raclopride and Alcoholism

It appears clear that ethanol reinforcement, like that of many abused drugs, utilizes the mesolimbic DA pathways. From the data presented on microinjection of DA agonists and antagonists, it would seem that only part of the regulatory process controlling ethanol drinking is directly involved with this pathway. Once drinking has begun, the DA antagonist raclopride results in a rapid termination of drinking. This appears to be a blocking effect of what may be conditioned reinforcement resulting from prior ethanol reinforcement initiation procedures. Microinjection of the DA agonists d-amphetamine and quinpirole prolonged drinking, with little signs of normal termination apparent in the 30-min session in many animals. This appeared to be the result of interference with normal termination processes. While it remains to be demonstrated that oral ethanol consumption results in the release of DA in the nucleus accumbens, evidence from prior work and the present studies support a role for the mesolimbic DA system in ethanol reinforcement.

Topics: Alcoholism; Animals; Dextroamphetamine; Dopamine; Dopamine Agents; Dopamine Antagonists; Ergolines; Ethanol; Limbic System; Microinjections; Nucleus Accumbens; Quinpirole; Raclopride; Rats; Receptors, Dopamine; Salicylamides; Self Administration

Excessive alcohol use, a major cause of morbidity and mortality, is less well understood than other addictive disorders. Dopamine release in ventral striatum is a common element of drug reward, but alcohol has an unusually complex pharmacology, and humans vary greatly in their alcohol responses. This variation is related to genetic susceptibility for alcoholism, which contributes more than half of alcoholism risk. Here, we report that a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and [(11)C]-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. To directly establish the causal role of OPRM1 A118G variation, we generated two humanized mouse lines, carrying the respective human sequence variant. Brain microdialysis showed a fourfold greater peak dopamine response to an alcohol challenge in h/mOPRM1-118GG than in h/mOPRM1-118AA mice. OPRM1 A118G variation is a genetic determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward.

Topics: Adult; Alcoholism; Alleles; Animals; Corpus Striatum; Dopamine; Ethanol; Genetic Predisposition to Disease; Genetic Variation; Genotype; Heterozygote; Humans; Male; Mice; Mice, Transgenic; Middle Aged; Positron-Emission Tomography; Raclopride; Receptors, Opioid, mu

Imaging studies in patients with Type II alcohol dependence have revealed significant reductions in dopamine (DA) D2 receptor availability. Here we assessed the effects of alcohol detoxification in DA D2 receptors in alcoholic subjects. We evaluated 14 patients with Type II alcohol dependence tested within 6 weeks of detoxification and then re-tested 1-4 months later while alcohol free. The comparison group comprised 11 healthy controls. PET was used with [11C]raclopride to measure DA D2 receptors. Eight alcoholics and all control subjects were tested with a CTI 931 PET scanner and six alcoholics with a Siemens HR+ PET scanner. Data were analyzed separately for the studies done in the different scanners. Comparisons between early and late alcohol detoxification showed no significant changes in DA D2 receptor availability (B(max)/K(d)) for the studies done with the CTI and the HR+ scanners. Comparison with controls showed lower DA D2 receptor levels in caudate and putamen in alcoholics tested during early detoxification and in caudate during late detoxification. These studies replicate previous findings of lower striatal DA D2 receptors in alcoholics than in controls and absence of significant recovery during alcohol detoxification. These findings suggest that low DA D2 receptor availability in alcoholics is not due to alcohol withdrawal and may reflect a predisposing factor.

