Isotope shift calculations for atoms with one valence electron

This work presents a method for the ab initio calculation of isotope shift in atoms and ions with one valence electron above closed shells. As a zero approximation we use relativistic Hartree-Fock and then calculate correlation corrections. The main motivation for developing the method comes from the need to analyse whether different isotope abundances in early universe can contribute to the observed anomalies in quasar absorption spectra. The current best explanation for these anomalies is the assumption that the fine structure constant, alpha, was smaller at early epoch. We test the isotope shift method by comparing the calculated and experimental isotope shift for the alkali and alkali-like atoms Na, MgII, K, CaII and BaII. The agreement is found to be good. We then calculate the isotope shift for some astronomically relevant transitions in SiII and SiIV, MgII, ZnII and GeII.Comment: 11 page

CRH SIGNALING AND THE DARK SIDE OF ADDICTION: LONG LASTING HYPERREACTIVITY TO STRESS IN ANIMALS WITH A HISTORY OF ALCOHOL DEPENDENCE

It is increasingly recognized that anti-reward systems are progressively recruited during the development of ethanol dependence, and may constitute a key component in maintaining the dependent phenotype. We recently demonstrated that in rodents, repeated cycles of ethanol intoxication and withdrawal for a prolonged period of time induces a phenotype of long-lasting increased ethanol drinking that models several facets of human alcoholism. Here, we found that elevated stress sensitivity parallels the high ethanol preference in this model, and contributes to the propensity to consume increased amounts of ethanol. After 7 weeks of daily cycles of intoxication and withdrawal rats were allowed to recover for 3 weeks without access to ethanol. In the first experiment we subjected rats to a punished drinking test (Vogel) w/o antagonist pretreatment with a corticotropin releasing hormone receptor 1 (CRH1R). Dependent rats showed a more pronounced behavioral suppression during the punished drinking period than controls. This suppression was alleviated by the CRH1R antagonist.exposed rats and controls were subjected to a 2-bottle freechoice, continuous access drinking paradigm. We then tested the effect of theantagonist on drinking behavior in a 2-bottle free choice, 1 hr-limited accessparadigm. No effect of the drug on ethanol consumption was found. In a second setof rats we asked whether the increased sensitivity to stress affects home cage drinking. As expected, previously exposed rats consumemarkedly higher amounts ofethanol than controls. Rats were than subjected for 3 consecutive days to sessions ofinescapable stress (forced swimming in cold water). During the week after thestressor rats with a history of dependence showed a sustained increase in drinkingfrom their previous base line, while control rats did not. A third group of animals wasanalyzed for CRH1R receptor expression and density. In conclusion, we provideevidence for an overactive CRH system in rats with a history of dependence causing hyper-emotionality and thereby contributing to relapse behavior

CRH signaling and the dark side of addiction: Long-lasting hyper-reactivity to stress in animals with a history of ethanol dependence

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

RECRUITMENT OF INHIBITORY MEK/ERK SIGNALING IN BRAIN REWARD CIRCUITRY FOLLOWING A HISTORY OF ETHANOL DEPENDENCE

Mitogen-activated and extracellular regulated kinase (MEK) and extracellular signal-regulated protein kinase (ERK) pathways may underlie ethanol-induced neuroplasticity. Here, the MEK inhibitor UO126 was used 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. Ethanol (1.5 g/kg, i.p.) induced c-fos expression 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), and a similar pattern in the paraventricular nucleus (PVN). In contrast, following a history of dependence, a markedly suppressed c-fos response to acute ethanol was found in orbitofrontal cortex (OFC) and nucleus accumbens shell (AcbSh), key components of circuitry mediating positive drug reinforcement. The suppressed ethanol response in these regions was returned to normal by pre-treatment with UO126, demonstrating a recruitment of an ERK mediated inhibitory regulation in the post-dependent state. Conversely, in brain areas involved in stress responses (MeA, PVN), a MEK/ERK mediated cellular activation by acute ethanol was lost following a history of dependence. These data reveal highly region-specifi c neuroadaptations encompassing the MEK/ERK pathway in ethanol dependence. Recruitment of MEK/ERK mediated suppression of the ethanol response in OFC and AcbSh may refl ect 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

Dissociation of antidepressant-like activity of escitalopram and nortriptyline on behaviour and hippocampal BDNF expression in female rats.

