Hormone; Adult; Alcoholism; beta-Endorphin; beta-Lipotropin; Body Mass Index; Fasting; Female; Humans; Immunoradiometric Assay; Male; Naloxone; Narcotic Antagonists; Sensitivity and Specificity; Sports

Among other actions, opioid antagonists modulate the control endogenous opioids exert on the hypothalamic-pituitary-adrenal (HPA) axis. Naloxone, nalmefene, and naltrexone are the opioid antagonists approved for use in man and are primarily mu-opioid selective. Naltrexone and nalmefene have been demonstrated to be useful in the treatment of alcoholism. Compared with naloxone, nalmefene has a longer half-life, is more potent at the mu-receptor, and has a higher affinity for kappa- and delta-opioid receptors. We conducted an inpatient study comparing the effects of 10 and 30 mg doses of intravenous naloxone and nalmefene in normal, nonsubstance nor alcohol-abusing, volunteers. Significant increases in ACTH and cortisol were observed after both antagonists, without an apparent dose-response relationship; however, both doses of nalmefene resulted in greater HPA axis activation than either dose of naloxone (ACTH: p <0.005). These results indicate that kappa- and delta-opioids may play important roles in the regulation of the HPA axis; nalmefene may be useful as both a probe to explore the HPA axis physiology and as a pharmacotherapeutic agent.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Alcoholism; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Infusions, Intravenous; Male; Middle Aged; Naloxone; Naltrexone; Narcotic Antagonists; Pituitary-Adrenal System; Treatment Outcome

[3H]Naloxone binding was measured in frontal gray cortex, caudate nucleus, amygdala, hippocampus and cerebellar cortex obtained post mortem from human alcoholic and nonalcoholic subjects. Binding was found to be higher in alcoholics than in nonalcoholics for all of the brain regions examined, with a significant difference in the frontal cortex. When subjects were grouped by the presence or absence of the A1 (minor) allele of the D2 dopamine receptor gene, [3H]naloxone binding was lower in all brain regions examined of subjects with the A1 allele than in those without this allele, with a significant difference in the caudate nucleus. These findings suggest that one of the consequences of chronic alcohol exposure in humans is an enhancement of the brain opiate receptor system. However, the decreased [3H]naloxone binding observed in subjects with the A1 allele may be a compensatory response to their decreased dopaminergic modulation of opiate receptor activity.

Topics: Alcoholism; Alleles; Brain; DNA; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Polymorphism, Genetic; Receptors, Dopamine D2; Receptors, Opioid

Abnormal baseline hypothalamic-pituitary-adrenal axis function and dexamethasone suppressibility seen in withdrawing alcoholics returns to normal on abstinence, but some studies report blunting of the ACTH response to CRH persisting during the early abstinence phase. Reduced central levels of endogenous opioid peptides have been postulated to have an aetiological role in alcohol addiction.. To evaluate hypothalamic-pituitary-adrenal axis function in a group of recently abstinent alcoholics using basal hormone data, naloxone (an opioid receptor antagonist), and ovine CRH.. Nine alcoholics (age 41.4 +/- 3.1 years) studied more than one week after the acute withdrawal period but within 6 weeks of cessation of drinking, and nine age and sex matched non-alcoholic controls.. Cortisol, ACTH, CRH and AVP levels were measured every 20 minutes for 2 hours between 0900 and 1100h Twenty mg naloxone i.v. was administered at 1100h (0 minutes) and further samples for the above hormones were taken at 15, 30, 45, 60, 90 and 120 minutes. On a separate occasion, again at 1100h, oCRH 1 microgram/kg (n = 7 alcoholics, n = 6 controls) was administered, with samples for cortisol, ACTH and AVP taken at the same times.. Results were examined by analysis of variance for repeated measures (ANOVA), while incremental hormone response and area under the secretory curve (AUC) in alcoholics versus controls were compared by the two-tailed Student's t-test. Linear regression analysis was carried out to examine the relation between basal cortisol and hormone responses to naloxone and oCRH.. Basal hormone levels did not differ between the groups. The alcoholics had a blunted ACTH incremental response to naloxone (11.4 +/- 3.0 vs 21.1 +/- 2.5 pmol/l, P < 0.05) but the cortisol response was not significantly different (205 +/- 51 vs 305 +/- 42 nmol/l, P = 0.15). The alcoholics also had a blunted ACTH incremental response to oCRH (28.7 +/- 4.2 vs 41.2 +/- 3.7 pmol/l, P = 0.052) and by ANOVA a significant main effect of group (alcoholic vs control) was seen (P < 0.02) for the ACTH response to oCRH. There was no difference between the groups in the cortisol incremental response to oCRH. In the control subjects, a negative correlation was found between basal cortisol and the cortisol increment (r = -0.82, P < 0.05) and ACTH increment (r = -0.81, P = 0.052) following oCRH, while in contrast, basal cortisol correlated positively with cortisol increment (r = 0.72, P < 0.05) following naloxone. There was also a trend for basal cortisol to correlate positively with ACTH increment following naloxone in the controls (r = 0.63, P < 0.07). In the alcoholics, the normal negative effect of basal cortisol on the cortisol increment after oCRH was reversed, with a positive correlation between basal cortisol and cortisol increment (r = 0.75, P = 0.05).. Recently abstinent alcoholics with normal basal HPA axis hormone levels have a blunted ACTH response to naloxone and oCRH. While reduced levels of central endogenous opioid peptides may be a factor in the blunted ACTH response to naloxone in the alcoholics, it is proposed that the alcoholics have reduced pituitary responsiveness to CRH. This may be via a direct pituitary effect of the chronic ethanol exposure or by a reduction in hypothalamic-hypophyseal vasopressin levels.