Topics: Adult; Alcoholism; Brain; Dopamine Antagonists; Female; Humans; Inactivation, Metabolic; Male; Raclopride; Receptors, Dopamine D2; Tomography, Emission-Computed

Striatal D2 dopamine receptor characteristics of nine male patients with alcohol dependence abstinent for 1-68 weeks and eight healthy male volunteers were studied in vivo with positron emission tomography. The selective D2 receptor ligand [11C]raclopride and equilibrium model was used for D2 receptor density (Bmax) and affinity (Kd) measurements. A trend for a decreased striatal D2 receptor density and for reduced D2 receptor affinity was observed in patients with alcohol dependence. These parameters were not statistically significantly different between alcoholics and controls, but the ratio between D2 receptor density and affinity (Bmax/Kd or the striatum/cerebellum ratio from the high specific activity scan) was highly significantly lower in alcoholics than that of controls. In conclusion, the low D2 dopamine receptor Bmax/Kd ratio (striatum/cerebellum ratio) indicates that specific aspects of striatal [11C]raclopride binding in vivo are deviant in alcoholics compared to controls. The result is compatible with a reduced avidity of striatal dopamine D2 receptors in alcoholics, which is in line with the idea that D2 dopaminergic mechanisms are involved in the biology of alcohol dependence in man.

Topics: Adult; Alcoholism; Dopamine Antagonists; Humans; Male; Neostriatum; Raclopride; Receptors, Dopamine D2; Salicylamides; Tomography, Emission-Computed; Tomography, X-Ray Computed

Whereas striatal dopamine D2 receptor (D2R) availability has shown to be altered in individuals with alcohol use disorder (AUD) and in healthy individuals with a family history of AUD, the role of D2R in the development of AUD is unknown. In this positron emission tomography (PET) study, we measured whether D2R availability is associated with subsequent alcohol use and alcohol-related factors, at a follow-up 8 to 16 years post-PET scan, in social drinkers.. Longitudinal study investigating the association between PET data and later self-report measures in healthy individuals.. Academic research imaging centre in Stockholm, Sweden.. There were 71 individuals (68 of whom had evaluable PET data, 5 females, 42.0 years mean age) from a series of previous PET studies.. One PET examination with the D2R antagonist radioligand [. We found no evidence for an association between D2R availability and later alcohol use (B = -0.019, B 95% CI = -0.043 to -0.006, P = 0.147) nor for the majority of the alcohol-related factors (B 95% CI = -0.034 to 0.004, P = 0.273-0.288). A negative association with a small effect size was found between D2R availability and later impulsivity (B = -0.017, B 95% CI = -0.034 to -0.001, P = 0.046).. Low striatal dopamine D2 receptor availability may not be a strong predictor in the development of alcohol use disorder.

Topics: Adult; Alcohol Drinking; Alcoholism; Corpus Striatum; Dopamine D2 Receptor Antagonists; Ethanol; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3

Dopamine receptor concentrations, primarily in the striatum, are hypothesized to contribute to a developmental imbalance between subcortical and prefrontal control systems in emerging adulthood potentially biasing motivation and increasing risky behaviors. Positron emission tomography studies have found significant reductions in striatal dopamine D2 receptors, and blunted amphetamine-induced dopamine release, in substance users compared with healthy controls. Extant literature is limited and inconsistent concerning vulnerability associated with having a family history of substance abuse (FH+). Some studies have reported familial liability associated with higher dopamine receptor levels, reduced dopamine response to stimulant challenges and decreased response to oral alcohol. However, other reports have failed to find group differences based on family history. We explored the interaction of familial liability and behavioral risk with multi-modal molecular and neural imaging of the dopaminergic system. Forty-four young adult male subjects performed monetary incentive delay tasks during both [

Topics: Adolescent; Adult; Age of Onset; Alcoholic Intoxication; Alcoholism; Child of Impaired Parents; Delay Discounting; Dopamine; Dopamine Antagonists; Feedback; Functional Neuroimaging; Humans; Magnetic Resonance Imaging; Male; Neostriatum; Nucleus Accumbens; Positron-Emission Tomography; Raclopride; Reward; Risk; Ventral Striatum; Young Adult

