The role of protein kinase A and stress in ethanol-induced locomotor sensitization

There is a growing body of literature dedicated to elucidating the mechanisms involved in behavioral sensitization. The following studies examined the ability of alterations in PKA signaling (via genetic knockout) and CRF signaling (via pharmacological blockade) to modulate ethanol-induced locomotor sensitization and restraint stress-induced crosssensitization. Experiment 1 utilized the RIIβ knockout model to determine if alterations in PKA signaling affect locomotor activation in response to ethanol as well as the development of ethanol-induced locomotor sensitization. RIIβ-/- mice consistently showed significantly greater ethanol-induced locomotor activity relative to RIIβ+/+ mice. RIIβ-/- mice also showed increased sensitivity to ethanol-induced locomotor sensitization, an effect that may be dependent on genetic background and/or testing paradigm. Importantly, increased locomotor activity by RIIβ-/- mice was specific to ethanol injections, absent following saline injections, and not associated with altered blood ethanol levels. Experiment 2 attempted to discern a few of the mechanisms underlying the restraint stress-induced cross-sensitized response to ethanol in mice. Chronic exposure to restraint stress (2hrs for 10 days) induced a cross-sensitized response to ethanol in two commercially available inbred strains of mice, C57BL/6J and DBA/2J. The RIIβ knockout mouse model was also utilized to test if enhanced sensitivity to stress might be a factor contributing to the previously observed heightened sensitivity to ethanol-induced locomotor sensitization in these mice. RIIβ-/- and RIIβ+/+ showed no differences in the effect of stress on ethanolinduced locomotor activity. Finally, pretreatment with CRF Receptor 1 antagonist, CP- 154,526, prior to restraint stress sessions in male DBA/2J mice failed to block the acquisition of a cross-sensitized response to ethanol. Experiment 3 used a CRF Receptor 1 antagonist, CP-154,526, in an attempt to block the acquisition and expression of ethanol-induced locomotor sensitization in male DBA/2J mice. Pretreatment with CP-154,526 was ineffective in blocking the acquisition of a sensitized response to ethanol. In contrast, pretreatment with CP-154,526 effectively blocked expression of a sensitized response in DBA/2J mice that had been previously sensitized to the locomotor stimulating effects of ethanol. These effects were not attributable to alterations in blood ethanol levels, and ethanol naïve DBA/2J mice when pretreated with CP-154,526 show no such reductions in locomotor activity in response to ethanol. These experiments suggest a role for both PKA and CRF signaling in the mechanisms underlying ethanol-induced locomotor sensitization. Additionally, the ability of chronic restraint stress to elicit a cross-sensitized response to ethanol in mice is demonstrated. Ultimately, it remains unclear if alterations in PKA or CRF signaling are involved in the mechanisms associated with restraint stress-induced cross sensitization

Elevated anxiety-like behavior following ethanol exposure in mutant mice lacking neuropeptide Y (NPY)

Neuropeptide Y (NPY) is a neuromodulator with anxiolytic properties. Recent evidence suggests that NPY modulates neurobiological responses to ethanol. Because withdrawal from ethanol is associated with elevated anxiety-like behavior, and because central NPY modulates anxiety, we assessed anxiety-like behavior in mutant mice lacking normal production of NPY (NPY−/−) and in normal wild-type mice (NPY+/+) 6-hours after removal of a liquid diet containing 4.5% ethanol

Predictors of High Ethanol Consumption in RII?? Knock-Out Mice: Assessment of Anxiety and Ethanol-Induced Sedation

