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Despite its limited immediate reinforcement value, alcohol has a potent ability to induce neuroadaptations that promote its incentive salience, escalation of voluntary alcohol intake and aversion-resistant alcohol seeking. A constellation of these traits, collectively called 'post-dependent', emerges following brain exposure to repeated cycles of intoxication and withdrawal. The medial prefrontal cortex (mPFC) and its subdivisions exert top-down regulation of approach and avoidance behaviors, including those that lead to alcohol intake. Here, we review an emerging literature which indicates that a reprogramming of mPFC function occurs with prolonged exposure of the brain to cycles of alcohol intoxication and withdrawal. This reprogramming results in molecular dysregulations that contribute to the post-dependent syndrome. Convergent evidence has identified neuroadaptations resulting in altered glutamatergic and BDNF-mediated signaling, and for these pathways, direct evidence for a mechanistic role has been obtained. Additional evidence points to a dysregulation of pathways involving calcium homeostasis and neurotransmitter release. Recent findings indicate that global DNA hypermethylation is a key factor in reprogramming the mPFC genome after a history of dependence. As one of the results of this epigenetic remodeling, several histone modifying epigenetic enzymes are repressed. Among these, PR-domain zinc-finger protein 2, a methyltransferase that selectively mono-methylates histone H3 at lysine 9 has been functionally validated to drive several of the molecular and behavioral long-term consequences of alcohol dependence. Information processing within the mPFC involves formation of dynamic neuronal networks, or functional ensembles that are shaped by transcriptional responses. The epigenetic dysregulations identified by our molecular studies are likely to alter this dynamic processing in multiple ways. In summary, epigenetic molecular switches in the mPFC appear to be turned on as alcoholism develops. Strategies to reverse these processes may offer targets for disease-modifying treatments.

With its capability to quantify absolute iodine concentrations, Dual-Energy CT (DECT) promises to add considerable diagnostic information in the field of abdominal oncologic imaging (Agrawal et al., 2014). Iodine maps contain quantifiable information about tumor vascularity and viability and may be used to evaluate treatment response (Apfaltrer et al., 2012; Chen et al., 2014). Hence, reproducible measurements are essential for further treatment decisions. Similar to the measurement of tumor size, the analysis of iodine uptake has hitherto relied on measurements in 2 dimensions (2D) (Zhang et al., 2010). However, recent technological advances enable three-dimensional (3D)-measurements. The aim of this study was to compare interobserver reproducibility of a semiautomatic tool for 3D-segmentation and quantification of iodine uptake in hepatic colorectal metastases with 2D-measurements in DECT., peer-reviewed

Beta-arrestin 2 is a multifunctional key component of the G-protein coupled receptor complex and is involved in l-opiate and dopamine D2 receptor signalling, both of which are thought to mediate the rewarding effects of ethanol consumption. We identified elevated expression and of the beta-arrestin 2 gene (Arrb2) in the striatum and the hippocampus of ethanol preferring AA rats compared to their non-preferring counterpart ANA line. Differential mRNA expression was accompanied by different levels of Arrb2 protein. The elevated expression was associated with a 7-marker haplotype in complete linkage disequilibrium, which segregated fully between the lines, and was unique to the preferring line. These findings were functionally validated using mice lacking Arrb2, which displayed both reduced voluntary ethanol consumption and ethanol induced psychomotor stimulation. Our results demonstrate that beta-arrestin 2 modulates acute responses to ethanol and is an important mediator of ethanol reward.

Endocannabinoid signaling has recently been implicated in ethanol-seeking behavior. We analyzed the expression of endocannabinoid-related genes in key brain regions of reward and dependence, and compared them between the alcohol-preferring AA (Alko Alcohol) and nonpreferring ANA (Alko Non-Alcohol) rat lines. A decreased expression of fatty acid amidohydrolase (FAAH), the main endocannabinoid-degrading enzyme, was found in prefrontal cortex (PFC) of AA rats, and was accompanied by decreased enzyme activity in this region. Binding of the endocannabinoid-cannabinoid 1 (CB1) receptor ligand 3[H]SR141716A, and [35S]GTPitalic gammaS incorporation stimulated by the CB1 agonist WIN 55,212-2 were downregulated in the same area. Together, this suggests an overactive endocannabinoid transmission in the PFC of AA animals, and a compensatory downregulation of CB1 signaling. The functional role of impaired FAAH function for alcohol self-administration was validated in two independent ways. The CB1 antagonist SR141716A potently and dose-dependently suppressed self-administration in AA rats when given systemically, or locally into the PFC, but not in the striatum. Conversely, intra-PFC injections of the competitive FAAH inhibitor URB597 increased ethanol self-administration in nonselected Wistar rats. These results show for the first time that impaired FAAH function may confer a phenotype of high voluntary alcohol intake, and point to a FAAH both as a potential susceptibility factor and a therapeutic target.