A major hypothesis of depression postulates that a dysregulation of the neurotrophin systems is directly involved in the pathophysiology of depression, and that restoration of such deficits may underlie the therapeutic efficacy of antidepressant treatment. One key finding supporting this hypothesis is upregulation of brain derived neurotrophic factor (BDNF) in the hippocampus after antidepressant treatment. Here, we further test the hypothesis of BDNF involvement in antidepressant action in a genetic rat model of depression after chronic oral treatment with escitalopram, nortriptyline or placebo. Active treatments had significant behavioural antidepressant-like actions in female rats of the Flinders Sensitive Line (FSL) and non-selected Sprague Dawley (SD) rats, while Flinders Resistant Line (FRL) rats were unaffected. Escitalopram, but not nortriptyline, markedly reduced BDNF mRNA levels in the dentate gyrus of FSL rats. The BDNF downregulation was common to the four major promoters of the gene. Treatments did not affect BDNF expression in FRL or SD strains. We conclude that the antidepressant effects of escitalopram and nortriptyline, two common drugs with different pharmacological profiles, appear to be unrelated to the regulation of hippocampal BDNF expression in female rats. These results indicate that the tropic hypothesis of depression has limitations and emphasize the need for validated disease models of depression to assess potential treatment targets

Plasticity and impact of the central renin-angiotensin system during development of ethanol dependence

Pharmacological and genetic interference with the renin-angiotensin system (RAS) seems to alter voluntary ethanol consumption. However, understanding the influence of the RAS on ethanol dependence and its treatment requires modeling the neuroadaptations that occur with prolonged exposure to ethanol. Increased ethanol consumption was induced in rats through repeated cycles of intoxication and withdrawal. Expression of angiotensinogen, angiotensin-converting enzyme, and the angiotensin II receptor, AT1a, was examined by quantitative reverse transcription polymerase chain reaction. Increased ethanol consumption after a history of dependence was associated with increased angiotensinogen expression in medial prefrontal cortex but not in nucleus accumbens or amygdala. Increased angiotensinogen expression also demonstrates that the astroglia is an integral part of the plasticity underlying the development of dependence. The effects of low central RAS activity on increased ethanol consumption were investigated using either spirapril, a blood-brain barrier-penetrating inhibitor of angiotensin-converting enzyme, or transgenic rats (TGR(ASrAOGEN)680) with reduced central angiotensinogen expression. Spirapril reduced ethanol intake in dependent rats compared to controls. After induction of dependence, TGR(ASrAOGEN)680 rats had increased ethanol consumption but to a lesser degree than Wistar rats with the same history of dependence. These data suggest that the central RAS is sensitized in its modulatory control of ethanol consumption in the dependent state, but pharmacological or genetic blockade of the system appears to be insufficient to halt the progression of dependence

Upregulation of Voluntary Alcohol Intake, Behavioral Sensitivity to Stress, and Amygdala Crhr1 Expression Following a History of Dependence.

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

Modulation of voluntary ethanol consumption by beta-arrestin 2

Beta-arrestin 2 is a multifunctional key component of the G protein-coupled receptor complex and is involved in micro-opiate and dopamine D2 receptor signaling, both of which are thought to mediate the rewarding effects of ethanol consumption. We identified elevated expression of the beta-arrestin 2 gene (Arrb2) in the striatum and the hippocampus of ethanol-preferring AA rats compared to their nonpreferring 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. Furthermore, a single, distinct, and highly significant quantitative trait locus for Arrb2 expression in hippocampus and striatum was identified at the locus of this gene, providing evidence that genetic variation may affect a cis-regulatory mechanism for expression and regional control of Arrb2. 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