Topics: Adrenocorticotropic Hormone; Adult; Alcoholism; Corticotropin-Releasing Hormone; Deamino Arginine Vasopressin; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Naloxone; Opioid Peptides; Pituitary-Adrenal System

Topics: Alcoholism; Female; Humans; Male; Naloxone

The activity of membrane-bound and soluble enkephalin convertase was determined with dansyl-Phe-Leu-Arg as substrate in midbrain, including hypothalamus, of Wistar rats, who were given ethanol (20% solution i.g., 9-15 g/kg per day during 4 days) or naloxone (2 mg/kg i.p. twice a day during 4 days) or their combination. It was shown that activation of membrane-bound enzyme, observed after alcohol treatment of rats, didn't develop by combined ethanol-naloxone administration. It's supposed that alcohol-stimulating effect on this enzyme realizes throughout the hyperstimulation of opioid receptors by enkephalins and, possible, by other opioid-active compounds.

Topics: Alcoholism; Animals; Carboxypeptidase H; Carboxypeptidases; Enzyme Activation; Hypothalamus; Male; Membrane Proteins; Mesencephalon; Naloxone; Rats; Rats, Wistar; Solubility; Substrate Specificity

The effect of morphine on adenylate cyclase activity in lymphocytes was tested in 20 normal controls, 16 alcoholics in withdrawal and 9 sober alcoholics. Alcoholics in withdrawal were characterized by a significantly increased stimulatory effect of morphine, whereas sober alcoholics showed an inhibitory effect. The morphine effect was abolished by naloxone and correlated with the severity of withdrawal and alcohol intoxication.

Topics: Adenylyl Cyclases; Adult; Alcohol Withdrawal Delirium; Alcoholism; Enzyme Activation; Humans; Lymphocytes; Male; Morphine; Naloxone

The course of plasma cortisol and beta-endorphin-like immunoreactivity (beta-EP-IR) was determined following a single i.v. administration of 20 mg naloxone. The test subjects included 20 male alcoholics (medication-free), investigated one to three days and four weeks after the onset of abstinence, as well as 10 short-time abstinent alcohol abusers and 10 healthy control subjects. The mean baseline values of cortisol and beta-EP-IR remained within normal limits in all groups. The significant decrease in the plasma cortisol baseline values in the alcoholics after 4 weeks abstinence may indicate a lower level of the regulation of the hypothalamic-pituitary-adrenal axis (HPA) under conditions of abstinence. After naloxone administration an increase in plasma cortisol and beta-EP-IR was observed in all groups. The multivariate trend analysis showed significant differences in the time course of plasma cortisol between the three groups, however not in the course of beta-EP-IR. The changes in the dynamic regulation of the HPA axis, resulting from chronic alcohol consumption, appears to be irrespective of whether the drinking pattern is dependent or abusive. In alcoholics these changes could still be identified following a 4-week abstinence period.

