Alcohol-induced Stimulation Research Articles

Assessing the Stimulant and Sedative Effects of Alcohol With Explicit and Implicit Measures in a Balanced Placebo Design

Alcohol consumption is characterized by bi-phasic stimulant and sedative effects. In previous studies, various tools were used to assess these effects, including expectancy questionnaires, implicit association tests, and self-report scales. The present study was aimed at clarifying the relationships between these measures. Three different measures were used to directly or indirectly assess the stimulant and sedative effects of alcohol in 61 undergraduate students. The participants completed the Alcohol Expectancy Questionnaire (AEQ) and performed two unipolar Implicit Association Tasks to assess implicit associations between alcohol and the concepts of "stimulation" and "sedation." The levels of alcohol consumption also were recorded by means of the Alcohol Use Disorders Identification Test. An alcohol (0.4 g/kg) or placebo challenge was then administered using a balanced placebo design. After alcohol/placebo administration, the participants completed the Biphasic Alcohol Effects Scale (BAES). Alcohol consumption significantly correlated with AEQ alcohol explicit expectancies of arousal and relaxation, whereas no significant correlations were obtained with the implicit associations. There were positive correlations between AEQ and BAES subscales, especially for the arousal subscale of the AEQ. Self-reported sedation recorded with the BAES was significantly affected by what the participants believed that they had drunk but not by the actual consumption of alcohol. These findings indicate that alcohol explicit expectancies of arousal measured with the AEQ best predict current alcohol consumption. Regarding explicit measures of alcohol-induced stimulation and sedation, BAES sub-scales seem to be more affected by alcohol drinking expectations than by actual alcohol consumption.

S10 * EMERGING DRUGS FOR TREATING ALCOHOL USE DISORDERS: PRECLINICAL EVIDENCE

S10 * EMERGING DRUGS FOR TREATING ALCOHOL USE DISORDERS: PRECLINICAL EVIDENCE

Subjective Response to Alcohol Among Alcohol‐Dependent Individuals: Effects of the Mu‐Opioid Receptor (OPRM1) Gene and Alcoholism Severity

Subjective response to alcohol has been examined as a marker of alcoholism risk. The A118G single-nucleotide polymorphism (SNP) of the mu-opioid receptor (OPRM1) gene has been previously associated with subjective response to alcohol in heavy drinkers. This study seeks to extend the literature by examining the effect of OPRM1 genotype on responses to alcohol in a sample of alcohol-dependent individuals. A secondary aim of this study is to examine alcoholism severity as a predictor of subjective responses to alcohol. Nontreatment seeking problem drinkers (n = 295) were assessed in the laboratory for clinical dimensions of alcohol dependence. Following prospective genotyping, 43 alcohol-dependent individuals across the 2 genotype conditions (AA, n = 23 and AG/GG, n = 20) were randomized to 2 intravenous infusion sessions: 1 of alcohol (target breath alcohol concentration = 0.06 g/dl) and 1 of saline. Measures of subjective responses to alcohol were administered in both infusion sessions. Alcohol-dependent G-allele carriers reported greater alcohol-induced stimulation, vigor, and positive mood, as compared to A-allele homozygotes. There was no genotype effect on alcohol-induced sedation or craving. There was a statistical trend-level severity × alcohol interaction such that individuals at higher levels of severity reported greater alcohol-induced tension reduction. These results support the hypothesis that OPRM1 genotype moderates the hedonic effects of alcohol, but not the sedative and unpleasant effects of alcohol, in a sample of alcohol-dependent patients. Results are discussed in light of a clinical neuroscience framework to alcoholism.

Delta and kappa opioid receptor polymorphisms influence the effects of naltrexone on subjective responses to alcohol