Striatal dopamine (DA) has been implicated in alcohol use disorders, but it is still unclear whether or not alcohol can induce dopamine release in social drinkers. Furthermore, no data exist on dopamine responses to alcohol in dependent drinkers. We sought to characterize the DA responses to alcohol intoxication in moderately large samples of social drinkers (SD) and nontreatment-seeking alcoholics (NTS).. Twenty-four SD and twenty-one NTS received two [(11)C]raclopride (RAC) PET scans; one at rest, and one during an intravenous alcohol infusion, with a prescribed ascent to a target breath alcohol concentration (BrAC), at which it was then "clamped." The alcohol clamp was started 5min after scan start, with a linear increase in BrAC over 15min to the target of 80mg%, the legal threshold for intoxication. Target BrAC was maintained for 30min. Voxel-wise binding potential (BPND) was estimated with MRTM2.. IV EtOH induced significant increases in DA in the right ventral striatum in NTS, but not SD. No decreases in DA were observed in either group.. Alcohol intoxication results in distinct anatomic profiles of DA responses in SD and NTS, suggesting that in NTS, the striatal DA system may process effects of alcohol intoxication differently than in SD.

Topics: Administration, Intravenous; Adult; Alcohol Drinking; Alcoholic Intoxication; Alcoholism; Breath Tests; Central Nervous System Depressants; Dopamine; Ethanol; Female; Humans; Male; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Ventral Striatum

Dopamine signals through D1-like and D2-like receptors, which can stimulate or inhibit, respectively, neuronal activity. Here we assessed the balance between D1 or D2 receptor signaling in the human brain and how it is affected in alcoholism. Using PET, we measured the relationship between changes in dopamine and brain glucose metabolism induced by methylphenidate in controls and alcoholics. We show that methylphenidate induced significant DA increases in striatum, amygdala, and medial orbitofrontal cortex, whereas it decreased metabolism in these brain regions. Methylphenidate-induced dopamine increases were greater in controls than in alcoholics, whereas methylphenidate-induced metabolic decreases were greater in alcoholics. For both groups, methylphenidate-induced dopamine increases were associated with decreases in regional brain metabolism, and the correlations were strongest in subthalamic nuclei, anterior cingulate, and medial orbitofrontal cortex. These correlations were more extensive and robust and the slopes steeper in alcoholics than in controls despite their attenuated dopamine responses to methylphenidate, which suggests an impaired modulation of dopamine signals in the brain of alcoholic subjects. These findings are consistent with a predominant inhibitory effect of dopamine in the human brain that is likely mediated by the prominence of dopamine D2/D3 receptors.

Topics: Adult; Alcoholism; Analysis of Variance; Brain; Brain Mapping; Carbon Radioisotopes; Cardiovascular Physiological Phenomena; Dopamine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Fluorodeoxyglucose F18; Humans; Male; Methylphenidate; Middle Aged; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Regression Analysis; Time Factors

Striatal dopamine (DA) is increased by virtually all drugs of abuse, including alcohol. However, drug-associated cues are also known to provoke striatal DA transmission- a phenomenon linked to the motivated behaviors associated with addiction. To our knowledge, no one has tested if alcohol's classically conditioned flavor cues, in the absence of a significant pharmacologic effect, are capable of eliciting striatal DA release in humans. Employing positron emission tomography (PET), we hypothesized that beer's flavor alone can reduce the binding potential (BP) of [(11)C]raclopride (RAC; a reflection of striatal DA release) in the ventral striatum, relative to an appetitive flavor control. Forty-nine men, ranging from social to heavy drinking, mean age 25, with a varied family history of alcoholism underwent two [(11)C]RAC PET scans: one while tasting beer, and one while tasting Gatorade. Relative to the control flavor of Gatorade, beer flavor significantly increased self-reported desire to drink, and reduced [(11)C]RAC BP, indicating that the alcohol-associated flavor cues induced DA release. BP reductions were strongest in subjects with first-degree alcoholic relatives. These results demonstrate that alcohol-conditioned flavor cues can provoke ventral striatal DA release, absent significant pharmacologic effects, and that the response is strongest in subjects with a greater genetic risk for alcoholism. Striatal DA responses to salient alcohol cues may thus be an inherited risk factor for alcoholism.

