Maintenance Of Alcohol Dependence Research Articles

Brain Reward System And Its Volumetric Investigations In Alcohol Addiction

IntroductionAlcohol use disorder (AUD) is a diagnosis that includes both addiction and abuse concepts that entered our lives with the DSM-5. The prevalence of AUD is 8.1% in men and 1.7% in women in Türkiye, and it is getting more and more common. Biopsychosocial factors play a role in the etiology of AUD.ObjectivesThe brain reward system, which includes many cortical and subcortical structures, plays an active role in the initiation and maintenance of alcohol dependence. In this study, we aimed to reveal the structural changes in alcohol dependence.Methods15 cases with AUD and 17 healthy controls were compared in terms of total white matter, total gray matter, nucleus accumbens, amygdala and hippocampus volumes. AUDIT, MAST and alcohol addiction severity scale were administered to all participants. Magnetic resonance imaging of all participants was performed. Then, the relevant regions were painted cross-sectionally and volume measurements were made. The case group was evaluated for the diagnosis of AUD with SCID-V. Volume averages were evaluated with Student’s t test. ANCOVA was used to remove confounding factors and re-evaluate the difference between volumes.ResultsAlthough there were differences between volumes in the first analyzes with Student’s t test, they were not statistically significant.Age and gender variables, which were determined by the literature to have an effect on volume measurements, were re-evaluated with the ANCOVA test. When the effects of age and gender variables were removed in the evaluation, the right hippocampus volume was found to be significantly reduced in the AUD group compared to the control group (F=5.26, p=0.03). Again, no significant difference was observed in the two groups in terms of areas other than the volume of the right hippocampus. Pearson correlation analysis was used to evaluate the relationship between scale scores, duration of alcohol use and amount taken, and volumetric measurements, but no statistically significant relationship was found.ConclusionsDifferent findings have been reported in the literature regarding the examined region volumes. Our study found volumetric changes consistent with most previous studies. For more generalizable results, studies with a large number of participants are needed.Disclosure of InterestNone Declared

Voluntary and forced exposure to ethanol vapor produces similar escalation of alcohol drinking but differential recruitment of brain regions related to stress, habit, and reward in male rats

A major limitation of the most widely used current animal models of alcohol dependence is that they use forced exposure to ethanol including ethanol-containing liquid diet and chronic intermittent ethanol (CIE) vapor to produce clinically relevant blood alcohol levels (BAL) and addiction-like behaviors. We recently developed a novel animal model of voluntary induction of alcohol dependence using ethanol vapor self-administration (EVSA). However, it is unknown whether EVSA leads to an escalation of alcohol drinking per se, and whether such escalation is associated with neuroadaptations in brain regions related to stress, reward, and habit. To address these issues, we compared the levels of alcohol drinking during withdrawal between rats passively exposed to alcohol (CIE) or voluntarily exposed to EVSA and measured the number of Fos+ neurons during acute withdrawal (16 h) in key brain regions important for stress, reward, and habit-related processes. CIE and EVSA rats exhibited similar BAL and similar escalation of alcohol drinking and motivation for alcohol during withdrawal. Acute withdrawal from EVSA and CIE recruited a similar number of Fos+ neurons in the Central Amygdala (CeA), however, acute withdrawal from EVSA recruited a higher number of Fos+ neurons in every other brain region analyzed compared to acute withdrawal from CIE. In summary, while the behavioral measures of alcohol dependence between the voluntary (EVSA) and passive (CIE) model were similar, the recruitment of neuronal ensembles during acute withdrawal was very different. The EVSA model may be particularly useful to unveil the neuronal networks and pharmacology responsible for the voluntary induction and maintenance of alcohol dependence and may improve translational studies by providing preclinical researchers with an animal model that highlights the volitional aspects of alcohol use disorder.

Assessing negative affect in mice during abstinence from alcohol drinking: Limitations and future challenges.