Topics: Adaptation, Physiological; Adult; Alcoholism; Analysis of Variance; beta-Endorphin; Diagnosis, Differential; Discriminant Analysis; Drug Evaluation; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Immunoassay; Male; Middle Aged; Naloxone; Pituitary-Adrenal System; Temperance

A wide variety of drugs have been tested in experimental animals and several have been found that reduce voluntary alcohol drinking. The available evidence suggested that the same drugs also reduce alcohol drinking in alcoholics. Various factors limited or prevented the clinical use of the these drugs. Our working hypothesis has been that alcohol drinking is a learned response, reinforced primarily from alcohol in the brain, and that an alcoholic is a person in which this response and the related craving have become so strong that they dominate the behaviour and interfere with normal functioning. Learned responses are extinguished if they are made repeatedly while the reinforcement is blocked, and opiate antagonists appear to block the reinforcement from alcohol. A series of experiments support the hypothesis that drinking alcohol while an antagonist is present extinguishes the alcohol-drinking response in rats. The antagonists are non-addictive and at least naloxone appears to be safe. Clinical trials are now needed, but the present results suggest that this extinction procedure might be a useful adjunct to the treatment of alcoholism.

Topics: Alcohol Drinking; Alcoholism; Animals; Extinction, Psychological; Male; Naloxone; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Rats; Rats, Inbred Strains

Beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) plasma concentrations were examined in ten chronic alcohol abusers, eight men and two women aged 25-56 years with histories of continuously elevated ethanol consumption dating from 5-30 years. Plasma levels of the two peptides were measured after acute alcohol consumption and then after 3, 6 and 9 days of forced abstinence, during chlordiazepoxide treatment. Beta-EP and beta-LPH concentrations were normal on all four occasions. A reduced sensitivity of opioid receptors to acute alcohol administration due to chronic alcohol consumption is suggested.

Topics: Adult; Alcohol Withdrawal Delirium; Alcoholic Intoxication; Alcoholism; beta-Endorphin; beta-Lipotropin; Female; Humans; Male; Middle Aged; Naloxone; Psychoses, Alcoholic; Receptors, Opioid

We have tested whether the opioid antagonists naloxone (2 mg/kg), naltrexone (2 mg/kg) and diprenorphine (0.2 mg/kg), and the agonist morphine (4-8 mg/kg) given subcutaneously (10 min before ethanol for 7 days) modify the ethanol withdrawal syndrome (audiogenic seizures) following chronic ethanol intoxication in rats. We found that naloxone, naltrexone and diprenorphine modified the ethanol withdrawal syndrome. These findings do not rule out the possibility of a biochemical link between the action of ethanol and opiates at the level of opioid receptors.

Topics: Alcoholism; Animals; Diprenorphine; Female; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Seizures; Substance Withdrawal Syndrome

beta-Endorphin was measured in the plasma of control subjects and 12 chronic alcoholics in the acute stage of ethanol intoxication. Naloxone was administered and the level of beta-endorphin was compared before and after treatment. The increased level of beta-endorphin in the intoxicated subjects supports the presence of ethanol interactions with the opioid system, since pituitary secretion does not seem to be involved. Furthermore, the coexistence of high levels of beta-endorphin and an effective naloxone response suggest a possible link between the two.

Topics: Adult; Alcoholism; beta-Endorphin; Endorphins; Ethanol; Humans; Naloxone; Radioimmunoassay

Topics: Alcoholism; Animals; Brain; Diazepam; Emotions; Ethanol; Humans; Naloxone; Rats; Receptors, GABA-A; Receptors, Opioid; Substance Withdrawal Syndrome; Time Factors

Adult male Long-Evans rats were maintained on an ethanol-containing liquid diet. During development of ethanol dependence, the rats were given daily i.p. injections of either naloxone (2 mg/kg) or saline daily. At the beginning of ethanol withdrawal, the rats were injected with either naloxone (10 mg/kg) or saline i.p. Rats injected with naloxone during the development of ethanol dependence consumed significantly more of the ethanol diet and therefore more ethanol than rats injected with saline. Rats treated with naloxone throughout both the development of ethanol dependence and during ethanol-withdrawal showed delayed or reduced withdrawal symptomatology compared to rats injected with only saline, naloxone only during the development of dependence and naloxone only during ethanol withdrawal. These results indicate that naloxone can alter the effects of chronic ethanol exposure and further suggest that ethanol may exert some of its actions via the brain opioid system.