Naltrexone, one of four FDA-approved pharmacotherapies for alcohol dependence, has shown moderate efficacy in clinical trials. Pharmacogenetic effects have been reported such that allelic variation at the gene encoding the mu-opioid receptor (OPRM1, rs1799971) predicts naltrexone-induced blunting of the positively reinforcing effects of alcohol. However, naltrexone also binds, albeit to a lesser degree, to kappa and delta opioid receptors in the brain. This alternate binding presents the possibility that single nucleotide polymorphisms (SNPs) in the kappa and delta opioid receptor (OPRK1 and OPRD1) genes may contribute to naltrexone pharmacogenetics. Therefore, the goal of this exploratory study was to re-examine data from a double-blind placebo controlled laboratory trial of naltrexone for pharmacogenetic effects at kappa and delta opioid receptor tag SNPs. Participants were 40 heavy drinkers (12 female) who underwent an intravenous alcohol challenge paradigm after receiving naltrexone (50mg) or placebo in randomized and crossover fashion. Dependent variables were self-reported alcohol-induced stimulation, sedation, and craving. Multilevel models revealed a significant Naltrexone×OPRK1 Genotype (rs997917) interaction predicting alcohol-induced sedation, such that TT homozygotes reported lower naltrexone-induced alcohol sedation as compared to carriers of the C allele. Moreover, there was a significant Naltrexone×OPRD1 Genotype (rs4654327) interaction predicting alcohol-induced stimulation and craving, such that carriers of the A allele at this locus reported greater naltrexone-induced blunting of alcohol stimulation and alcohol craving compared to GG homozygotes. These findings suggest that additional pharmacogenetic effects in the opioid receptor system may account for individual differences in response to naltrexone in the human laboratory.

The alcohol-induced locomotor stimulation and accumbal dopamine release is suppressed in ghrelin knockout mice

Ghrelin, the first endogenous ligand for the type 1A growth hormone secretagogue receptor (GHS-R1A), plays a role in energy balance, feeding behavior, and reward. Previously, we showed that pharmacologic and genetic suppression of the GHS-R1A attenuates the alcohol-induced stimulation, accumbal dopamine release, and conditioned place preference as well as alcohol consumption in mice, implying that the GHS-R1A is required for alcohol reward. The present study further elucidates the role of ghrelin for alcohol-induced dopamine release in nucleus accumbens and locomotor stimulation by means of ghrelin knockout mice. We found that the ability of alcohol to increase accumbal dopamine release in wild-type mice is not observed in ghrelin knockout mice. Furthermore, alcohol induced a locomotor stimulation in the wild-type mice and ghrelin knockout mice; however, the locomotor stimulation in homozygote mice was significantly lower than in the wild-type mice. The present series of experiments suggest that endogenous ghrelin may be required for the ability of alcohol to activate the mesolimbic dopamine system.

Effects of Naltrexone During the Descending Limb of the Blood Alcohol Curve

The neuropharmacological effects of alcohol are known to vary by limb of the blood alcohol curve, yet human laboratory studies of alcoholism pharmacotherapies have largely failed to consider limb of intoxication when examining medication effects on subjective responses to alcohol. This study examined the effects of naltrexone compared to placebo on subjective responses to alcohol at the descending limb of the blood alcohol curve following a controlled intravenous (IV) alcohol administration. Non-treatment-seeking hazardous drinkers (n = 38) completed two double-blind counterbalanced IV alcohol challenge sessions, one after taking naltrexone (50 mg) for three days and one after taking a placebo for three days. During each session, participants reported on subjective responses to alcohol during the descending limb of the blood alcohol curve. Analyses revealed significant main effects of naltrexone, reflecting significantly decreased alcohol-induced stimulation, craving, vigor, positive mood, and alcohol "high" and increased tension as compared to placebo. These findings suggest that naltrexone may exert some of its therapeutic effects via alterations to experiential aspects of intoxication during the descending limb of alcohol intoxication. Additionally, these results highlight the potential utility of considering limb of blood alcohol curve when examining the mechanisms of action of pharmacotherapies thought to alter subjective responses to alcohol.

Association of a Functional Polymorphism in the μ-Opioid Receptor Gene With Alcohol Response and Consumption in Male Rhesus Macaques

Innate differences in opioid neurotransmission are hypothesized to influence abuse liability of alcohol. In humans, a variant of the mu-opioid receptor gene (OPRM1A118G) increases receptor affinity, alcohol-induced euphoria, and risk for alcohol use disorders. To determine whether a variant in the mu-opioid receptor gene (OPRM1C77G) that increases affinity of the receptor is associated with alcohol response and consumption in macaques. Young adult rhesus macaques (Macaca mulatta) were intravenously administered 2.0 to 2.1 g of ethanol per kilogram of body weight and assessed for alcohol response. Animals were later given simultaneous access to an aspartame-sweetened 8.4% (vol/vol) ethanol solution and a vehicle for 1 hour per day, 5 days a week, for a period of 6 weeks. Animals (N = 82) were genotyped for the OPRM1C77G polymorphism; the effects of the genotype on alcohol response and consumption were determined by analysis of variance, with sex included as a nominal independent variable. Alcohol response (ataxia, stimulation, and sedation), average alcohol consumption, the percentage of days during which an animal consumed alcohol at a level sufficient to produce intoxication (> or =0.67 g of alcohol per kilogram of body weight), and alcohol preference (calculated as 100 x {alcoholic solution/[alcoholic solution + nonalcoholic solution]}). Increased alcohol-induced stimulation was observed among male macaques carrying the OPRM1C77G allele. OPRM1C77G allele carriers consumed more ethanol and exhibited increased ethanol preference. Male carriers of the OPRM1C77G allele exhibited higher alcohol preference and consumption, and drank to intoxication more frequently than did C/C males. These findings demonstrate that the rhesus macaques' equivalent of the OPRM1A118G variant is associated with increased alcohol response, consumption, and preference. Our results reveal effects of the OPRM1C77G genotype to be male-restricted or more marked among male macaques. This is of interest, given the fact that early-onset type II alcoholism is more common among men and that, among addicted individuals, men are more responsive to mu-opioid receptor blockade.

