Increased ethanol choice in social drinkers following ethanol preload

This study showed that normal social drinkers were more likely to consume ethanol after receiving a "priming" (preload) dose of ethanol. Twenty-eight non-problem drinkers (average consumption 9 drinks/week) participated in a six-session, double-blind choice procedure. On the first two sessions they sampled beverages containing ethanol (0.8g/kg) or placebo (mix alone), between which they would choose on subsequent choice sessions. On the third session ("dummy" choice session) subjects were first asked to indicate verbally which beverage they preferred. If they chose the ethanol-containing beverage the experimenter negotiated with each subject to determine the minimum amount of money (from $1 to $30) needed to switch his or her choice from ethanol to placebo. Once this amount was determined it remained fixed for the subsequent three preload/choice sessions. Thus, on choice sessions subjects chose between the beverage which contained ethanol, and placebo plus the amount of money established in Session 3. On the preload/choice test sessions (Sessions 4-6) subjects received preloads of ethanol (0, 0.25 or 0.5g/kg) 1h before being given the choice between the sampled ethanol beverage and the placebo beverage plus money. The frequency of ethanol choice was the primary dependent variable. Subjective drug effects, including ratings of desire for the sampled substances, were also measured. Twenty subjects initially chose ethanol on Session 3 and switched their choice with a monetary incentive. Of these 20 subjects, four chose ethanol after the placebo preload, seven chose ethanol after the low-dose ethanol preload, and 11 chose ethanol after the higher ethanol preload (significant linear trend, Mantel-Haenszel test, p < 0.03). Ratings of desire for the ethanol-containing beverage increased after the higher preload. These results suggest that ingestion of a moderate dose of ethanol increases the tendency to continue drinking, even among normal social drinkers.     

Assessing individual differences in ethanol preference using a cumulative dosing procedure

Preference for ethanol versus a placebo was assessed in 12 normal volunteers using a cumulative dosing preference test. The test consisted of four sampling sessions followed by three choice sessions. During the sampling sessions subjects received either five cumulating oral doses of ethanol (0.1g/kg per dose) or equal volumes of placebo, at 15-min intervals. Subjective and observer-rated drug effects, psychomotor performance, drug liking ratings, and breath ethanol levels were measured at regular intervals. During choice sessions, subjects first chose which of the two substances (drug or placebo) they wished to take and ingested one unit dose. Then, at 15-min intervals throughout the session, they could ingest up to ten additional unit doses of the same substance (i.e., up to 1.1 g/kg ethanol). On average, the subjects chose the ethanol-containing beverage on 75% of the choice sessions, and they self-administered a mean total dose of 0.8g/kg per session. Subjects varied in the amount of ethanol ingested on choice sessions, and the amount they chose was related to their subjective responses to the drug during sampling. Subjects who chose the most ethanol reported experiencing stimulant-like effects from the ethanol, whereas the subjects who chose ethanol less frequently and ingested lower doses reported primarily sedative-like effects from the drug. The results demonstrate that the cumulative dosing procedure can be used effectively to evaluate drug preferences and dose preferences in normal volunteers.     

U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking

Rationale: The role of endogenous opiate systems in cigarette smoking remains unclear. In laboratory animals, opiate antagonists block many of the effects of nicotine, but in humans they do not consistently alter smoking behavior. Objective: This study explored the effects of naltrexone, alone and in combination with nicotine, on smoking behavior. Methods: In a double-blind, double-dummy, within-subjects design, 19 regular smokers received four treatments of 1 week duration: naltrexone tablet (50 mg) plus placebo skin patch, placebo tablet plus nicotine skin patch (21 mg/24 h), naltrexone tablet plus nicotine skin patch, and placebo tablet plus placebo skin patch. During each treatment, subjects rated their responses to nicotine-containing and denicotinized cigarettes in the laboratory, and to their own brand of cigarette smoked ad libitum outside the laboratory. Results: Pretreatment with the nicotine patch attenuated smoking-induced decreases in craving, negative affect, and rates of ad lib smoking, and potentiated the aversiveness of a cigarette. Naltrexone reversed these effects of the nicotine patch, and produced negative effects on mood. Conclusions: The blockade of nicotine’s effects by naltrexone supports a role for opioid mechanisms in cigarette smoking. Received: 9 October 1997/Final version: 3 December 1998     