Topics: Alcohol Drinking; Alcohol Withdrawal Delirium; Alcoholism; Animals; Arousal; Humans; Male; Naloxone; Rats; Receptors, Opioid

The binding characteristics of the delta opioid receptor ligand, 3H-D-Ala2-D-Leu5 enkephalin, were markedly altered in brains obtained from mice fed an ethanol-containing diet for five days. Control mice exhibited both a high and low affinity site for 3H-D-Ala2-D-Leu5 enkephalin, whereas those consuming the ethanol diet were found to possess only one binding site. This singular site has an intermediate KD value with an increase in receptor number when compared to the high and low affinity sites observed in control mice. The in vitro addition of ethanol to a brain membrane preparation obtained from untreated mice, at a concentration equivalent to that found in the blood of the ethanol-treated mice, did not markedly affect D-Ala2-D-Leu5 enkephalin binding characteristics. No alteration in the binding characteristics of 3H-naloxone, a mu receptor ligand, was noted following five days of ethanol consumption. Mice maintained on the ethanol-containing diet were tolerant to the activity-stimulating effects of acute ethanol administration. These results suggest that mice consuming an ethanol diet in sufficient quantities to render them tolerant exhibit a specific loss of a 3H-D-Ala2-D-Leu5 enkephalin binding site, while the binding of 3H-naloxone was unchanged.

Topics: Alcoholism; Animals; Brain; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Ethanol; Humans; Male; Mice; Naloxone; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu

Acute effects of the opiate antagonist, naloxone, on alcohol intake have been examined and compared in naive and behaviorally dependent rats. In naive rats the aversion to an 8% alcohol solution exhibited in a 30 min presentation was selectively augmented by an IP administration of naloxone (1 mg/kg) 30 min before a morning drinking session. In other rats, behavioral dependence was established by 15 days of IG administration of intoxicating doses of alcohol. This dependence was exhibited by a sustained preference for ethanol for 6 days. Naloxone (1 mg/kg) abolishes the acquired preference for ethanol tested during an 8 hour day time presentation. These effects of naloxone on alcohol intake in ethanol naive and dependent rats are interpreted in relation to a general non-specific action of naloxone on preferred or aversive flavoured solutions.

Topics: Alcohol Drinking; Alcohol Withdrawal Delirium; Alcoholism; Animals; Avoidance Learning; Choice Behavior; Humans; Male; Naloxone; Rats; Rats, Inbred Strains; Taste

Mice which have been selectively bred for differences in sensitivity to acute doses of alcohol have also been shown to differ in severity of seizures upon withdrawal from chronic alcohol administration. We investigated the responsiveness of these mice to withdrawal from chronic morphine treatment. Mice were made dependent on morphine via pellet implantation, and withdrawal was precipitated with naloxone challenge. Mice which are less sensitive to the hypnotic effects of ethanol (short sleep: SS) displayed more jumping and wet dog shakes during withdrawal than did the more sensitive long sleep (LS) mice. In addition, the amount of jumping was dependent on the dose of naloxone in both lines. Differences between lines in naloxone precipitated withdrawal may reflect differences in alterations in extrapyramidal dopaminergic activity, but other substrates for the observed differences cannot be discounted. Finally, the observed difference between SS and LS mice in severity of morphine withdrawal parallels the previously reported difference between these lines in seizure severity during withdrawal from alcohol.

Topics: Alcoholism; Animals; Behavior, Animal; Humans; Mice; Mice, Inbred Strains; Morphine; Morphine Dependence; Naloxone; Seizures; Substance Withdrawal Syndrome

Topics: Alcoholism; Animals; Disease Models, Animal; Ethanol; Humans; Isoquinolines; Macaca mulatta; Male; Naloxone; Naltrexone; Narcotics; Rats; Rats, Inbred Strains; Self Administration; Tetrahydroisoquinolines

Topics: Alcohol Drinking; Alcoholism; Animals; Disease Models, Animal; Ethanol; Humans; Isoquinolines; Male; Morphine; Motor Activity; Naloxone; Rats; Rats, Inbred Strains; Tetrahydroisoquinolines

