Dopamine-modulated aversive emotion processing fails in alcohol-dependent patients.

Negative mood states after alcohol detoxification may enhance the relapse risk. As recently shown in healthy volunteers, dopamine storage capacity (V d) in the left amygdala was positively correlated with functional activation in the left amygdala and anterior cingulate cortex (ACC) during an emotional task; high functional connectivity between the amygdala and the ACC, a region important for emotion regulation, was associated with low trait anxiety. Based on these findings, we now tested whether detoxified alcohol-dependent patients have a disrupted modulation of the anterior cingulate cortex activation in response to aversive stimuli by amygdala dopamine. Furthermore, we asked whether disrupted functional coupling between amygdala and ACC during aversive processing is related to trait anxiety.We used combined 6-[18F]-fluoro-l-DOPA positron emission tomography (PET), functional magnetic resonance imaging (fMRI) and Spielberger's state-trait anxiety questionnaire (STAI) in 11 male detoxified alcohol-dependent patients compared to 13 matched healthy controls.Unlike healthy controls, patients showed no significant correlation between our PET metric for dopamine storage capacity (FDOPA V d), in left amygdala and activation in left ACC. Moreover, the functional connectivity between amygdala and ACC during processing of aversive emotional stimuli was reduced in patients. Voxel-based morphometry did not reveal any discernible group differences in amygdala volume.These results suggest that dopamine-modulated corticolimbic circuit function is important for responding to emotional information such that apparent functional deficits in this neuromodulatory circuitry may contribute to trait anxiety in alcohol-dependent patients.

Neurotransmitter systems in alcohol dependence.

An interplay of different neurotransmitter systems has been implicated in the development and maintenance of alcohol dependence. Here we focus on neuroadaptations in reward-related neurotransmitter systems and their impact on central processing of alcohol-associated and reward-indicating stimuli. We discuss genotype effects on cue-induced neuronal activation and present new computational methods based on machine learning to deal with complex genotype-phenotype interactions, e.g. between brain atrophy and genes associated with glutamatergic and dopaminergic neurotransmission.

Synergistic effects of the dopaminergic and glutamatergic system on hippocampal volume in alcohol-dependent patients.

Several genes of the dopaminergic and glutamatergic neurotransmitter systems have been found to be associated with alcohol disease and related intermediate phenotypes. Here, we evaluated genetic variants of the catechol-O-methyltransferase (COMT) and the metabotropic glutamate receptor 3 (mGluR3) genes in alcohol-dependent patients and their association with volumetric measurements of brain structures. By combined analysis of imaging data and genotyping results, large numbers of variables are produced that overstrain conventional statistical methods based on tests for group differences. Limitations in assessment of epistatic effects and multiple testing problems are encountered. Therefore, we introduce a novel method for detecting associations between a set of genetic markers and phenotypical measurements based on machine learning techniques. Hippocampal volume was found to be associated with epistatic effects of the COMT-mGluR3 genes in alcohol-dependent patients but not in controls. These data are in line with prior studies supporting a role for dopamine-glutamate interaction in modulation of alcohol disease.

[Aggressive and impulsive behavior: neurobiological models explain how affectregulation might work and social skills develop]. / Impulsives Verhalten, Aggressivität und Sucht: Umwelt oder Gene--wo liegt die Ursache?

A person's impulsive actions are characterized by a lack of sufficient planning or an assessment of possibly harmful consequences. An impulse control disorder can be diagnosed if such actions occur frequently, even in low-stress situations. In psychiatry there are a number of syndromes that are associated with an impulse control disorder. Neurobiological findings point to a reduced turnover of serotonin in the brain of persons with an impulse control disorder and aggressive behaviour. However, a reduced turnover of serotonin is also found in persons who can consume immoderate amounts of alcohol but who experience no such unpleasant effects and thus have a high risk of becoming dependent. The serotonin turnover of an individual is controlled by environmental influences in interaction with genetic factors. In this article, impulse control disorders will be discussed with regard to their origin and social effects.

Development of alcohol-associated cues and cue-induced brain activation in alcoholics.