Effects of naltrexone pretreatment on the subjective and performance effects of ethanol in social drinkers

Clinical trials suggest that opioid antagonists may be effective in the treatment of alcoholism. For example, two recent clinical trials reported that alcoholics treated with the opioid antagonist naltrexone exhibited higher abstinence rates, decreased craving and a decrease in the amount of alcohol consumed if drinking occurred. The present study examined the hypothesis that naltrexone pretreatment would attenuate the behavioral responses to an acute dose of ethanol in normal, healthy social drinkers. Thirteen healthy male and female social drinkers participated in a six-session, double-blind, placebo-controlled, crossover design study. On each session, subjects ingested a capsule containing naltrexone (25 or 50mg) or placebo and one hour later consumed a beverage containing ethanol (0.5g/kg) or placebo. For three hours after the beverage was consumed, breath alcohol levels were measured and subjects completed standardized subjective effects questionnaires and performance tasks at regular intervals. Ethanol alone produced its prototypic effects, including positive subjective responses such as euphoria and increased ratings of overall liking, as well as increased ratings of confusion. Ethanol also impaired performance on a verbal recall task. Naltrexone alone produced few subjective effects and did not impair psychomotor or verbal recall performance. Contrary to our hypothesis, pretreatment with naltrexone did not alter the positive subjective effects, or any other effects, of ethanol. Further research is needed to determine the influence of factors such as baseline level of ethanol consumption or duration of naltrexone treatment on the interaction between ethanol and the endogenous opioid system.     

Naltrexone effects on ethanol consumption and response to ethanol conditioned cues in C57BL/6 mice

RATIONALE: The conditions under which naltrexone reduces ethanol consumption and its effect on behavior controlled by ethanol conditioned stimuli remain unclear. OBJECTIVES: The objectives were to determine the effects of naltrexone on ethanol consumption by C57BL/6 (B6) mice when injected subcutaneously (expt 1) or delivered by osmotic minipump (expt 2), and on ethanol conditioned cues (expt 3). METHODS: Naltrexone effects on ethanol consumption and preference were measured in a continuous access two-bottle choice paradigm in groups of mice implanted with osmotic minipumps delivering 0-3.0 mg/kg per day or injected subcutaneously with 0-6.0 mg/kg doses. Naltrexone's (0-3.0 mg/kg) effect on ethanol-conditioned cues was indexed by its effect on the expression of ethanol place conditioning (expt 3). RESULTS: Naltrexone produced a transient reduction in ethanol consumption and a consistent reduction in preference when injected; however, it had no effect on ethanol consumption or preference when delivered continuously by osmotic minipump. Naltrexone attenuated the expression of ethanol place conditioning in a U-shaped dose-response function. CONCLUSIONS: The transient reduction in ethanol consumption produced by injected naltrexone and the absence of an effect when continuously delivered confirms a report that maintaining naltrexone at steady state levels may antagonize its attenuation of ethanol consumption. The reduced expression of ethanol place conditioning in naltrexone-injected mice suggests that the drug can attenuate the reinforcing effects of ethanol conditioned stimuli as was recently reported for lever responding maintained by ethanol conditioned stimuli in rats. These effects were observed at naltrexone doses with no readily apparent adverse side-effects, supporting its usefulness for treating alcoholism.     

Behavioral responses to ethanol in light and moderate social drinkers following naltrexone pretreatment

The opioid antagonist naltrexone has been shown to be effective in the treatment of alcoholism, possibly by dampening the subjective effects of ethanol. However, naltrexone does not consistently attenuate the effects of ethanol in social drinkers in laboratory-based challenge studies. In the present study, 25 healthy volunteers, who were either light drinkers (mean=3 drinks per week) or moderate drinkers (mean=16 drinks per week), participated in six evening sessions. At each session, subjects ingested a capsule containing naltrexone (25 or 50 mg) or placebo, and 1 hr later they consumed a beverage containing ethanol (0.25 g/kg, equivalent to about two standard alcoholic drinks) or placebo. Subjects received all combinations of pretreatments and beverages. They completed self-report mood questionnaires and psychomotor tests at regular intervals. This low dose of ethanol produced modest but significant effects on self-report measures such as ratings of feeling a drug effect and of liking the drug effect. However, naltrexone (25 or 50 mg) pretreatment had no dampening effect on subjects' responses to ethanol. These results indicate that acute doses of naltrexone that are effective when administered chronically to alcoholics do not attenuate the acute effects of a low dose of ethanol in non-problem drinkers.     