Topics: Adult; Alcoholism; Beer; Behavior, Addictive; Conditioning, Classical; Corpus Striatum; Cues; Dopamine; Dopamine Antagonists; Family Health; Functional Neuroimaging; Genetic Predisposition to Disease; Humans; Male; Raclopride

The classical dopamine D2 receptor has been widely studied in alcoholism. Recently, different studies have explored the role of the CB1 receptor in alcohol-related behavior. In alcohol addiction, relapse is one of the central features. In light of this, we investigated the functional roles of and interactions between CB1 and D2 receptors in alcohol relapse. We used the learned task of alcohol operant self-administration in Wistar rats. In order to evaluate alcohol relapse, we set up a protocol essentially based on the alcohol deprivation effect. We found that subchronic activation of CB1 (WIN 55,212-2, 2 mg/kg), but not D2 receptors (quinpirole, 1 mg/kg), during a period of alcohol deprivation increased long-lasting alcohol relapse. The cannabinoid-induced potentiation of alcohol relapse was mediated by a motivational and appetitive component, and not merely by alcohol consumption. This potentiation was prevented by the pharmacological inactivation of D2 receptors (raclopride, 0.1-0.3 mg/kg). Together, these results essentially demonstrate that activation of CB1 receptors plays a key role in the increase of alcohol relapse, whereas inactivation of D2 receptors modulates this aberrant behavior. We suggest that there exists a functional and interactive relationship between both receptor systems, which controls alcohol relapse and alcohol-learned tasks.

Topics: Alcoholism; Analgesics; Animals; Benzoxazines; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Male; Morpholines; Motivation; Naphthalenes; Quinpirole; Raclopride; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Dopamine D2; Recurrence; Self Administration; Substance Withdrawal Syndrome

The value of rewards (natural rewards and drugs) is associated with dopamine increases in the nucleus accumbens and varies as a function of context. The prefrontal cortex has been implicated in the context dependency of rewards and in the fixated high value that drugs have in addiction, although the mechanisms are not properly understood. Here we test the hypothesis that the prefrontal cortex regulates the value of rewards by modulating dopamine increases in nucleus accumbens and that this regulation is disrupted in addicted subjects. We used positron emission tomography to evaluate the activity of the prefrontal cortex (measuring brain glucose metabolism with [18F]fluorodeoxyglucose) and dopamine increases (measured with [11C]raclopride, a D2/D3 receptor ligand with binding that is sensitive to endogenous dopamine) induced by the stimulant drug methylphenidate in 20 controls and 20 detoxified alcoholics, most of whom smoked. In all subjects, methylphenidate significantly increased dopamine in striatum. In ventral striatum (where the nucleus accumbens is located) and in putamen, dopamine increases were associated with the rewarding effects of methylphenidate (drug liking and high) and were profoundly attenuated in alcoholics (70 and 50% lower than controls, respectively). In controls, but not in alcoholics, metabolism in orbitofrontal cortex (region involved with salience attribution) was negatively associated with methylphenidate-induced dopamine increases in ventral striatum. These results are consistent with the hypothesis that the orbitofrontal cortex modulates the value of rewards by regulating the magnitude of dopamine increases in the ventral striatum and that disruption of this regulation may underlie the decreased sensitivity to rewards in addicted subjects.

Topics: Adult; Alcohol-Induced Disorders, Nervous System; Alcoholism; Brain Chemistry; Central Nervous System Depressants; Corpus Striatum; Dopamine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Down-Regulation; Ethanol; Glucose; Humans; Male; Methylphenidate; Middle Aged; Neural Pathways; Positron-Emission Tomography; Prefrontal Cortex; Raclopride; Reward