BACKGROUND: A history of alcohol dependence recruits increased voluntary alcohol intake and sensitivity to stress. Corticotropin-releasing hormone (CRH) has been implicated in this transition, but underlying molecular mechanisms remain unclear. METHODS: A postdependent state was induced using intermittent alcohol exposure. Experiments were carried out following >/=3 weeks of recovery to eliminate contributions of acute withdrawal. Voluntary alcohol consumption was assessed in a two-bottle, free choice procedure. Behavioral sensitivity to stress was examined using fear suppression of behavior in a punished drinking (Vogel) conflict test. Effects of forced swim stress on voluntary alcohol intake were examined as a function of exposure history. Expression of Crh, Crhr1, and Crhr2 transcripts was analyzed by in situ hybridization histochemistry. RESULTS: Alcohol drinking was upregulated long-term following a history of dependence. Fear suppression of behavior was selectively potentiated in postdependent animals. This persisted 3 months after alcohol exposure and was reversed by the selective CRH-R1 antagonist 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo [1,2-b]pyridazine (MTIP) (10 mg/kg). Forced swim stress increased alcohol intake in postdependent animals but not in control animals. Behavioral changes were paralleled by an upregulation of Crhr1 transcript expression within basolateral (BLA) and medial (MeA) amygdala and Crh messenger RNA (mRNA) in central amygdala (CeA). In contrast, Crhr2 expression was down in the BLA. CONCLUSIONS: Neuroadaptations encompassing amygdala CRH signaling contribute to the behavioral phenotype of postdependent animals.

It is widely believed that the opiate system is involved in the development of alcoholism. Beta arrestin 2 (Arrb2) is a crucial modulator of this system; suggesting that Arrb2 is important for drug reward behaviors. In this study we further elucidated the putative role of Arrb2 in ethanol consumption. We fi rst compared Arrb2 brain expression levels between alcohol-preferring AA and nonpreferring ANA rats by in situ hybridization. We found differential expression levels in ventral and dorsal striatum, as well as hippocampus. Sequence analysis of Arrb2 showed a novel haplotype variant that completely discriminates between the lines. We then characterized the impact of this gene on ethanol related behaviors using Arrb2 null-mutant mice. Compared to wild type animals, Arrb2 mutant and heterozygote mice demonstrate reduced voluntary ethanol consumption and reduced ethanol induced locomotion. Mutant mice also show a decreased sensitivity to ethanol-induced sedation. Our data support a role for Arrb2 in mediating the rewarding effects of ethanol.

It is increasingly recognized that anti-reward systems (i.e. negative reinforcement through stress and fear systems) are progressively recruited during the development of alcoholism, and may constitute a key component in maintaining the dependent phenotype. Extra-hypothalamic CRH (corticotrophin releasing hormone) signaling is thought to be of crucial importance in this process. However, understanding the impact of the CRH mediated neurotransmission in ethanol dependence and its potential value as a candidate target for treatment of ethanol use disorders requires modeling the neuroadaptations which occur with prolonged exposure of the brain to ethanol. To this end we have recently developed an animal model, which based on repeated cycles of intoxication and withdrawal, mimics the natural history of alcoholism and triggers long lasting plasticity. Methods: Male Wistar rats were exposed to either 4 or 7 weeks of daily cycles of ethanol vapor intoxication and withdrawal followed by 3 weeks of abstinence. Animals were then assigned to 3 separate experiments to investigate: 1) voluntary home cage ethanol consumption in a 2-bottle, free choice drinking paradigm; 2) fear-induced suppression of behavior in a punished drinking paradigm with or without pretreatment with a CRH receptor 1 antagonist; and 3) sacrificed for the study CRH and its receptors in the medial prefrontal cortex and the extended amygdala by in situ hybridization and receptor autoradiography. Results: Only 7-weeks exposed animals show signs of withdrawal at the end of the exposure cycle and consume significantly more ethanol after the 3 weeks resting period (p < 0.05, 7-weeks exposed vs. control). Associated with the drinking phenotype was an increased fear response in the conflict test (p < 0.01), increased expression of CRH in the central amygdala (p < 0.05) and its receptor CRH-R1 in central (p < 0.05), medial (p < 0.01) as well as basolateral amygdala (p < 0.001) in 7-weeks exposed animals compared to non-exposed controls. There was a trend to significant increased fear- suppression also in animals with a history of only 4 weeks cyclic intoxication and withdrawal, but no alterations in CRH signaling. Furthermore, heightened fear response was still visible fourteen weeks after the induction of the high-drinking phenotype and was completely abolished by a specific, highly brain-penetrant CRH-R1 antagonist. Discussion: Enhanced fear suppression seems to be an early onset and long-lasting phenotype in the development of ethanol dependence and is accompanied by long-term upregulation of CRH circuits in the amygdala. Together, these data support the hypothesis of an early recruitment of anti-reward systems in the descent into alcoholism and emphasize the potential of the CRH-R1 receptor as a treatment target for this disorder.