Acamprosate and naltrexone treatment effects on ethanol and sucrose seeking and intake in ethanol-dependent and nondependent rats

Rationale  Two pharmacotherapies are approved for treating alcohol craving (acamprosate and naltrexone), but both have shown mixed findings in animals and humans. Objectives  The present experiments utilized a “reinforcer blocking” approach (i.e., rats were able to consume ethanol during treatment) to better understand the efficacy of these treatments for ethanol seeking and drinking using ethanol-dependent and nondependent rats. Materials and methods  In “nondependent” experiments, drugs (acamprosate 50, 100, and 200 mg/kg; naltrexone 0.1, 0.3, and 1.0 mg/kg) were administered over 3-week periods prior to operant sessions with a low response requirement to gain access to reinforcers for 20 min. For “dependent” experiments, rats were made dependent in vapor/inhalation chambers. Results  Acamprosate and naltrexone had similar effects on intake in nondependent and dependent rats; neither drug was selective for ethanol over sucrose drinking. In nondependent animals, naltrexone was more efficacious at more doses than acamprosate, and acamprosate’s effects were limited to a dose that also had adverse effects on body weight. Both pharmacotherapies showed more selectivity when examining reinforcer seeking. In nondependent rats, acamprosate and naltrexone had response-attenuating effects in ethanol, but not sucrose, groups. In dependent animals, acamprosate had selective effects limited to a decrease in sucrose seeking. Naltrexone, however, selectively decreased ethanol-seeking in nondependent rats. Conclusions  The naltrexone-induced decreases in seeking suggested a change in incentive motivation which was selective for ethanol in nondependent rats. The “nondependent” paradigm may model early stages of “problem drinking” in humans, and the findings suggest that naltrexone could be a good intervention for this level of alcohol abuse and relapse prevention.     

Interaction between naltrexone and oral THC in heavy marijuana smokers

Abstract Rationale. Studies in non-human animals suggest that opioid antagonists block the reinforcing effects of cannabinoids. Objective. The present studies in humans investigated how naltrexone modulates (1) the subjective and physiological effects of oral THC in comparison to methadone, (2) the reinforcing effects of oral THC, and (3) plasma levels of oral THC. Methods. In study 1, marijuana smokers (n=9) received naltrexone (0, 50 mg) followed 30 min later by THC (0, 15, 30 mg) or methadone (5, 10 mg). Subjective effects, task performance, pupillary diameter, and cardiovascular parameters were measured repeatedly. In study 2a, marijuana smokers (n=23) were randomly assigned to one THC dose condition (0, 15 or 30 mg). One set of color-coded capsules containing THC and active naltrexone (50 mg) was given in one session, while another set of color-coded capsules containing THC and placebo naltrexone was given in another session. In the final three sessions, participants chose which color capsules they would receive. In study 2b, a subset of participants from study 2a (n=7) received naltrexone (0, 50 mg) 30 min prior to oral THC (30 mg) administration, and blood was drawn repeatedly. Results. Pretreatment with naltrexone significantly increased many of the "positive" subjective effects of oral THC (30 mg) e.g. ratings of Good Drug Effect and Capsule Liking. Naltrexone tended to increase the reinforcing effects of oral THC (30 mg), as indicated by performance in a drug choice test. Naltrexone did not alter plasma THC levels. Conclusions. These studies demonstrate that naltrexone increases the subjective effects of oral THC. Thus, oral THC's effects are enhanced rather than antagonized by opioid receptor blockade in heavy marijuana smokers. Electronic Publication     

Naltrexone pretreatment decreases the reinforcing effectiveness of ethanol and saccharin but not PCP or food under concurrent progressive-ratio schedules in rhesus monkeys