The objective of this study was to develop new standardized alcohol-associated cues and assess their effects on brain activation with functional magnetic resonance imaging (fMRI). Pictures of alcoholic and neutral beverages and affectively neutral pictures were presented to 44 abstinent alcoholics and 37 age-matched healthy control subjects. We assessed the skin conductance response, and the elicited arousal and valence. Alcoholics and control subjects did not differ in arousal, valence or skin conductance response evoked by alcohol-associated and affectively neutral stimuli, while nonalcoholic beverages were rated as more unpleasant and arousing by alcoholics compared with control subjects. In the fMRI pilot study, alcohol and abstract pictures were presented to six abstinent alcoholics and induced a significant activation of brain areas associated with visual emotional processes such as the fusiform gyrus, parts of the brain reward system (basal ganglia and orbitofrontal gyrus) and further brain regions in the frontal and parietal cortices associated with the attention network. These observations suggest that standardized pictures of alcoholic beverages can be used to assess brain circuits involved in the processing and evaluation of alcohol cues.

[Multimodal imaging with PET, fMRI and genetic research]. / Multimodale Bildgebung mit PET, fMRI und genetischen Untersuchungen.

Within the last decades, functional magnetic resonance imaging (fMRI) has widely replaced previously used methods such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) in the assessment of functional brain activation. However, PET and SPECT remain important tools for in vivo assessment of neurotransmitter receptors and transporters and for the assessment of baseline regional cerebral blood flow. PET and SPECT also provide a unique opportunity to directly quantify genotype effects on protein expression. We review current nuclear imaging techniques for quantification of genotype effects on neurotransmitter receptors and transporters. Furthermore, we describe first multimodal imaging studies that combined PET, fMRI and genetic data in order to measure effects of genotype or the availability of receptor or transporters on functional brain activation. The clinical relevance of these studies will be illustrated and discussed.

[Neurobiology of substance-related addiction: findings of neuroimaging]. / Neurobiologie stoffgebundener Abhängigkeitserkrankungen - Befunde bildgebender Verfahren.

Neuroimaging provides insight into the main biological mechanisms underlying drug and alcohol dependence. Cardinal symptoms of drug dependence are the development of tolerance against drug effects, withdrawal symptoms, drug craving, reduced control over drug intake and harmful consequences of drug consumption. Brain imaging studies support the hypothesis that tolerance development can be understood as a neuroadaptive mechanism to ensure homeostasis during chronic drug intake. When drug consumption is suddenly interrupted during detoxification, the loss of homeostasis can manifest as a withdrawal syndrome. While tolerance development reduces the effects of chronic drug intake, sensitization is a neuroadaptive process that increases the effects of a drug dose. Brain imaging studies indicate that sensitisation and drug craving are associated with neuroadaptive processes in the brain reward system. Harmful consequences of drug intake include neurotoxic effects on the central nervous system. Besides discussing brain imaging studies on the neurobiological correlates of drug dependence, this review also presents studies on vulnerability factors that predispose individuals to excessive drug intake.

[Alcohol-related disorders: etiopathology and therapeutic considerations]. / Alkoholbedingte störungen - ätiopathogenese und therapeutischer ausblick.

The scientific understanding of the neurobiological priniciples of alcoholism has made significant progress in recent years. Especially the effects of ethanol on the neurotransmitter-systems are well studied. Dopaminergic and GABAergic facilitation contribute to the stimulating effects of low doses of alcohol while many of its adverse effects are mediated by glutamatergic inhibition at higher doses. A reduced serotonine-metabolism was shown to be a risk factor for the development of an alcohol dependence. The historic success of absinthe is discussed in this context. Absinthe is a mixture of ethanol and thujone, a substance that leads to a GABAergic inhibition as well as a reduced serotonergic responsiveness. Many studies substantiate the role of cannabinoid as well as striatal opiate-receptors in alcohol-related disorders. Neuroimaging studies could prove the important role of the reward system in this connection. Genetic factors were shown to be predisposing, however biological and environmental factors have a regulatory effect on the gene expression. Disturbances of the hpa-axis (hypothalamus-pituitary gland-adrenal cortex) were also shown to play a role in alcohol dependence. The understanding of these neurobiological principles of alcohol-related disorders should contribute to enhance and improve their therapeutic options.

Gene-gene effects on central processing of aversive stimuli.