Genetic and pharmacological evidence suggests that the cyclic adenosine monophosphate–dependent protein kinase A pathway modulates neurobiological responses to ethanol. Mutant mice lacking the RIIβ subunit of protein kinase A (RIIβ) are resistant to ethanol-induced sedation and drink significantly more ethanol than littermate wild-type mice (RIIβ). We determined whether high ethanol intake by the RIIβ mice on alternate genetic backgrounds is reliably predicted by high basal levels of anxiety or resistance to the sedative effects of ethanol. Two-bottle choice procedures and a battery of behavioral tests (elevated plus maze, open-field activity, and zero maze) were used to assess voluntary ethanol consumption and basal levels of anxiety in RIIβ and RIIβ mice on either a C57BL/6J or a 129/SvEv × C57BL/6J genetic background. Additionally, ethanol-induced sedation and blood ethanol levels were determined in RIIβ and RIIβ mice after intraperitoneal injection of ethanol (3.8 g/kg). RIIβ mice on both genetic backgrounds consumed more ethanol and had a greater preference for ethanol relative to RIIβ mice. However, RIIβ mice showed reduced basal levels of anxiety when maintained on the C57BL/6J background but showed increased anxiety when maintained on the 129/SvEv × C57BL/6J background. Consistent with prior research, RIIβ mice were resistant to the sedative effects of ethanol, regardless of the genetic background. Finally, RIIβ and RIIβ mice showed similar blood ethanol levels. These results indicate that high ethanol consumption is associated with resistance to the sedative effects of ethanol but that basal levels of anxiety, as well as ethanol metabolism, do not reliably predict high ethanol drinking by RIIβ mice

The Alcohol Deprivation Effect (ADE) in C57BL/6J mice is observed using operant self-administration procedures and is modulated by CRF-1 receptor signaling

The alcohol deprivation effect (ADE) is characterized by transient excessive alcohol consumption upon reinstatement of ethanol following a period of ethanol deprivation. While this phenomenon has been observed in rats using both bottle drinking (consummatory behavior) and operant self-administration (consummatory and appetitive “ethanol-seeking” behavior) procedures, ADE studies in mice have primarily relied on bottle drinking measures. Furthermore, the neurochemical pathways that modulate the ADE are not well understood. Therefore, we determined whether the ADE can be observed in C57BL/6J mice using operant self-administration procedures and if expression of the ADE is modulated by the corticotropin releasing factor-1 (CRF-1) receptor

Blockade of the Corticotropin Releasing Factor Type 1 Receptor Attenuates Elevated Ethanol Drinking Associated With Drinking in the Dark Procedures

Drinking in the dark (DID) procedures have recently been developed to induce high levels of ethanol drinking in C57BL/6J mice, which result in blood ethanol concentrations (BECs) reaching levels that have measurable affects on physiology and/or behavior. The present experiments determined whether the increased ethanol drinking caused by DID procedures can be attenuated by pretreatment with CP-154,526; a corticotropin releasing factor type-1 (CRF1) receptor antagonist

Peripheral and Central Administration of a Selective Neuropeptide Y Y1 Receptor Antagonist Suppresses Ethanol Intake by C57BL/6J Mice

Neuropeptide Y (NPY) is a 36–amino acid neuromodulator that is expressed throughout the central nervous system. Recent genetic and pharmacological evidence suggests that the NPY Y1 receptor modulates ethanol intake. To further characterize the role of the Y1 receptor, we examined voluntary ethanol consumption by mice after administration of [(−)-2-[1-(3-chloro-5-isopropyloxycarbonylaminophenyl)ethylamino]-6-[2-(5-ethyl-4-methyl-1,3-tiazol-2-yl)ethyl]-4-morpholinopyridine] (compound A), a novel and selective Y1 receptor antagonist (Y1RA) that acts centrally on brain receptors when administered peripherally