 The purpose of this experiment was to determine whether attenuation of ethanol consumption by naltrexone is the result of selective changes in the reinforcing effectiveness of drug and non-drug reinforcers. A range of naltrexone doses (0.1–1.0 mg/kg) was administered for 5 days, and the effects on the reinforcing effects of orally delivered 8% (w/v) ethanol, 0.25 mg/ml phencyclidine (PCP), 0.03% (w/v) saccharin and food were studied in eight rhesus monkeys. Food and liquids were available under independent and concurrent progressive-ratio (PR) schedules (ratio range 8–4096) during daily 3-h sessions. Ethanol-maintained responding was attenuated by 0.3 and 1.0 mg/kg doses of naltrexone, while saccharin-maintained responding was decreased at the 1.0 mg/kg dose. Furthermore, there was a significant linear trend that consumption of available ethanol and saccharin was attenuated dose-dependently by naltrexone. Following 5 days of naltrexone pretreatment, ethanol- and saccharin-maintained responding immediately returned to or exceeded baseline levels. Food- and PCP-maintained responding and intake were not significantly affected by any of the naltrexone doses examined. The decreased break point (BP) values for ethanol and saccharin suggest that their reinforcing effects are mediated through opioid reinforcement mechanisms. The lack of naltrexone attenuation of PCP- and food-maintained responding suggests that these reinforcers: 1) are not sensitive to naltrexone antagonism at the doses examined, 2) are mediated by non-opioid reinforcement mechanisms, and/or 3) have less intrinsic palatability. Received: 13 May 1998 / Final version: 28 July 1998     

Naltrexone reduces the relative reinforcing value of nicotine in a cigarette smoking choice paradigm

Rationale Human behavioral pharmacology studies can examine how medications that target different neurotransmitter systems influence different aspects of smoking. Naltrexone and bupropion have been shown to alter ad lib smoking behavior; however, medication effects on nicotine reward in a cigarette choice paradigm have yet to be investigated.Objective This study explored the effects of an acute dose of naltrexone, bupropion, or placebo on the relative reinforcing value of nicotine from cigarette smoking using new nicotine and de-nicotinized (Quest, 0.6 and 0.05 mg = denicotinized) cigarettes.Methods In a double-blind, within-subjects design, 26 dependent smokers participated in three experimental cigarette smoking sessions following pretreatment with either naltrexone (50 mg), bupropion (300 mg), or placebo. After medication administration and 2 h of monitored deprivation from cigarettes and food, participants rated their responses to the initial exposure to the cigarettes and then participated in four choice sessions over a 2-h period during which they could take four puffs from either cigarette.Results The relative reinforcing value of nicotine, as measured by the number of nicotine puffs chosen out of 16, was significantly lower following naltrexone compared to placebo. There were no effects of an acute dose of bupropion on nicotine choices.Conclusions These results suggest that naltrexone may reduce the relative reinforcing effects of nicotine via cigarette smoking and support ongoing investigation of opioid antagonists as potential smoking cessation pharmacotherapies.     

Effect of setting on the reinforcing and subjective effects of ethanol in social drinkers

The reinforcing and subjective effects of two doses of ethanol [0.5 g/kg (LOW) and 0.8 g/kg (HIGH)] were evaluated under two conditions, a social condition (SOC), in which subjects were tested with two or three other subjects, and a socially isolated condition (ISO), in which subjects were tested alone. Forty-one social drinkers participated in a double-blind, seven-session choice procedure. Subjects were randomly assigned to one of four experimental groups: SOC-LOW, SOC-HIGH, ISO-LOW, or ISO-HIGH. On the first four sessions, subjects sampled ethanol (0.5 or 0.8 g/kg) on two occasions and placebo on the other two occasions. On the three remaining sessions, subjects selected and consumed whichever of the two previously sampled substances they preferred. The number of sessions on which they chose ethanol was the primary measure of the reinforcing effects of ethanol. Standardized self-report questionnaires and a psychomotor test were used to measure subjective and objective drug effects. Subjects in the SOC condition chose ethanol over placebo on significantly more sessions than subjects in the ISO condition. Ethanol produced positive subjective effects (e.g., increased ratings of drug liking and euphoria) for subjects in the SOC condition, but for subjects in the ISO condition, it produced apparently negative effects (e.g., increased ratings of dysphoria). These results extend previous reports that the behavioral effects of ethanol depend upon the social condition in which it is consumed.     