Modulation of morphine and alcohol motor stimulant effects by cannabinoid receptors ligands

Previous studies evidenced in rats the suppression by cannabinoids of motor stimulant effects of various drugs of abuse. Here we investigated, in mice, the effects of an acute or a chronic administration with the cannabinoid agonist HU 210 on the motor stimulant effects of either morphine or alcohol. HU 210 (12.5–200 μg/kg), when acutely administered, antagonized the stimulant effects of morphine (7.5 mg/kg) or alcohol (1 or 1.5 g/kg). A tolerance to this antagonistic interaction with morphine and alcohol occurred after a 7-day or a 14-day HU 210 treatment, leading to the reappearance of morphine- and alcohol-induced stimulation. The CB 1 receptor antagonist rimonabant (10 mg/kg) enhanced the stimulant effect induced by low doses of morphine (5 or 7.5 mg/kg). Rimonabant (3 or 10 mg/kg) altered the locomotor effect of alcohol in a biphasic manner. It enhanced the stimulant effect of low doses of alcohol (1 or 1.5 g/kg) while decreasing the locomotor activity of mice treated with a high dose (3 g/kg) of alcohol. Furthermore, rimonabant (3 and 10 mg/kg) enhanced the duration of alcohol-induced loss of righting reflex (4 g/kg), suggesting a dual implication of cannabinoidergic pathways in acute effects of alcohol.

Dopamine and Benzodiazepine-Dependent Mechanisms Regulate the EtOH-Enhanced Locomotor Stimulation in the GABAA α1 Subunit Null Mutant Mice

The present study investigated the role of the alpha1-containing GABA(A) receptors in the neurobehavioral actions of alcohol. In Experiment 1, mice lacking the alpha1 subunit (alpha1 (-/-)) were tested for their capacity to initiate operant-lever press responding for alcohol or sucrose. Alcohol intake in the home cage was also measured. In Experiment 2, the alpha1 (-/-) mice were injected with a range of alcohol doses (0.875-4.0 g/kg; i.p.) to evaluate the significance of the alpha1 subunit in alcohol's stimulant actions. In Experiment 3, we determined if the alcohol-induced stimulant effects were regulated via dopaminergic (DA) or benzodiazepine (BDZ)-dependent mechanisms. To accomplish this, we investigated the capacity of DA (eticlopride, SCH 23390) and BDZ (flumazenil, betaCCt) receptor antagonists to attenuate the alcohol-induced stimulant actions. Compared with wild-type mice (alpha1 (+/+)), the null mutants showed marked reductions in both EtOH and sucrose-maintained responding, and home-cage alcohol drinking. The null mutants also showed significant increases in locomotor behaviors after injections of low-moderate alcohol doses (1.75-3.0 g/kg). betaCCt, flumazenil, eticlopride, and SCH 23390 were able to attenuate the alcohol-induced stimulation in mutant mice, in the absence of intrinsic effects. These data suggest the alpha1 receptor plays an important role in alcohol-motivated behaviors; however, it also appears crucial in regulating the reinforcing properties associated with normal ingestive behaviors. Deleting the alpha1 subunit of the GABA(A) receptor appears to unmask alcohol's stimulatory effects; these effects appear to be regulated via an interaction of both DA- and GABA(A) BDZ-dependent mechanisms.

GENOTYPE EFFECTS ON NEURODEGENERATION AND NEUROADAPTATION IN MONOAMINERGIC NEUROTRANSMITTER SYSTEMS.