Resonance Raman studies of Rieske-type proteins

Resonance Raman (RR) spectra are reported for the [2Fe-2S] Rieske protein from Thermus thermophilus (TRP) and phthalate dioxygenase from Pseudomonas cepacia (PDO) as a function of pH and excitation wavelength. Depolarization ratio measurements are presented for the RR spectra of spinach ferredoxin (SFD), TRP, and PDO at 74 K. By comparison with previously published RR spectra of SFD, we suggest reasonable assignments for the spectra of TRP and PDO. The spectra of PDO exhibit virtually no pH dependence, while significant changes are observed in TRP spectra upon raising the pH from 7.3 to 10.1. One band near 270 cm-1, which consists of components at 266 cm-1 and 274 cm-1, is attributed to Fe(III)-N(His) stretching motions. We suggest that these two components arise from conformers having a protonated-hydrogen-bonded imidazole (266 cm-1) and deprotonated-hydrogen-bonded imidazolate (274 cm-1) coordinated to the Fe/S cluster and that the relative populations of the two species are pH-dependent; a simple structural model is proposed to account for this behavior in the respiratory-type Rieske proteins. In addition, we have identified RR peaks associated with the bridging and terminal sulfur atoms of the Fe-S-N cluster. The RR excitation profiles of peaks associated with these atoms are indistinguishable from each other in TRP (pH 7.3) and PDO and differ greatly from those of [2Fe-2S] ferredoxins. The profiles are bimodal with maxima near 490 nm and > approx. 550 nm. By contrast, bands associated with the Fe-N stretch show a somewhat different enhancement profile. Upon reduction, RR peaks assigned to Fe-N vibrations are no longer observed, with the resulting spectrum being remarkably similar to that reported for reduced adrenodoxin. This indicates that only modes associated with Fe-S bonds are observed and supports the idea that the reducing electron resides on the iron atom coordinated to the two histidine residues. Taken as a whole, the data are consistent with an St2FeSb2Fe[N(His)]t2 structure for the Rieske-type cluster.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29687/1/0000014.pd

First recorded eruption of Nabro volcano, Eritrea, 2011

We present a synthesis of diverse observations of the first recorded eruption of Nabro volcano, Eritrea, which began on 12 June 2011. While no monitoring of the volcano was in effect at the time, it has been possible to reconstruct the nature and evolution of the eruption through analysis of re- gional seismological and infrasound data and satellite remote sensing data, supplemented by petrological analysis of erupted products and brief field surveys. The event is notable for the comparative rarity of recorded historical eruptions in the region and of caldera systems in general, for the prodi- gious quantity of SO2 emitted into the atmosphere and the significant human impacts that ensued notwithstanding the low population density of the Afar region. It is also relevant in understanding the broader magmatic and tectonic signifi- cance of the volcanic massif of which Nabro forms a part and which strikes obliquely to the principal rifting directions in the Red Sea and northern Afar. The whole-rock compositions of Editorial responsibility: G. Giordano the erupted lavas and tephra range from trachybasaltic to trachybasaltic andesite, and crystal-hosted melt inclusions contain up to 3,000 ppm of sulphur by weight. The eruption was preceded by significant seismicity, detected by regional networks of sensors and accompanied by sustained tremor. Substantial infrasound was recorded at distances of hundreds to thousands of kilometres from the vent, beginning at the onset of the eruption and continuing for weeks. Analysis of ground deformation suggests the eruption was fed by a shal- low, NW–SE-trending dike, which is consistent with field and satellite observations of vent distributions. Despite lack of prior planning and preparedness for volcanic events in the country, rapid coordination of the emergency response miti- gated the human costs of the eruption

Diel surface temperature range scales with lake size

Ecological and biogeochemical processes in lakes are strongly dependent upon water temperature. Long-term surface warming of many lakes is unequivocal, but little is known about the comparative magnitude of temperature variation at diel timescales, due to a lack of appropriately resolved data. Here we quantify the pattern and magnitude of diel temperature variability of surface waters using high-frequency data from 100 lakes. We show that the near-surface diel temperature range can be substantial in summer relative to long-term change and, for lakes smaller than 3 km2, increases sharply and predictably with decreasing lake area. Most small lakes included in this study experience average summer diel ranges in their near-surface temperatures of between 4 and 7°C. Large diel temperature fluctuations in the majority of lakes undoubtedly influence their structure, function and role in biogeochemical cycles, but the full implications remain largely unexplored