Alcohol use disorder (AUD) is frequently comorbid with mood disorders, and these co-occurring neuropsychiatric disorders contribute to the development and maintenance of alcohol dependence and relapse. In preclinical models, mice chronically exposed to alcohol display anxiety-like and depressive-like behaviors during acute withdrawal and protracted abstinence. However, in total, results from studies using voluntary alcohol-drinking paradigms show variable behavioral outcomes in assays measuring negative affective behaviors. Thus, the main objective of this review is to summarize the literature on the variability of negative affective behaviors in mice after chronic alcohol exposure. We compare the behavioral phenotypes that emerge during abstinence across different exposure models, including models of alcohol and stress interactions. The complicated outcomes from these studies highlight the difficulties of assessing negative affective behaviors in mouse models designed for the study of AUD. We discuss new behavioral assays, comprehensive platforms, and unbiased machine-learning algorithms as promising approaches to better understand the interaction between alcohol and negative affect in mice. New data-driven approaches in the understanding of mouse behavior hold promise for improving the identification of mechanisms, cell subtypes, and neurocircuits that mediate negative affect. In turn, improving our understanding of the neurobehavioral basis of alcohol-associated negative affect will provide a platform to test hypotheses in mouse models that aim to improve the development of more effective strategies for treating individuals with AUD and co-occurring mood disorders.

The association of plasma acyl ghrelin level with alcohol craving in early abstinent alcohol dependent patients

Background:Craving plays an important role in maintenance of alcohol dependence. Earlier studies have analyzed the role of ghrelin in craving and their results have been heterogenous. Acyl ghrelin is its more active form as it crosses the blood brain barrier. Hence we aimed to examine the relationship between plasma acyl ghrelin and craving in Indian patients having alcohol dependence syndrome.Methods:The present study was a hospital-based prospective study. A total of 60 drug-naive patients of alcohol dependence and 30 healthy controls were included. After taking informed consent fasting blood samples were collected from them on day 1 and tested for plasma acyl ghrelin level. Fasting blood samples were repeated in all cases on day 14. During this time, we also assessed the patients' cravings by obsessive compulsive drinking scale, and alcohol craving questionnaire; and withdrawal by clinical institute withdrawal assessment for alcohol scale. These scales were repeated on day 14. Data analysis was done by SPSS version 25.0.Results:Plasma concentrations of acyl ghrelin increased significantly during early abstinence in patients from day 1 to day 14 (P < 0.0001). Pearson correlation test revealed a trend of positive correlation between plasma concentration of acyl ghrelin on day 14 and severity of craving on day 1.Conclusion:Our results suggest the plasma concentration of acyl ghrelin may be a predictor of severity of alcohol craving during early abstinence. Anti-craving drugs acting on acyl ghrelin level in brain may open an innovative avenue for optimum treatment of alcohol dependence.

Bioinformatics identification and pharmacological validation of Kcnn3/KCa2 channels as a mediator of negative affective behaviors and excessive alcohol drinking in mice

Mood disorders are often comorbid with alcohol use disorder (AUD) and play a considerable role in the development and maintenance of alcohol dependence and relapse. Because of this high comorbidity, it is necessary to determine shared and unique genetic factors driving heavy drinking and negative affective behaviors. In order to identify novel pharmacogenetic targets, a bioinformatics analysis was used to quantify the expression of amygdala K+ channel genes that covary with anxiety-related phenotypes in the well-phenotyped and fully sequenced family of BXD strains. We used a model of stress-induced escalation of drinking in alcohol-dependent mice to measure negative affective behaviors during abstinence. A pharmacological approach was used to validate the key bioinformatics findings in alcohol-dependent, stressed mice. Amygdalar expression of Kcnn3 correlated significantly with 40 anxiety-associated phenotypes. Further examination of Kcnn3 expression revealed a strong eigentrait for anxiety-like behaviors and negative correlations with binge-like and voluntary alcohol drinking. Mice treated with chronic intermittent alcohol exposure and repeated swim stress consumed more alcohol in their home cages and showed hypophagia on the novelty-suppressed feeding test during abstinence. Pharmacologically targeting Kcnn gene products with the KCa2 (SK) channel-positive modulator 1-EBIO decreased drinking and reduced feeding latency in alcohol-dependent, stressed mice. Collectively, these validation studies provide central nervous system links into the covariance of stress, negative affective behaviors, and AUD in the BXD strains. Further, the bioinformatics discovery tool is effective in identifying promising targets (i.e., KCa2 channels) for treating alcohol dependence exacerbated by comorbid mood disorders.

