Journal Article

Poster Session PA2

in Alcohol and Alcoholism

Volume 42, issue suppl_1, pages i49-i51
Published in print August 2007 | ISSN: 0735-0414
Published online January 2007 | e-ISSN: 1464-3502 | DOI: https://dx.doi.org/10.1093/alcalc/agm126
Poster Session PA2

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PA2-1

Shape analysis of insula in alcohol dependence

Jung YC, Jang D-P, Lee E, Kim J-J, Chung T-S, Namkoong K

Yonsei University College of Medicine

Aims. Excessive chronic alcohol consumption is associated with significant shrinkage of brain tissue and impairment of associated cognitive functions. In the present study, we have chosen to investigate the effects of chronic alcohol consumption on the insula. Convergent evidence has supported the anterior-posterior functional organization within the insular cortex: the anterior insular cortex subserves a role as a limbic integrating cortex, while the posterior insular cortex subserves ascending visceral symptoms. Recently, some experimental studies have suggested that the dysfunction of the anterior insular cortex may be involved in substance abuse. We hypothesized that the anterior part of the insula is more vulnerable to the posterior part of the insula to alcohol-related damage and that the shape deformity of anterior insula would correlate with poorer neurocognitive performance.

Methods. Subjects were 20 patients with alcohol dependence and 20 normal healthy subjects. A landmark-based structural and surface shape analysis of the insula was performed using high-spatial resolution magnetic resonance imaging. We investigated the correlation between the shape deformation of insula and the clinical/neurocognitive characteristics.

Results. The findings demonstrated shape deformations in the inferior side, which corresponds to the central dysgranular region, of the left and right insula in alcohol dependent patients compared with normal controls. Furthermore, the inferior shape deformations demonstrated significant correlations with the memory impairment.

Conclusions. Shape analysis of the insula could provide a more sensitive approach than volumetric measures for detecting small volume changes that might be restricted to subregions of the insula.

PA2-2

Morphometric changes of corpus callosum in chronic alcoholics—A magnetic resonance imaging study

Choi JH, Kim K

Seoul Veterans Hospital

Aims. The purpose of this study determines the difference on corpus callosum between chronic alcoholic patients and controls, and relationship between the severity of ethanol intake and the degree of this atrophy.

Methods. A clinicoradiologic study was carried out in 20 chronic alcoholics and age-matched controls. All subjects were male and right-handedness. To estimate alcohol habits for subjects, structured interviews have been made. Measurement of the midsagittal corpus callosum area and thickness (genu, truncus and splenium), as well as the frontal lobe index (FLI) and the width of the cortical sulci (SWS) on T1- and T2-weighted Magnetic Resonance Images were performed.

Results. Compared to controls, alcoholics had a significantly decreased corpus callosum area and thickness (mainly in genu), and significantly increased FLI and SWS. The callosal area negatively correlated with the cortical atrophies and the area of genu of the corpus callosum negatively correlated with the frontal atrophies.

Moreover, the reduction of corpus callosum correlated with the total lifetime dose of ethanol consumed.

Conclusions. In chronic alcoholics, atrophy of the corpus callosum is a common finding and may reflect the severity and pattern of cortical damage. And the degree of callosal atrophy correlated with the severity of ethanol intake as well.

PA2-3

Cerebral glucose metabolism measured with 18-FDG-PET in alcoholics and subjects at high-risk for alcoholism

Hohmann N, Dielentheis TF, Landvogt C, Buchholz H-G, Hobusch K, Hirsch J, Bartenstein P, Gruender G, Fehr C, Schreckenberger M (Germany)

Aims. A decrease in the global cerebral glucose metabolism has been repeatedly described among alcohol dependent patients. It is unclear whether theses changes result from long-term alcohol use or whether these differences are disease defining traits. Therefore, we measured in vivo cerebral metabolic differences between alcohol dependent patients, first-degree relatives and healthy control persons.

Methods. 10 male alcoholics, 10 subjects at risk for alcoholism (sons of alcoholics) and 18 healthy male controls underwent two 18-FDG PET (180 ± 20 MBq) scans with or without a lorazepam (2 mg) pretreatment. The PET data were analysed using SPM. All subjects were interviewed with the German version of the European Addiction Severity Index (EuropASI).