Neuroadaptation and neurodegeneration in central dopaminergic and serotonergic systems are central to vulnerability, process and consequences of addictive behavior. Serotonergic dysfunction has been associated with behavior disinhibition and negative mood states that may predispose to excessive alcohol intake, while alcohol-induced stimulation of dopaminergic neurotransmission may encode the reinforcing properties of alcohol consumption. Chronic alcohol intake induces neuroadaptive reductions in striatal dopamine transporter (DAT) and D2 receptor availability, which were reversible during early abstinence. A polymorphism of the DAT gene (SLC6A3) was associated with the in vivo transporter availability in the putamen of abstinent alcoholics and control subjects. The same genotype was associated with severity of alcohol withdrawal symptoms, hypothetically due to interactions of genotype and alcohol-induced neuroadaptation. Reduction in raphe serotonin transporter (5-HTT) availability was observed in abstinent male alcoholics and it may be the result of neurodegeneration rather than reversible neuroadaptation. Neurotoxic reduction in 5-HTT protein expression seems to be limited to homozygous carriers of a long, more transcriptionally active allele of a promoter repeat polymorphism of the 5-HTT gene (SCL6A4). This genotype was also associated with a low level of acute unpleasant effects of alcohol consumption, a factor predisposing to excessive alcohol intake. The time course of neuroadaptation and recovery of monoaminergic neurotransmission in alcohol intake and withdrawal imply that monoamine transporter genotype could profoundly influence alcohol-induced reinforcement and, perhaps, contribute to neurochemical changes which are long lasting or permanent.

Genotype effects on neurodegeneration and neuroadaptation in monoaminergic neurotransmitter systems

Neuroadaptation and neurodegeneration in central dopaminergic and serotonergic systems are central to vulnerability, process and consequences of addictive behavior. Serotonergic dysfunction has been associated with behavior disinhibition and negative mood states that may predispose to excessive alcohol intake, while alcohol-induced stimulation of dopaminergic neurotransmission may encode the reinforcing properties of alcohol consumption. Chronic alcohol intake induces neuroadaptive reductions in striatal dopamine transporter (DAT) and D2 receptor availability, which were reversible during early abstinence. A polymorphism of the DAT gene (SLC6A3) was associated with the in vivo transporter availability in the putamen of abstinent alcoholics and control subjects. The same genotype was associated with severity of alcohol withdrawal symptoms, hypothetically due to interactions of genotype and alcohol-induced neuroadaptation. Reduction in raphe serotonin transporter (5-HTT) availability was observed in abstinent male alcoholics and it may be the result of neurodegeneration rather than reversible neuroadaptation. Neurotoxic reduction in 5-HTT protein expression seems to be limited to homozygous carriers of a long, more transcriptionally active allele of a promoter repeat polymorphism of the 5-HTT gene (SCL6A4). This genotype was also associated with a low level of acute unpleasant effects of alcohol consumption, a factor predisposing to excessive alcohol intake. The time course of neuroadaptation and recovery of monoaminergic neurotransmission in alcohol intake and withdrawal imply that monoamine transporter genotype could profoundly influence alcohol-induced reinforcement and, perhaps, contribute to neurochemical changes which are long lasting or permanent.

Effects of Propranolol on Cardiovascular and Neurohumoral Actions of Alcohol in Hypertensive Patients

Alcohol ingestion acutely lowers blood pressure (BP) with vasodilation and sympathetic activation in Oriental subjects. We examined the effects of beta blockade on cardiovascular and neurohumoral actions of alcohol in Japanese men with mild-to-moderate essential hypertension. Ten hypertensive patients (54+/-5 years, mean+/-SE) were given 1 ml/kg of alcohol or isocaloric control drink with a light meal in the evening before and 5-7 days after treatment with propranolol (20 mg three times daily). BP and heart rate (HR) were measured every 30 min for 24 h in each period. Blood sampling and echocardiographic examination were carried out before (17.00 h) and after (19.00 h) intake of alcohol or control drink, Before treatment, alcohol ingestion caused significant decreases in BP, total peripheral resistance and serum potassium concentration, while it increased heart rate (HR), cardiac output (CO), plasma norepinephrine and plasma renin activity (PRA). Treatment with propranolol significantly decreased BP and HR for 24 h. Propranolol and alcohol showed an additive depressor effect on night-time BP, and the alcohol-induced hypotension was similar before and after propranolol treatment. The alcohol-induced changes in HR, CO, PRA and serum potassium were significantly attenuated by propranolol. These results suggest that activation of the sympathetic nervous system plays a role in alcohol-induced cardiac stimulation, renin release and hypokalemia through beta receptors. Moderate doses of beta-blockers may not modify alcohol-induced BP reduction in Oriental subjects with hypertension.