Voluntary induction and maintenance of alcohol dependence in rats using alcohol vapor self-administration.

A major issue in the addiction field is the limited number of animal models of the voluntary induction and maintenance of alcohol dependence in outbred rats. To address this issue, we developed a novel apparatus that vaporizes alcohol for 2-10min after an active nosepoke response. Male Wistar rats were allowed to self-administer alcohol vapor for 8h/day every other day for 24 sessions (escalated) or eight sessions (non-escalated). Escalated and non-escalated rats were then tested for progressive ratio responding. Anxiety-like behavior, somatic signs of withdrawal, and hyperalgesia were assessed during acute withdrawal. The results showed that rats exhibited excellent discrimination between the active and inactive operanda (>85%), and the escalated rats quickly increased their blood alcohol levels from ~50 to >200mg% in ~6weeks. Compared with non-escalated rats, escalated rats exhibited severe addiction-like behavior, including somatic signs of withdrawal, anxiety-like behavior, hyperalgesia, and higher responding on a progressive ratio schedule of reinforcement. These results demonstrate that outbred rats will voluntarily self-administer alcohol vapor to the point of dependence without the use of forced alcohol administration, sweeteners, food/water restriction, operant pretraining, or behavioral/genetic selection. This novel animal model may be particularly useful for medication development to help unveil the neuronal circuitry that underlies the voluntary induction of alcohol addiction and identify novel molecular targets that are specifically recruited after the voluntary induction and maintenance of alcohol dependence.

Negative Association Between MR-Spectroscopic Glutamate Markers and Gray Matter Volume After Alcohol Withdrawal in the Hippocampus: A Translational Study in Humans and Rats.

Both chronic alcohol consumption and alcohol withdrawal lead to neural tissue damage which partly recovers during abstinence. This study investigated withdrawal-associated changes in glutamatergic compounds, markers of neuronal integrity, and gray matter volumes during acute alcohol withdrawal in the hippocampus, a key region in development and maintenance of alcohol dependence in humans and rats. Alcohol-dependent patients (N=39) underwent magnetic resonance imaging (MRI) and MR spectroscopy (MRS) measurements within 24hours after the last drink and after 2weeks of abstinence. MRI and MRS data of healthy controls (N=34) were acquired once. Our thorough quality criteria resulted in N=15 available spectra from the first and of N=21 from the second measurement in patients, and of N=19 from healthy controls. In a translational approach, chronic intermittent ethanol-exposed rats and respective controls (8/group) underwent 5 MRS measurements covering baseline, intoxication, 12 and 60hours of withdrawal, and 3weeks of abstinence. In both species, higher levels of markers of glutamatergic metabolism were associated with lower gray matter volumes in the hippocampus in early abstinence. Trends of reduced N-acetylaspartate levels during intoxication persisted in patients with severe alcohol withdrawal symptoms over 2weeks of abstinence. We observed a higher ratio of glutamate to glutamine during alcohol withdrawal in our animal model. Due to limited statistical power, we regard the results as preliminary and discuss them in the framework of the hypothesis of withdrawal-induced hyperglutamatergic neurotoxicity, alcohol-induced neural changes, and training-associated effects of abstinence on hippocampal tissue integrity.