Results. Overall cerebral metabolism did not differ between the alcohol dependent patients, their first degree relatives and the normal controls. SPM analyses of the rCGM in the baseline condition revealed a significantly higher metabolic activity in the bilateral caudate nucleus and a significantly lower metabolism in the left insula in detoxified alcoholics compared to controls. However, we did not detect similar differences between the subjects at high risk for alcoholism and the controls.

Conclusions. The results from our study do not confirm the hypothesis of a global metabolic decrease among alcohol dependent patients. A metabolic decrease was found within the left insula, but a significant metabolic increase was found within the bilateral caudate nucleus covering parts of the dorsal striatum. As these findings were limited to alcohol dependent patients, the observed differences might critically rely on long term alcohol use.

PA2-4

Neuroplasticity in brain reward circuitry following a history of ethanol dependence: A candidate anti-reward process

Hansson AC, Rimondini R, Sommer WH, Heilig M (USA)

Aims. Mitogen-activated and extracellular regulated kinase (MEK) and extracellular signal-regulated protein kinase (ERK) pathways may underlie ethanol-induced neuroplasticity. Here, we used the MEK inhibitor UO126 to probe the role of MEK/ERK signaling for the cellular response to an acute ethanol challenge in rats with or without a history of ethanol dependence.

Methods. A post-dependent state was induced using repeated cycles of alcohol intoxication and withdrawal in Wistar rats. We reasoned that the expression of both c-fos and egr-1 after acute ethanol challenge, administered in the presence or absence of the MEK1/2 inhibitor UO126, would delineate structures differentially involved in the initial ethanol response in dependent and non-dependent animals, respectively, and would thus serve as a marker for neuroadaptive processes associated with the development of the dependent state. In situ hybridization for c-fos and egr-1 mRNA was carried out in forebrain structures known to be involved in the mediation of positive and negative drug reinforcement.

Results. Ethanol (1.5 g/kg, i.p.) induced expression of the marker genes c-fos and egr-1 in brain regions associated both with rewarding and stressful ethanol actions. Under non-dependent conditions, alcohol-induced c-fos expression was generally not affected by MEK inhibition, with the exception of medial amygdala (MeA). In contrast, following a history of dependence, a markedly suppressed c-fos response to acute ethanol was found in orbitofrontal cortex (OFC). The suppressed ethanol response in the OFC and in nucleus accumbens shell (AcbSh), key components of circuitry mediating positive drug reinforcement, was returned to normal by pre-treatment with UO126, demonstrating a recruitment of an ERK/MEK mediated inhibitory regulation in the post-dependent state. Conversely, in brain areas involved in stress responses (MeA, paraventricular nucleus, PVN), a MEK/ERK mediated cellular activation by acute ethanol was lost following a history of dependence.

Conclusions. These data reveal highly region-specific neuroadaptations encompassing the MEK/ERK pathway in ethanol dependence. Recruitment of MEK/ERK mediated suppression of the ethanol response in OFC and AcbSh may reflect devaluation of ethanol as a reinforcer, while loss of a MEK/ERK mediated response in MeA and PVN may reflect tolerance to its aversive actions. These two neuroadaptations could act in concert to facilitate progression into ethanol dependence.

PA2-5

Influence of emotional state- and context-related craving on neuronal cue-reactivity in alcohol dependent patients

Leménager T, Klein S, Klein O, Hintz T, Vollmert C, Zimmer A, Mann K, Smolka MN (Germany)

Objectives. Two headings are there. Please check Y The functional imaging literature on alcohol associated cue-reactivity in alcoholics shows a high heterogeneity of study results. We investigated whether the influence of context- and emotional state-related craving in alcohol dependent patients is able to explain some of these heterogeneous results. In order to do so, we distinguished different types of ‘alcohol temptation’ (craving) in association with brain activity.

Methods. 53 abstinent alcoholics underwent fMRI while watching alcohol associated, abstract and neutral stimuli.