Predisposition to alcoholism is likely an interaction between genetic and environmental factors that confer vulnerability and protection. Alcoholic subjects have low levels of dopamine D(2) receptors in striatum, and increasing D(2) receptor levels in laboratory animals reduces alcohol consumption.. To test whether high levels of D(2) receptors may be protective against alcoholism and whether this is mediated by their modulation of activity in orbitofrontal cortex and cingulate gyrus (regions involved in salience attribution, emotional reactivity, and inhibitory control).. Research (nonalcoholic subjects with a family history of alcoholism) and comparison (nonalcoholic subjects with a negative family history) sample.. Outpatient setting.. Fifteen nonalcoholic subjects who had an alcoholic father and at least 2 other first- or second-degree relatives who were alcoholics (family-positive group) and 16 nonalcoholic controls with no family history of alcoholism (family-negative group).. Results of positron emission tomography with raclopride C 11 to assess D(2) receptors and with fludeoxyglucose F 18 to assess brain glucose metabolism (marker of brain function). Personality measures were obtained with the Multidimensional Personality Questionnaire.. Availability of D(2) receptors was significantly higher in caudate and ventral striatum in family-positive than family-negative subjects. In family-positive but not family-negative subjects, striatal D(2) receptors were associated with metabolism in anterior cingulate (Brodmann area 24/25) and orbitofrontal (Brodmann area 11) and prefrontal (Brodmann area 9/10) cortices, and with personality scores of positive emotionality.. The higher-than-normal D(2) receptor availability in nonalcoholic members of alcoholic families supports the hypothesis that high levels of D(2) receptors may protect against alcoholism. The significant associations between D(2) receptors and metabolism in frontal regions involved with emotional reactivity and executive control suggest that high levels of D(2) receptors could protect against alcoholism by regulating circuits involved in inhibiting behavioral responses and in controlling emotions.

Topics: Adult; Alcoholism; Ambulatory Care; Basal Ganglia; Brain; Caudate Nucleus; Emotions; Family; Female; Fluorodeoxyglucose F18; Frontal Lobe; Genetic Predisposition to Disease; Glucose; Gyrus Cinguli; Humans; Male; Personality; Personality Assessment; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2

The mesolimbic dopaminergic system is thought to mediate alcohol abuse and dependence. Determining the relationship between in vivo dopamine and the subjective response to alcohol could improve understanding of the mechanisms that lead to alcohol abuse and dependence. Here, we examined the relationship between dopamine D2 receptors in the nucleus accumbens and scores of perceived "high" and "intoxication" during an intravenous (IV) alcohol infusion.. Nine healthy control subjects received [C]raclopride PET scanning at baseline. Eight subjects received a second [C]raclopride scan during a pharmacodynamically modeled and controlled rise of IV alcohol, followed by steady state (60 mg% +/- 5 mg%) alcohol infusion. Numerical ratings of "high" and "intoxication" were tested for correlations with measures of dopaminergic function.. Baseline D2 receptor availability in the left nucleus accumbens was significantly correlated with peak perceived "intoxication" (p = 0.02) and marginally correlated with peak perceived "high" (p = 0.07).. Resting D2 receptor availability may predict healthy subject responses to alcohol exposure.

Topics: Adult; Alcohol Drinking; Alcoholism; Calcium Radioisotopes; Dopamine; Emotions; Ethanol; Female; Functional Laterality; Humans; Infusions, Intravenous; Male; Nucleus Accumbens; Perception; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Surveys and Questionnaires

A decrease in dopamine type 2 receptors (D2) and mesolimbic dopamine transmission predisposes animals to consume alcohol. This study measured D2 receptors and dopamine transmission in human alcohol-dependent (AD) subjects using positron emission tomography (PET) and [11C]raclopride.. Fifteen AD and 15 healthy control (HC) subjects were scanned before and after a psychostimulant challenge (amphetamine .3 mg/kg intravenous). The outcome measures for baseline D2 receptor availability were binding potential (BP) and the equilibrium partition coefficient (V3''). Amphetamine-induced [11C]raclopride displacement was measured as the difference in V3'' between the two scans.. [11C]raclopride BP was significantly reduced by 16.6% in the limbic striatum, 19.2% in the associative striatum, and 21.3% in the sensorimotor striatum in AD subjects compared with HC. The alcohol-dependent subjects showed a blunting of amphetamine-induced dopamine release in the limbic striatum: [11C]raclopride displacement was -5.2% +/- 3.6% in AD subjects compared with -13.0% +/- 8.8% in HC. However, no significant difference in [11C]raclopride displacement was seen in the associative (-4.6% +/- 5.8% in AD subjects vs. -6.7 +/- 5.4% in HC) and sensorimotor (-12.3% +/- 7.3% in AD subjects vs. -13.7 +/- 7.5% in HC) subdivisions of the striatum between the two groups.. Alcohol dependence was associated with a decrease in D2 receptors in each striatal subdivision, whereas amphetamine-induced dopamine release was reduced in the limbic striatum only.