Targeted intervention: Computational approaches to elucidate and predict relapse in alcoholism

Alcohol use disorder (AUD) and addiction in general is characterized by failures of choice resulting in repeated drug intake despite severe negative consequences. Behavioral change is hard to accomplish and relapse after detoxification is common and can be promoted by consumption of small amounts of alcohol as well as exposure to alcohol-associated cues or stress. While those environmental factors contributing to relapse have long been identified, the underlying psychological and neurobiological mechanism on which those factors act are to date incompletely understood. Based on the reinforcing effects of drugs of abuse, animal experiments showed that drug, cue and stress exposure affect Pavlovian and instrumental learning processes, which can increase salience of drug cues and promote habitual drug intake. In humans, computational approaches can help to quantify changes in key learning mechanisms during the development and maintenance of alcohol dependence, e.g. by using sequential decision making in combination with computational modeling to elucidate individual differences in model-free versus more complex, model-based learning strategies and their neurobiological correlates such as prediction error signaling in fronto-striatal circuits. Computational models can also help to explain how alcohol-associated cues trigger relapse: mechanisms such as Pavlovian-to-Instrumental Transfer can quantify to which degree Pavlovian conditioned stimuli can facilitate approach behavior including alcohol seeking and intake. By using generative models of behavioral and neural data, computational approaches can help to quantify individual differences in psychophysiological mechanisms that underlie the development and maintenance of AUD and thus promote targeted intervention.

Attentional alterations in alcohol dependence are underpinned by specific executive control deficits.

Attentional biases and deficits play a central role in the development and maintenance of alcohol dependence, but the underlying attentional processes accounting for these deficits have been very little explored. Importantly, the differential alterations across the 3 attentional networks (alerting, orienting, and executive control) remain unclear in this pathology. Thirty recently detoxified alcohol-dependent individuals and 30 paired controls completed the Attention Network Test, which allow exploring the attentional alterations specifically related to the 3 attentional networks. Alcohol-dependent individuals presented globally delayed reaction times compared to controls. More centrally, they showed a differential deficit across attention networks, with a preserved performance for alerting and orienting networks but impaired executive control (p < 0.001). This deficit was not related to psychopathological comorbidities but was positively correlated with the duration of alcohol-dependence habits, the number of previous detoxification treatments and the mean alcohol consumption before detoxification. These results suggest that attentional alterations in alcohol dependence are centrally due to a specific alteration of executive control. Intervention programs focusing on executive components of attention should be promoted, and these results support the frontal lobe hypothesis.

Towards a Crossmodal Exploration of Cognitive Deficits in Psychopathology

Face-voice integration has been extensively explored among healthy participants during the last decades. Nevertheless, while binding alterations constitute a core feature of many psychiatric diseases and have been thoroughly investigated in schizophrenia and autism, these crossmodal processes have been little explored in other psychiatric populations, and notably in addictions. As an illustration, alcohol-dependence is associated with a wide range of psychological, cognitive and cerebral consequences, among which affective disturbances hold a crucial position. Indeed, it has been shown during the last decade that alcohol-dependent individuals present important emotional impairments, particularly in the decoding of affective faces and voices. In view of the role they play in the development and maintenance of alcohol-dependence, it appears crucial to deepen the understanding of these deficits, and notably to determine their evolution in more ecological settings. Indeed, these decoding deficits have up to now been exclusively explored in unimodal studies (i.e. focusing on one sensorial modality) while in real life situations, emotional stimulations are most often multimodal. The central objective of the present paper is thus to present recent studies using an integrative approach combining behavioural, electrophysiological and neuroimaging techniques to explore the audio-visual integration of emotional stimuli in alcohol-dependence. These results, clearly showing that alcohol-dependence leads to altered crossmodal processing of affective faces and voices, constitute a first step towards a multidisciplinary exploration of crossmodal processing in psychiatry, extending to other stimulations, sensorial modalities and populations. Finally, the fundamental and clinical implications of this research perspective will also be underlined.