Drug preference in normal volunteers: Effects of age and time of day

These experiments assessed the influence of two variables, age of subjects and time of drug administration, on the reinforcing properties of amphetamine and of diazepam in normal volunteers. Three groups of subjects were tested: i) a group of 40–55-year-old subjects (AGE group; N=11) who were tested in the morning, ii) a group of 21–35-year-old subjects (CTL group; N=12) who were also tested in the morning, and iii) a group of 21–35-year-olds who were tested in the late afternoon (AFT group; N=13). All subjects participated in three separate experiments comparing one drug (5 mg d,l-amphetamine, 5 mg diazepam or 10 mg diazepam) to placebo. Each experiment consisted of nine sessions: On the first four sessions subjects sampled two color-coded capsules on alternate sessions and on the following five sessions they chose and ingested the capsule they preferred. Subjective effects of the drugs were monitored using the Profile of Mood States (POMS) and a shortened version of the Addiction Research Center Inventory (ARCI). Subjects in all three groups chose 5 mg diazepam as often as placebo but preferred placebo to 10 mg diazepam. In contrast, they chose amphetamine either as often as or more often than placebo. The subjective effects of diazepam (i.e. sedation) were similar across all three groups, but after amphetamine the AGE group showed greater stimulant effects. In addition, the AFT group showed fewer positive mood effects after amphetamine than the CTL group. The AFT and AGE groups also differed from the CTL group on several measures of mood, independently of drug administration. Despite the modest group differences in subjective effects, it was concluded that neither time of day nor age of subjects substantially affected the reinforcing properties of either drug.     

Effect of a selective dopamine D1 agonist (ABT-431) on smoked cocaine self-administration in humans

Rationale: Data in laboratory animals suggest that D₁ receptor agonists may have potential utility for the treatment of cocaine abuse. Objective: The effects of ABT-431, a selective agonist at the dopamine D₁ receptor, on the reinforcing, cardiovascular and subjective effects of cocaine were investigated in humans. Method: Nine experienced cocaine smokers (8M, 1F), participated in nine self-administration sessions while residing on an inpatient research unit: three doses of ABT-431 (0, 2, 4 mg IV) were each given in combination with three doses of smoked cocaine (0, 12, 50 mg). ABT-431 was intravenously administered over a 1-h period immediately prior to cocaine self-administration sessions. A six-trial choice procedure (cocaine versus $5 merchandise vouchers) was utilized, with sessions consisting of: (a) one sample trial, where participants received the cocaine dose available that day, and (b) five choice trials, where participants chose between the available cocaine dose and one merchandise voucher. Results: ABT-431 did not affect the number of times participants chose to smoke each dose of cocaine, but produced significant dose-dependent decreases in the subjective effects of cocaine, including ratings of “High,”“Stimulated,” dose liking, estimates of dose value, “Quality,” and “Potency.” Furthermore, there was a trend for ABT-431 (4 mg) to decrease cocaine craving. ABT-431 also increased heart rate, while decreasing systolic and diastolic pressure at each dose of cocaine. Conclusions: These data suggest that D₁ agonists may have potential utility for the treatment of cocaine abuse. Received: 18 August 1998/Final version: 16 October 1998     

Evaluation of the <Emphasis Type="Italic">mu</Emphasis> and <Emphasis Type="Italic">kappa</Emphasis> opioid actions of butorphanol in humans through differential naltrexone blockade

Rationale Butorphanol exerts activity at mu, kappa, and delta opiate receptors in rats and monkeys but produces predominant mu-like effects in humans. Objectives The aim of this study was to determine if the kappa receptor-mediated actions of butorphanol could be unmasked or enhanced by giving it in combination with naltrexone, an opioid antagonist with higher affinity for mu vs kappa receptors. Materials and methods Ten healthy adult inpatient volunteers (eight men, two women), with opioid abuse histories, completed this double-blind, randomized, placebo-controlled study. Naltrexone (0, 1, 3, 10, or 30 mg, p.o.) was administered 1 h before butorphanol (0, 6, or 12 mg/70 kg, i.m.) during 15 test sessions. An array of physiological (e.g., vital signs, urine output, and subject- and observer-rated) measures was collected before and for 4 h after drug administration. Results Naltrexone alone produced no direct effects. Butorphanol alone produced typical mu-, but not kappa-, related physiological effects (e.g., miosis, respiratory depression) and produced mood and drug effects considered typical of both mu (e.g., “liking,” “good drug effects”) and kappa agonists (e.g., increases in perceptual disturbances). Naltrexone pretreatment led to significant butorphanol-induced diuresis (i.e., increased urine output and decreased urine osmolality). Naltrexone generally produced a dose-dependent blockade of subjective responses. Conclusion These data suggest that naltrexone antagonism unveiled the kappaergic activity of butorphanol as measured by diuresis, while subjective responses generally attributed to mu vs kappa receptors were not dissociable. Moreover, these data demonstrate that butorphanol exerts physiologically relevant kappa agonist activity at these supraanalgesic doses in humans.     