Alcohol-Induced Stimulation and Sedation: Relation to Physical Aggression

The relation between the stimulating and the sedating effects of acute alcohol consumption on human physical aggression was examined. Sixty male social drinkers were assigned to either an alcohol or a sober group. Aggression was measured using a modified version of S. Taylor's (1967) aggression paradigm, in which electric shocks are received from and administered to a fictitious opponent during a competitive task. Aggression was operationalized as the intensity and the duration of the shocks selected. Stimulation and sedation were measured using a self-report inventory. Results demonstrated that stimulation was positively related to aggression, but only in the intoxicated state. Sedation was not related to aggression in either the intoxicated or the sober state.

Alcohol-preferring rats: Genetic sensitivity to alcohol-induced stimulation of dopamine metabolism

The effect of ethanol on brain dopamine (DA) metabolism in the caudate nucleus (CN), olfactory tubercle (OT) and medial prefrontal cortex (MPFC) was compared in two selectively bred rat lines, one ethanol preferring and the other ethanol nonpreferring. Male rats from the 16th and 17th generations of both lines that never experienced ethanol beforehand were used. No differences in the basal concentrations of DA and its metabolites, DOPAC and HVA, in the above brain regions were found between the two lines. The oral administration of 2 g/kg of ethanol to ethanol-nonpreferring rats increased DOPAC and HVA and reduced DA levels in the CN and OT but was ineffective in the MPFC. On the other hand, ethanol administration to ethanol-preferring rats decreased DA content and increased DOPAC and HVA levels, not only in the CN and OT, but also in the MPFC. Moreover, the changes induced by ethanol on DA metabolism in the latter group were significantly greater than in ethanol nonpreferring rats. These results indicate that ethanol preferring rats have a genetic high sensitivity to the ethanol effect on DA metabolism, and suggest that such a trait might play a role in ethanol preference.

Alcohol-induced stimulation of phospholipase C in human platelets requires G-protein activation.

In previous studies we have demonstrated that ethanol activates hormone-sensitive phospholipase C in intact human platelets, resulting in the mobilization of intracellular Ca2+ and platelet shape change. The present study aims to localize further this effect of ethanol by examining its interaction with the regulation of phospholipase C in a permeabilized cell system. In platelets permeabilized with a minimal concentration (18 micrograms/ml) of saponin, ethanol by itself did not activate phospholipase C. However, ethanol potentiated the activation of phospholipase C in response to the non-hydrolysable GTP analogue GTP[S] (guanosine 5'-[gamma-thio]triphosphate), an effect similar to that observed with thrombin. Ethanol also potentiated the response to fluoride, which acts directly on G-proteins. Other short-chain alcohols also stimulated phospholipase C in a synergistic manner with GTP[S]. The ability of specific alcohols to stimulate phospholipase C was directly related to their respective lipid-solubilities, as determined by their partition coefficients. Moreover, the potencies of each alcohol correlated with their ability to elicit Ca2+ mobilization and shape change in intact platelets. These effects of ethanol were eliminated by a disruption of receptor-phospholipase C coupling induced by the addition of higher concentrations of saponin. These data indicate that the activation of phospholipase C by ethanol may occur by affecting protein-protein interactions in the signal-transduction complex involving GTP-binding regulatory proteins.

Simultaneous mechanisms on exocrine pancreatic secretion initiated by alcohol in the conscious dog.

Modifications of pancreatic secretion induced by the infusion of alcohol were investigated in seven Thomas fistula dogs. Acute intravenous injections of low doses of alcohol induced a significant increase of all parameters of pancreatic secretion. On the contrary the acute intravenous injection of high doses of alcohol induced a significant decrease of pancreatic secretion. A prolonged-alcohol intravenous infusion producing a stable blood alcohol level provoked at first a decrease of pancreatic secretion, significant only for protein output, followed by a significant increase of all parameters of pancreatic secretion. A spontaneous return to prealcohol values of pancreatic secretion was observed in all cases even if the blood alcohol level remained high and stable and despite four hours of experimentation. Upon the background of a stable blood alcohol level, pentolinium did not suppress alcohol-induced stimulation of water and bicarbonate outputs but did abolish the postalcohol changes in protein secretion. Furthermore, atropine abolished all postalcohol changes in pancreatic secretion. Consequently, there are two responses (inhibition and stimulation) to alcohol which coexist in normal dogs. They are related to the blood alcohol levels and are transitory. These responses involve the vagus nerves. Alcohol appears to stimulate the exocrine pancreas through receptors at different levels of the nervous system.