A Phase 2, Placebo-Controlled Study of the Opioid Receptor Antagonist LY2196044 for the Treatment of Alcohol Dependence

Endogenous opioid-mediated reward pathways may play a role in the development and maintenance of alcohol dependence. This study tested whether LY2196044, an opioid receptor antagonist, in combination with medical management would reduce drinking in alcohol-dependent patients. This was a multicenter, outpatient, randomized, double-blind, parallel, and placebo-controlled trial with a 16-week treatment period. Patients (N=375) were alcohol-dependent, treatment-seeking adults. Patients were randomly assigned to once-daily LY2196044 (final doses of 125 or 250mg/d) or placebo. DNA samples were collected at baseline. At each visit, patients underwent safety assessments, laboratory testing, efficacy measures, and medical management. Blood samples were also obtained for pharmacokinetic testing. The primary measure was the change from baseline in the percent heavy drinking days (HDD). Secondary efficacy measures were percent days abstinent per month and number of drinks per day. The treatment difference in change from baseline in % HDD between LY2196044 and placebo was not statistically significant (-43.02 vs. -38.72%, respectively; p=0.12). There was a trend toward greater change from baseline in the percent days abstinent per month for the LY2196044 group compared with the placebo group (33.49 vs. 28.12%, respectively; p=0.051). The decrease from baseline for mean number of drinks per day was statistically significantly greater in the LY2196044 group compared with the placebo group (-5.37 vs. -4.66drinks per day, respectively; p=0.013). LY2196044-treated patients who were dopamine receptor type 4-variable number tandem repeat L carriers had greater reductions in % HDD (p=0.0565), increased percent days abstinent (p=0.0496), and reduced drinks per day (p=0.0069) than placebo-treated L carriers. The safety profile for LY2196044 appeared similar to that of other opioid antagonists. The results from this proof-of-concept clinical trial warrant further evaluation of LY2196044 for the treatment of alcohol dependence.

Maladaptive Social Self-Beliefs in Alcohol-Dependence: A Specific Bias towards Excessive High Standards

BackgroundEmotional and interpersonal impairments associated with alcohol-dependence have been recently explored, but the distorted cognitive representations underlying these deficits remain poorly understood. The present study aims at exploring the presence of maladaptive social self-beliefs among alcohol-dependent individuals, as these biased self-beliefs have been recently shown to play a crucial role in the development and maintenance of other psychopathological states (social anxiety and depression).Methodology/Principal findingsTwenty-five recently detoxified alcohol-dependent participants and 25 matched controls filled in self-report questionnaires evaluating maladaptive social self-beliefs, interpersonal problems and several comorbid states (anxiety, social anxiety, depression). As compared to controls, alcohol-dependent individuals showed higher scores than controls for the three subcategories of maladaptive social self-beliefs (high standards, conditional beliefs and unconditional beliefs). Our key finding was that when comorbidities were controlled for, alcohol-dependence was associated with a specific bias towards exaggerated high standards in social contexts. Moreover, these high standards beliefs were strongly correlated with interpersonal problems.Conclusions/SignificanceThese results provide the first insights into the influence of cognitive biases on interpersonal problems in addictive states, and suggest that maladaptive self-beliefs could have a central influence on the development and maintenance of alcohol-dependence.

Experimental and clinical usefulness of crossmodal paradigms in psychiatry: an illustration from emotional processing in alcohol-dependence

Crossmodal processing (i.e., the construction of a unified representation stemming from distinct sensorial modalities inputs) constitutes a crucial ability in humans' everyday life. It has been extensively explored at cognitive and cerebral levels during the last decade among healthy controls. Paradoxically however, and while difficulties to perform this integrative process have been suggested in a large range of psychopathological states (e.g., schizophrenia and autism), these crossmodal paradigms have been very rarely used in the exploration of psychiatric populations. The main aim of the present paper is thus to underline the experimental and clinical usefulness of exploring crossmodal processes in psychiatry. We will illustrate this proposal by means of the recent data obtained in the crossmodal exploration of emotional alterations in alcohol-dependence. Indeed, emotional decoding impairments might have a role in the development and maintenance of alcohol-dependence, and have been extensively investigated by means of experiments using separated visual or auditory stimulations. Besides these unimodal explorations, we have recently conducted several studies using audio-visual crossmodal paradigms, which has allowed us to improve the ecological validity of the unimodal experimental designs and to offer new insights on the emotional alterations among alcohol-dependent individuals. We will show how these preliminary results can be extended to develop a coherent and ambitious research program using crossmodal designs in various psychiatric populations and sensory modalities. We will finally end the paper by underlining the various potential clinical applications and the fundamental implications that can be raised by this emerging project.