Emotional reactivity and regulation are fundamental to human behavior. As inter-individual behavioral variation is affected by a multitude of different genes, there is intense interest to investigate gene-gene effects. Functional sequence variation at two genes has been associated with response and resiliency to emotionally unpleasant stimuli. These genes are the catechol-O-methyltransferase gene (COMT Val158Met) and the regulatory region (5-HTTLPR) of the serotonin transporter gene. Recently, it has been proposed that 5-HTT expression is not only affected by the common S/L variant of 5-HTTLPR but also by an A to G substitution. Using functional magnetic resonance imaging, we assessed the effects of COMT Val(158)Met and both 5-HTT genotypes on brain activation by standardized affective visual stimuli (unpleasant, pleasant, and neutral) in 48 healthy subjects. Based on previous studies, the analysis of genotype effects was restricted to limbic brain areas. To determine allele-dose effects, the number of COMT Met158 alleles (i.e., lower activity of COMT) and the number of 5-HTT low expressing alleles (S and G) was correlated with the blood oxygen level-dependent (BOLD) response to pleasant or unpleasant stimuli compared to neutral stimuli. We observed an additive effect of COMT and both 5-HTT polymorphisms, accounting for 40% of the inter-individual variance in the averaged BOLD response of amygdala, hippocampal and limbic cortical regions elicited by unpleasant stimuli. Effects of 5-HTT and COMT genotypes did not affect brain processing of pleasant stimuli. These data indicate that functional brain imaging may be used to assess the interaction of multiple genes on the function of neuronal networks.

Midbrain serotonin transporter binding potential measured with [11C]DASB is affected by serotonin transporter genotype.

BACKGROUND: Homozygote carriers of two long (L) alleles of the serotonin transporter (5-HTT) regulatory region displayed in vitro a twofold increase in 5-HTT expression compared with carriers of one or two short (S) alleles. However, in vivo imaging studies yielded contradictory results. Recently, an A > G exchange leading to differential transcriptional activation of 5-HTT mRNA in lymphobalstoid cell lines was discovered in the 5-HTT regulatory region. In vitro and in vivo evidence suggests that [(11)C]DASB, a new 5-HTT ligand offers some advantages over the ligands used in previous studies in measuring 5-HTT density independent of synaptic levels of serotonin. METHOD: We assessed 5-HTT binding potential (BP (2)) in the midbrain of 19 healthy subjects with positron emission tomography and [(11)C]DASB. Accounting for the hypothesized functional similarity of L (G) and S in driving 5-HTT transcription, we assessed whether L (A) L (A) homozygotes display increased midbrain BP (2) compared with carriers of at least one S allele. RESULTS: BP (2) in the midbrain was significantly increased in L (A) L (A) homozygotes compared with carriers of at least one S allele. Interestingly, the genotype effect on the midbrain was significantly different from that on the thalamus and the amygdala where no group differences were detected. CONCLUSIONS: This in vivo study provides further evidence that subjects homozygous for the L (A) allele display increased expression of 5-HTT in the midbrain, the origin of central serotonergic projections.

[Cue-induced alcohol craving. Neurobiological correlates and clinical relevance]. / Reizinduziertes Alkoholverlangen. Grundlagen und klinische Bedeutung.

If there is no further intervention, relapse rates in detoxified alcoholics are high, up to 85%, even after complete remission of bodily withdrawal symptoms. It has been suggested that one relevant mechanism contributing to the relapse risk is the exposure to stimuli (cues) that have regularly been associated with alcohol intake. Such stimuli can become conditioned cues that elicit alcohol craving and intake as conditioned responses. Current brain imaging studies indicate that dysfunction of dopaminergic, glutamatergic, and opioidergic neurotransmission in the brain reward system (ventral striatum including the nucleus accumbens) is associated with alcohol craving and brain activation elicited by alcohol-associated pictures. These findings point to specific indications for psychotherapeutic and additive pharmacological treatment options.

Alcohol-associated stimuli activate the ventral striatum in abstinent alcoholics.

Alcohol-associated cues may act as conditioned stimuli that activate the brain reward system and motivate alcohol intake in alcoholics. Alcohol-associated visual stimuli were presented during functional magnetic resonance imaging. An activation of the ventral putamen was observed in alcoholics but not in control subjects. Patients with a strong activation of the ventral putamen relapsed during the next three months. This observation supports the hypothesis that alcohol use affects areas involved in brain reward circuits and that their stimulus-induced activation may be associated with an increased risk for relapse.

The influence of gender and emotional valence of visual cues on FMRI activation in humans.

Emotional neuroscience maps neurocircuits associated with the processing of affective stimuli. To assess gender differences in brain activation elicited by affective stimuli, we used pictures from the International Affective Picture System in a functional magnetic resonance imaging (fMRI) study. Ten male and ten female age-matched healthy volunteers were included and viewed affectively negative versus positive pictures, which were presented in an event related design. There was a significant interaction between valence of emotional stimuli and gender in the sublenticular extended amygdala (SLEA) and the rostral anterior cingulate. fMRI activation in these regions was stronger for negative compared to positive cues in women. In men fMRI activation was independent of stimulus valence. These results suggest to take gender differences into account when emotional paradigms are tested in functional brain imaging.