Contrasts were created to get evidence on different levels of activation in association with alcohol-stimuli compared to stimuli of neutral and abstract valence. Different context- and emotional-state related craving was assessed with four extracted factors of the alcohol abstinence self efficacy (AASE) ‘temptation’-scale (reward, relief, testing personal control, psychological and physical needs), whose 20 items were previously subjected to a principle component analysis. Image processing and statistical analysis were performed using SPM 5. The influence of the four factors on neurophysiological cue-reactivity was assessed by using a multiple linear regression analysis (p < 0.005).

Results. We found significant positive associations between ‘reward craving’ and activations in the mesolimbic reward system like the right dorsal striatum and prefrontal regions. A significant negative association was derived between the factor ‘relief craving’ and the activation of regions in the insula as well as frontal and parietal regions. Relevant positive correlations were observed between the ‘testing personal control’-factor and neuronal cue reactivitiy in the bilateral rostral anterior cingulum, prefrontal cortex and the left hippocampus with insula regions. Finally, craving due to psychological and physical needs was positively associated with activations in the bilateral cerebellum, left gyrus fusiformis and other occipital, temporal and parietal regions.

Conclusions. These results indicate that different contextual and emotional state factors are able to explain some of the heterogeneous study results in neuronal cue reactivity. The dominance of ‘reward craving’, more related to social stimuli, is linked to higher neuronal activity in the mesolimbic reward system. ‘Relief craving’, involving more intra-individual cues like anger and sadness, is associated with deactivations in regions related to drug urges (insula) and visual orientation (parietal and occipital). Craving in relation to ‘test one's control over drinking’ is associated with an activation of the anterior cingulate, a region involved in the regulation of emotional responses. The left gyrus fusifomis, which plays a role in object recognition, an aspect of visual object processing, is associated with craving due to ‘psychological and physical need’.

PA2-6

Biogenic amines metabolism in rat brain following ventriculo-cisternal perfusion by ethanol

Zimatkin SM, Denisenko AV (Belarus)

Aims. The estimation of changes of biogenic amines metabolism in rat brain following ventriculo-cisternal perfusion by ethanol solution.

Methods. Under the general anesthesia adult male Wistar rats were placed into the stereotaxic apparatus and artificial liquor was administrated into the lateral ventricle through the needle using the syringe automatic micropump, during 1 hour with a constant speed (12 ml/min). The samples of perfusate released from the large cistern (cisterna magna) of the brain stem through the needle and plastic capillary were collected every 10 min for examination. Then the artificial liquor was replaced for artificial liquor + 100 mM ethanol solution and 10 min samples of perfusate were collected during 2 hours. Then rats were sacrificed and the samples of 6 brain regions were analyzed and compared with the similar brain samples of rats perfused 3 hours with artificial liquor only. Biogenic amines, their precursors and metabolites were analyzed by HPLC with electrochemical detection.

Results. In perfusate released from cisterna magna tryptophan, 5-hydroxy-trypto-phan, serotonin, 5-hydroxy-indo-leacetic acid, tyrosine, 3,4-di-hydroxy-phenyl-ala-nine, 3,4-di-hydroxy-phenyl-acetic acid, homovanillic acid and 3-methoxy-4-hydroxy-phenyl-glycol have been found. In brain samples the same compound as well as dopamine, norepinephrine and 3-methoxytironin were detected.

It was found that ventriculo-cisternal perfusion by ethanol significantly increased the tryptophan, serotonin and tyrosine levels in perfusate. In addition the ventriculo-cisternal perfusion by ethanol during 3 hours significantly increased the tyrosine level in brain cortex and midbrain, DOPA in hypothalamus and midbrain, DOPAC in hypothalamus, but decreased the serotonin level in hypothalamus, 5-hydroxyindoleacetic acid in medulla oblongata and dopamine level in striatum.

Conclusions. The determination of biogenic amines, their precursors and metabolites in ventriculo-cisternal perfusate give the possibility to examine the dynamics of biogenic amines metabolism in the brain following ethanol administration.

PA2-7

Differential Expression of CRHR1 Affects Stress-induced Alcohol Consumption in Mice?