Effects of naltrexone and isradipine,alone or in combination,on cocaine responses in humans

Preclinical studies suggested that combination of naltrexone and isradipine may be useful for the treatment of cocaine addiction. This study examined whether naltrexone and isradipine, alone or in combination, would attenuate the subjective and physiological effects of cocaine in humans. Seven cocaine users participated in a randomized, double-blind, placebo-controlled inpatient study. Before each of the seven experimental sessions, subjects were treated orally with naltrexone (50 mg or placebo), isradipine (10 mg or placebo), or naltrexone plus isradipine. Subjects then received a single dose of intranasal cocaine (4 mg or 100 mg/70 kg). Isradipine alone attenuated the systolic blood pressure response to cocaine. In contrast, isradipine plus naltrexone treatment attenuated both the systolic and diastolic blood pressure responses. Naltrexone alone did not affect the blood pressure response to cocaine. For subjective response to cocaine, isradipine, alone or in combination with naltrexone, did not have significant effects. Naltrexone treatment alone attenuated the rating of "good effects" from cocaine without affecting other subjective responses. These results suggest that isradipine alone or in combination with naltrexone attenuates some of the physiological effects of cocaine.     

Moderate doses of ethanol fail to increase plasma levels of neurosteroid 3α-hydroxy-5α-pregnan-20-one-like immunoreactivity in healthy men and women

Rationale: The endogenous GABAergic neuroactive steroid 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP, allopregnanolone) has been proposed to contribute to ethanol actions. Humans synthesize 3α,5α-THP, but its role in response to systemic administration of ethanol is unclear. Objective: The present study aims to determine the effect of a moderate dose of ethanol on progesterone and 3α,5α-THP concentrations in plasma samples of healthy male and female subjects and to determine if these levels are related to the subjective effects of ethanol. Females were tested in both the follicular and luteal phases of the menstrual cycle. Methods: Healthy men (N=9) and women (N=12) aged 21–35 participated in the study. Men participated in two sessions on which they received ethanol (0.8 g/kg) or placebo. Women participated in four sessions on which they received ethanol (0.7 g/kg) or placebo during the follicular and luteal phases of their cycle. Subjective states and mood were measured by standardized self-report questionnaires and a measure of psychomotor performance. Steroid levels (progesterone, 3α,5α-THP, estradiol, and cortisol) were measured in plasma samples by radioimmunoassay. Results: Ethanol significantly increased plasma levels of progesterone, but not 3α,5α-THP-like immunoreactivity, in women in the luteal phase. Ethanol had no effect on progesterone or 3α,5α-THP-like immunoreactivity levels in women in the follicular phase or in men, and it did not increase cortisol in men or women. Ethanol also did not affect estradiol in men or women. Conclusions: 3α,5α-THP-like immunoreactivity levels in human plasma are not increased following moderate ethanol consumption, suggesting that circulating levels of progesterone or its tetrahydro-reduced metabolites do not play a major role in ethanol action. However, the possibility remains that ethanol increases endogenous brain production of GABAergic neurosteroids without affecting plasma levels. Moreover, humans synthesize 5β-reduced GABAergic steroids, and levels of these steroids may be altered in plasma or brain.     