S23 * NEUROBIOLOGICAL ENDOPHENOTYPES IN ALCOHOL DEPENDENCE * S23.1 * GENETIC DETERMINANTS OF ALCOHOL ADDICTION: SEARCHING FOR AN ENDOPHENOTYPE ASSOCIATED WITH SWEET LIKING IN POPULATION OF FAMILIES WITH HISTORY OF ALCOHOL ADDICTION

S23 * NEUROBIOLOGICAL ENDOPHENOTYPES IN ALCOHOL DEPENDENCE * S23.1 * GENETIC DETERMINANTS OF ALCOHOL ADDICTION: SEARCHING FOR AN ENDOPHENOTYPE ASSOCIATED WITH SWEET LIKING IN POPULATION OF FAMILIES WITH HISTORY OF ALCOHOL ADDICTION

Mindfulness is Inversely Associated with Alcohol Attentional Bias Among Recovering Alcohol-Dependent Adults

Although mindfulness has been linked with salutary clinical outcomes, less is known about its relation to cognitive mechanisms implicated in the onset and maintenance of alcohol dependence. Because trait mindfulness is associated with attentional control and emotion regulation, we hypothesized that trait mindfulness would be inversely associated with attentional bias towards visual alcohol cues. We tested this hypothesis in a sample of alcohol-dependent adults residing in a treatment facility, who completed questionnaires on trait mindfulness, craving, and stress, as well as a spatial cueing task designed to assess alcohol attentional bias. Recovering alcohol-dependent individuals high in trait mindfulness exhibited less alcohol attentional bias (AB), stress, and craving, and greater alcohol-related self-efficacy, than their counterparts low in trait mindfulness. Multiple linear regression analyses indicated that trait mindfulness was more predictive of alcohol AB than stress, craving, alcohol-related self-efficacy, time in treatment, or pre-treatment level of alcohol consumption. Identification of malleable traits that can offset automatic cognitive mechanisms implicated in addiction may prove to be crucial to treatment development efforts.

Opioid modulators for alcohol dependence

Introduction: Studies have shown that opioid antagonists like naltrexone are efficient in reducing heavy drinking. The neurobiological mechanism by which opioid modulators affect drinking behavior is based on the strong connection between the endogenous opioid system, the dopamine system and the influence of the CNS stress response.Areas covered: This review provides an overview of the pathophysiological role of the opioid system in alcohol dependence and the neurobiological mechanisms of possible pharmacological interventions. An extensive Medline and Internet research was performed to retrieve information on existing and currently investigated opioid modulators. The findings were assessed critically and interpreted with regard to an individualized therapy for alcohol dependence.Expert opinion: The opioid system is of crucial importance in the genesis and maintenance of alcohol dependence. Naltrexone – and to a lesser extent nalmefene – is an agent that modulates opioidergic transmission in the CNS and it shows a limited but well-studied efficacy in treating alcohol dependence. Several agents (LY2196044, ALKS-29, ALKS-33) that are currently undergoing Phase II and Phase III studies are of interest but first their efficacy must be proved in clinical practice.

Stability of fMRI striatal response to alcohol cues: A hierarchical linear modeling approach