Molander A, Deussing J, Wurst W, Spanagel R (Germany)

Aims. Dysregulation of the corticotrophin-releasing hormone (CRH) system mediating endocrine and behavioural responses to stress has been attributed to a variety of stress related psychiatric disorders, such as drug abuse and alcoholism. Two CRH receptors, CRH1 and CRH2, have been identified. Previous studies (Sillaber et al., 2002; Treutlein et al., 2006; Timpl et al., 1998) show that primarily the CRH1 receptor is associated with alcohol consumption and that global CRH1 knock-out (KO) mice (CRH1−/−) increase their alcohol intake after repeated exposure to stress (Sillaber et al.; 2002). In this study we investigate the role of centrally expressed CRH1 receptors on alcohol intake, comparing a CNS specific CRH1 KO mouse model (CRHR1 Nestin-Cre) to the global CRHR1−/−mice and wild-type (wt) controls.

Methods. After a habituation period of approx. 12 weeks to 8% (v/v) ethanol versus water, the voluntary alcohol consumption was measured: 1) before, during and after three days of consecutive exposure to the psychological and severe stressor ‘social defeat stress’, and 2) before, during and after three days of consecutive exposure to the mild and emotional stressor ‘swim stress’. There was a time-period of approx. four weeks in-between the social defeat and the swim stress sessions.

Results. We found no difference in daily ethanol intake between the CRHR1−/− mice and their wt controls during baseline measurements and before stress exposure. During social defeat stress the CRHR1−/− mice significantly increased their ethanol intake compared to baseline values and compared to the wt controls. The increase lasted 1–2 days after the last day of stress exposure, after which the ethanol intake returned to baseline levels. The (CRHR1 Nestin-Cre) KO mice also differed in their basal ethanol intake as compared to the wt mice during baseline measurements. However, during and shortly after (1–2 days) social defeat stress the (CRHR1 Nestin-Cre) KO decreased their ethanol intake compared to the wt controls. All mice responded similar to the ‘swim stress’, with a slight increase in ethanol intake, as compared to the baseline values.

Conclusions. These data show an opposing role of CRHR1 in CNS and the extrahypothalamic HPA system in terms of stress-induced alcohol consumption, since the CRHR1−/− and the (CRHR1 Nestin-Cre) KO mice increased respectively decreased their ethanol intake. The role of the CRHR1 will in the near future also be examined in alcohol deprivation as well as withdrawal and anxiety related drinking models.

PA2-8

Chronic ethanol exposure changes dopamine D2 receptor splice variants expression and impairs the cellular organisation during retinoic acid-induced differentiation of human neuroblastoma cells

Wernicke C, Hellmann J, Rommelspacher H (Germany)

Aim. There is a considerable amount of data demonstrating ethanol-induced impairment of neurotransmitter systems during the development and that dopaminergic neurons may be particularly targeted. Two splice variants of DRD2 are known, with the short one (DRD2s) representing the high-affinity autoreceptor and the long one (DRD2l) the low-affinity postsynaptic receptor. We searched for a model to investigate the impact of chronic ethanol exposure and withdrawal on the expression of these proteins and of DAT during neuronal differentiation.

Methods. Human neuroblastoma SH-SY5Y cells consist of a mixture of neuron-like and epithelium-like cells. Retinoic acid (RA) induces differentiation into the neuronal phenotype.

Results. Immunocytochemistry and Western blot analysis revealed downregulation of DAT and upregulation of DRD2 by RA and RA/brain derived neurotrophic factor (BDNF). The DAT is functional as demonstrated by [3H] dopamine uptake. Using real-time RT-PCR we found in the RA-induced neuronal phenotype that ethanol delayed the upregulation of DRD2s but not of DRD2l. Ethanol withdrawel caused an increased expression of DRD2l and a normalization of DRD2s.

Furthermore, the formation of cell clusters and bundles of neurites, typical for RA-induced neuronal differentiation, did not develop in RA/ethanol culture until the end of the 4 week observation period.

Conclusions. RA-differentiated SH-SY5Y cells are suited to study the effects of chronic ethanol and withdrawal. Chronic ethanol impairs differentiation-dependent adaptation of dopaminergic proteins, specifically DRD2s, and the organization of cell clusters and bundles of connecting neurites.

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Subjects: Public Health and Epidemiology

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