Topics: Adult; Alcoholism; Basal Ganglia; Carbon Radioisotopes; Dextroamphetamine; Dopamine; Female; Humans; Limbic System; Magnetic Resonance Imaging; Male; Middle Aged; Neural Inhibition; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Synaptic Transmission

The authors investigated whether striatal dopamine D2 receptor binding characteristics in vivo are similar in men and women and whether there are sex-related differences in the decline in D2 receptor density due to aging.. Striatal D2 receptor density (Bmax), affinity (Kd), and binding potential (Bmax/Kd) were measured with positron emission tomography and [11C]raclopride in 54 healthy subjects (33 men and 21 women).. Women had generally lower D2 receptor affinity than men, and this difference was statistically significant in the left striatum. Bmax and Bmax/Kd tended to decline with age twice as fast in men as in women, but the difference did not reach statistical significance.. These results confirm the age-related reduction of D2 receptor density and binding potential in both sexes in vivo. The lower D2 receptor affinity suggests an increased endogenous striatal dopamine concentration in women. This may have implications for the differential vulnerability of men and women to psychiatric disorders like schizophrenia and alcohol and substance dependence.

Topics: Adult; Aged; Aged, 80 and over; Aging; Alcoholism; Carbon Radioisotopes; Corpus Striatum; Female; Functional Laterality; Humans; Male; Menopause; Middle Aged; Raclopride; Radioligand Assay; Receptors, Dopamine; Salicylamides; Sex Factors; Tomography, Emission-Computed

It has been hypothesized that ethanol's actions on the dopamine (DA) system may participate in addiction. The purpose of this study was to evaluate the DA system in the brain of alcoholics. We evaluated 10 alcoholics and 17 nonalcoholics using positron emission tomography and [11C]raclopride to measure DA D2 receptors. In addition, in 5 of the alcoholics and 16 of the nonalcoholics, we also measured DA transporters with [11C]d-threo methylphenidate. The ratio of the distribution volumes in striatum to that in cerebellum, which corresponds to Bmax/Kd + 1, was used as model parameter of DA D2 receptor and transporter availability. Dopamine D2 receptor availability (Bmax/Kd) was significantly lower in alcoholics (2.1 +/- 0.5) than in nonalcoholics (2.7 +/- 0.6) (p < 0.05) and was not correlated with days since last alcohol use. Alcoholics showed DA transporter values similar to those in nonalcoholics. The ratio of DA D2 receptor to transporter availability was significantly higher in nonalcoholics (1.4 +/- 0.1) than in alcoholics (1.1 +/- 0.1) (p < 0.005). Alcoholics showed significant reductions in D2 receptors (postsynaptic marker) but not in DA transporter availability (presynaptic marker) when compared with nonalcoholics. Because D2 receptors in striatum are mainly localized in gamma-aminobutyric acid (GABA) cells these results provide evidence of GABAergic involvement in the dopaminergic abnormalities seen in alcoholics.

Topics: Adult; Alcohol Drinking; Alcoholism; Brain; Carbon Radioisotopes; Carrier Proteins; Corpus Striatum; Dopamine; Dopamine Plasma Membrane Transport Proteins; Ethanol; Female; gamma-Aminobutyric Acid; Humans; Male; Membrane Glycoproteins; Membrane Transport Proteins; Methylphenidate; Nerve Tissue Proteins; Raclopride; Receptors, Dopamine; Salicylamides; Tomography, Emission-Computed