An opioid receptor antagonist, naltrexone, does not alter taste and smell responses in humans

Several studies have shown that an opioid receptor antagonist, naltrexone, decreases palatable food consumption. Naltrexone has also been reported to reduce ethanol intake in alcohol-preferring rodents and human alcoholics. The aim of the present study was to assess the effects of naltrexone on taste and smell responses in healthy male volunteers. Naltrexone did not alter intensity and pleasantness of sucrose, quinine, citric acid, sodium chloride, and ethanol taste. Similarly, ratings of olfactory stimuli (orange extract and ethanol) and Coca-Cola flavor were not influenced by the opioid antagonist. Our findings may indicate that: (i) naltrexone exerts marginal, if any, effects on gustatory and olfactory responses in humans; (ii) the drug does not alter orosensory responses to ethanol.     

Effects of opiate antagonist treatment on the alcohol deprivation effect in long-term ethanol-experienced rats

Rationale: 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. Objective: 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. Methods: 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 (2×5 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. Results: 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. Conclusions: 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. Received: 29 September 1998 / Final version: 15 March 1999     

Ethanol as a hypnotic in insomniacs: self administration and effects on sleep and mood.

The purpose of this study was to assess the effects of low ethanol doses on sleep and mood and to assess its reinforcing effects used as a hypnotic. Twenty healthy adults, aged 21-45 yrs, all moderate social drinkers, were studied: eleven subjects had insomnia and nine were normal sleepers, as documented by clinical polysomnography. On two sampling nights each, ethanol (0.5 g/kg) or placebo was administered before sleep in color-coded cups presented in three doses (0.2, 0.2, and 0.1 g/kg) separated by 15 min. On three subsequent nights subjects chose their preferred presleep beverage (0.2 g/kg ethanol or placebo) based on cup color and were given an opportunity for 3 additional refills (0.2 g/kg each) of the chosen beverage at 15 min intervals, yielding a total possible dose of 0.8 g/kg. Insomniacs chose ethanol 67% of nights and normals 22%. Insomniacs chose significantly more ethanol refills than normals for an average nightly dose of 0.45 g/kg and normals took significantly more placebo refills. On the sampling nights 0.5 g/kg ethanol reduced REM sleep for both groups for the 8-hr sleep period and in insomniacs increased stage 3-4 sleep and reduced stage 1 sleep during the first half of the night to the level seen in the normals. Other sleep variables were not altered in either group or halves of the night. Presleep improvements in the Profile of Mood States tension and concentration factors were also associated with ethanol administration. Thus, acutely, both sleep and mood effects appear to be associated with the reinforcing effects of ethanol as a hypnotic for insomniacs.     

Quadazocine decreases responding reinforced by ethanol, sucrose, and phencyclidine fluid deliveries in rhesus monkeys: comparison to naltrexone’s effects

  Rationale: The endogenous opioid system may mediate the reinforcing effects of ethanol as well as sweet-tasting solutions. For example, opioid antagonists, such as naltrexone, reduce ethanol- and sucrose-reinforced responding in rhesus monkeys. If these effects are due to blockade of the μ-receptor, then an opioid antagonist such as quadazocine with a receptor selectivity profile similar to that of naltrexone should reduce responding at doses correlated with its μ-selectivity. Objectives: To determine whether quadazocine would reduce responding for ethanol and sucrose at μ-selective doses, and whether quadazocine and naltrexone would reduce responding for a bitter-tasting drug solution such as phencyclidine. Methods: Rhesus monkeys were given access to ethanol, sucrose, or phencyclidine concurrently with water. Prior to the drinking sessions, quadazocine (0.032–3.2 mg/kg) or saline was injected intramuscularly. During the phencyclidine experiment, naltrexone (0.1 and 0.32 mg/kg) was also tested. Results: The highest quadazocine doses (1 and 3.2 mg/kg) reduced ethanol and sucrose fluid deliveries without affecting the concurrently available water. Quadazocine reduced the fluid deliveries of both phencyclidine and water when concurrently available. Naltrexone reduced only phencyclidine fluid deliveries. Conclusions: The opioid antagonist effect on oral-reinforced responding is not selective for ethanol or sweet-tasting solutions; responding for phencyclidine was reduced as well. Quadazocine and NTX may reduce responding by blocking the μ-receptor because the relative potency of these antagonists to reduce oral self-administration was similar to their relative potency to produce withdrawal in morphine-dependent monkeys. However, water responding was low in these experiments, and thus we cannot rule out rate-dependent effects of the antagonists. Received: 24 June 1998 / Accepted: 18 February 1999