Topics: Acetaldehyde; Alcoholism; Animals; Endorphins; Enkephalins; Humans; Isoquinolines; Mice; Naloxone; Rats; Receptors, Opioid; Tetrahydroisoquinolines

Topics: Alcoholism; Animals; Corticosterone; Disease Models, Animal; Ethanol; Humans; Male; Naloxone; Rats; Starvation; Time Factors

Topics: Alcoholism; Animals; Child; Cross-Cultural Comparison; Culture; Dogs; Female; Humans; Infant; Infant, Newborn; Male; Mice; Models, Biological; Mood Disorders; Naloxone; Personality Development; Pregnancy; Rats; Receptors, Opioid; Sensory Deprivation; Sexual Behavior; Social Isolation; Substance-Related Disorders

Experimental and clinical results suggest a relationship between the action of ethanol and opiates. Therefore, we have tested whether the specific morphine antagonist naloxone (2 mg/kg intraperitoneally every six hours) affects signs of severe ethanol intoxication or modifies the withdrawal syndrome following chronic ethanol intoxication in rats. Using a double blind technique, we did not find any difference between saline treated and naloxone treated animals with respect to level of intoxication and severity of withdrawal symptoms. We must therefore conclude that naloxone does not modify signs of severe ethanol intoxication or change the ethanol withdrawal syndrome in the rat. These findings do not rule out that there might be a biochemical link between actions of ethanol and opiates, but this link is probably not localized at the level of specific drug receptor interaction.

Topics: Alcoholic Intoxication; Alcoholism; Animals; Double-Blind Method; Drug Evaluation, Preclinical; Humans; Injections, Intraperitoneal; Male; Naloxone; Rats; Substance Withdrawal Syndrome

Recently, the discovery of endogenous opiate peptides has reawakened new interest in the possibility that an endogenous chemical may mediate actions of alcohol and lead to ethanol dependence.

Topics: Alcoholism; Alkaloids; Animals; Binding Sites; Brain Chemistry; Calcium; Cricetinae; Dose-Response Relationship, Drug; Humans; Isoquinolines; Naloxone; Rats; Synaptic Membranes

Topics: Acupuncture Therapy; Alcoholism; Analgesia; Humans; Naloxone; Substance-Related Disorders

Various dysphoric states are seen both in mood depression and on taking opiates. On the hypothesis that opiate antagonists would alter mood level, naloxone (Narcan), 0.4--0.8 mg t.i.d., was given to five depressed patients in six trials for a duration of 6--12 days. The CSF endorphin and monoamine metabolite content was analyzed before and after naloxone treatment. We observed no positive effect on mood level. However, an abrupt worsening of symptoms was noted in two cases on discontinuation of treatment. Decreasing values of endorphin Fraction I as a result of treatment was noted as a general trend. Fraction II, although elevated, showed no distinct trend. 5HIAA increased in four of the six trials. The results suggest that naloxone treatment changes endorphin and serotonin activity, though not to a clinically observable extent.

Topics: Adult; Alcoholism; Biogenic Amines; Depression; Endorphins; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Middle Aged; Naloxone; Psychiatric Status Rating Scales

The data reported here together with recent reports from other investigations suggest that ethanol may act selectively to alter Ca++ metabolism in nerve cells. Changes in calcium content and binding after acute and chronic exposure to ethanol suggest that nerve cells may adapt to ethanol exposure through increasing endogenous calcium content on the synaptic membranes. Since calcium plays an integral role in neurotransmitter metabolism, it may be suggested that adaptation to ethanol may occur via such Ca++ dependent processes as altered membrane transport capabilities and excitation-secretion coupling mechanisms. Future research in these areas would hopefully be directed toward the role of Ca++ in neurotransmitter release and subsequent activation of cyclic nucleotide metabolism.

Topics: Alcoholism; Animals; Brain; Calcium; Humans; Male; Membrane Proteins; Membranes; Naloxone; Rats; Subcellular Fractions; Synaptic Membranes

Topics: Adult; Alcoholism; Boston; Cannabis; Depression; Emotions; Follow-Up Studies; Heroin Dependence; Humans; Internal-External Control; Male; Naloxone; Naltrexone; Patient Acceptance of Health Care; Patient Dropouts; Psychotherapy; Self Concept; Sleep