In functional magnetic resonance imaging (fMRI) studies of alcohol-dependent individuals, alcohol cues elicit activation of the ventral and dorsal aspects of the striatum (VS and DS), which are believed to underlie aspects of reward learning critical to the initiation and maintenance of alcohol dependence. Cue-elicited striatal activation may represent a biological substrate through which treatment efficacy may be measured. However, to be useful for this purpose, VS or DS activation must first demonstrate stability across time. Using hierarchical linear modeling (HLM), this study tested the stability of cue-elicited activation in anatomically and functionally defined regions of interest in bilateral VS and DS. Nine non-treatment-seeking alcohol-dependent participants twice completed an alcohol cue reactivity task during two fMRI scans separated by 14 days. HLM analyses demonstrated that, across all participants, alcohol cues elicited significant activation in each of the regions of interest. At the group level, these activations attenuated slightly between scans, but session-wise differences were not significant. Within-participants stability was best in the anatomically defined right VS and DS and in a functionally defined region that encompassed right caudate and putamen (intraclass correlation coefficients of .75, .81, and .76, respectively). Thus, within this small sample, alcohol cue-elicited fMRI activation had good reliability in the right striatum, though a larger sample is necessary to ensure generalizability and further evaluate stability. This study also demonstrates the utility of HLM analytic techniques for serial fMRI studies, in which separating within-participants variance (individual changes in activation) from between-participants factors (time or treatment) is critical.

Heart rate stress response dampening: The impact of alcohol, family history, and gender on at risk children and siblings

Objective In the following study we tested the stress response dampening (SRD) model which postulates that stress responses are more likely to be attenuated by alcohol in individuals at risk for alcohol dependence than in persons without that risk. In a laboratory experiment we examined a) if SRD effects exist for both sons and healthy daughters of alcohol dependent fathers, and b) if SRD effects exist for siblings of alcohol dependent males. Methods We recruited 104 subjects at risk and 51 matched control subjects. In a laboratory experiment, study subjects received alcohol in one of two laboratory sessions and a stress paradigm served to elicit heart rate stress responses. Results Heart rate stress responses were attenuated by alcohol in female family history positive (FHP) and female family history negative (FHN) subjects, however not in males. A multiple regression analysis revealed “Heart Rate Stress Response in the Non-Alcohol Condition” and “Blood Alcohol Level” as significant predictors of SRD. Conclusions According to our findings, females carry a distinct risk for developing alcohol dependence, regardless of their family history and regardless of their degree of familial relationship. This is an important issue for devising models concerning the development and maintenance of alcohol dependence in females. The study extends the current research literature, which mainly focuses on male subjects at risk, by including female subjects at risk, as well as siblings at risk of both genders.

Differentiating Heavy from Light Drinkers by Neural Responses to Visual Alcohol Cues and Other Motivational Stimuli

The course to alcohol dependence often starts with a preclinical period of heavy drinking. The present article reports functional magnetic resonance imaging data showing that even this pattern of alcohol consumption is associated with maladaptive neural responses to alcohol and other stimuli. When participants were confronted with visual cues related to alcohol, heavy drinkers showed amplified blood oxygen level-dependent signal responses in specific emotional areas (insular cortex) and in parts of the brain's reward circuitry (ventral striatum). This neuronal amplification was not present in light drinkers. Crucially, at the same time heavy drinkers showed reduced responses in frontal areas to pictures related to higher order life goals and in the cingulate cortex to appetitive food stimuli, suggesting that they have difficulty finding alternative, socially desirable goals. Using discriminant function analysis, we demonstrate that the combination of alcohol-related overactivation and underactivation to alternative goals allows heavy and light drinkers to be differentiated with a high degree of precision. Our findings highlight the diagnostic value of functional brain mapping of cue reactivity. Imaging measures may help to identify addictive dispositions in preclinical stages and to clarify the mechanisms that underlie the development and maintenance of alcohol dependence.

Medications Acting on the Dopaminergic System in the Treatment of Alcoholic Patients

An extensive literature supports the role of dopamine in the development and maintenance of alcohol dependence. Yet the organization of brain dopamine is complex, with multiple dopamine receptor subtypes and distinct effects on reinforcement, craving, motivation and behavior. Several modestly effective pharmacological treatments for alcoholism, including naltrexone, baclofen and ondansetron, affect dopaminergic systems indirectly. Direct dopamine antagonists, including tiapride, quetiapine, ondansetron and clozapine have been shown to be somewhat effective in reducing alcohol consumption in controlled clinical trials. The partial dopamine agonist, aripiprazole has shown mixed efficacy. Dopaminergic medications can have significant side effects. A better understanding of how dopamine affects the various aspects of addictive behavior may lead to more effective medications.