Aversive Stimuli Drive Drug Seeking in a State of Low Dopamine Tone

Background Stressors negatively impact emotional state and drive drug seeking, in part, by modulating the activity of the mesolimbic dopamine system. Unfortunately, the rapid regulation of dopamine signaling by the aversive stimuli that cause drug seeking is not well characterized. In a series of experiments, we scrutinized the subsecond regulation of dopamine signaling by the aversive stimulus, quinine, and tested its ability to cause cocaine seeking. Additionally, we examined the midbrain regulation of both dopamine signaling and cocaine seeking by the stress-sensitive peptide, corticotropin releasing factor (CRF). Methods Combining fast-scan cyclic voltammetry with behavioral pharmacology, we examined the effect of intraoral quinine administration on nucleus accumbens dopamine signaling and hedonic expression in 21 male Sprague-Dawley rats. We tested the role of CRF in modulating aversion-induced changes in dopamine concentration and cocaine seeking by bilaterally infusing the CRF antagonist, CP-376395, into the ventral tegmental area (VTA). Results We found that quinine rapidly reduced dopamine signaling on two distinct time scales. We determined that CRF acted in the VTA to mediate this reduction on only one of these time scales. Further, we found that the reduction of dopamine tone and quinine-induced cocaine seeking were eliminated by blocking the actions of CRF in the VTA during the experience of the aversive stimulus. Conclusions These data demonstrate that stress-induced drug seeking can occur in a terminal environment of low dopamine tone that is dependent on a CRF-induced decrease in midbrain dopamine activity

The Mass Dependance of Satellite Quenching in Milky Way-like Halos

Using the Sloan Digital Sky Survey, we examine the quenching of satellite galaxies around isolated Milky Way-like hosts in the local Universe. We find that the efficiency of satellite quenching around isolated galaxies is low and roughly constant over two orders of magnitude in satellite stellar mass ($M_{*}$ = $10^{8.5}-10^{10.5} \, M_{\odot}$), with only $\sim~20\%$ of systems quenched as a result of environmental processes. While largely independent of satellite stellar mass, satellite quenching does exhibit clear dependence on the properties of the host. We show that satellites of passive hosts are substantially more likely to be quenched than those of star-forming hosts, and we present evidence that more massive halos quench their satellites more efficiently. These results extend trends seen previously in more massive host halos and for higher satellite masses. Taken together, it appears that galaxies with stellar masses larger than about $10^{8}~M_{\odot}$ are uniformly resistant to environmental quenching, with the relative harshness of the host environment likely serving as the primary driver of satellite quenching. At lower stellar masses ($< 10^{8}~M_{\odot}$), however, observations of the Local Group suggest that the vast majority of satellite galaxies are quenched, potentially pointing towards a characteristic satellite mass scale below which quenching efficiency increases dramatically.Comment: 14 pages, 8 figure

A Dichotomy in Satellite Quenching Around L* Galaxies

We examine the star formation properties of bright (~0.1 L*) satellites around isolated ~L* hosts in the local Universe using spectroscopically confirmed systems in the Sloan Digital Sky Survey DR7. Our selection method is carefully designed with the aid of N-body simulations to avoid groups and clusters. We find that satellites are significantly more likely to be quenched than a stellar mass-matched sample of isolated galaxies. Remarkably, this quenching occurs only for satellites of hosts that are themselves quenched: while star formation is unaffected in the satellites of star-forming hosts, satellites around quiescent hosts are more than twice as likely to be quenched than stellar-mass matched field samples. One implication of this is that whatever shuts down star formation in isolated, passive L* galaxies also plays at least an indirect role in quenching star formation in their bright satellites. The previously-reported tendency for "galactic conformity" in color/morphology may be a by-product of this host-specific quenching dichotomy. The S\'ersic indices of quenched satellites are statistically identical to those of field galaxies with the same specific star formation rates, suggesting that environmental and secular quenching give rise to the same morphological structure. By studying the distribution of pairwise velocities between the hosts and satellites, we find dynamical evidence that passive host galaxies reside in dark matter halos that are ~45% more massive than those of star-forming host galaxies of the same stellar mass. We emphasize that even around passive hosts, the mere fact that galaxies become satellites does not typically result in star formation quenching: we find that only ~30% of ~0.1 L* galaxies that fall in from the field are quenched around passive hosts, compared with ~0% around star forming hosts.Comment: 14 pages, 9 figure

Importance of Biologically Active Aurora-like Ultraviolet Emission: Stochastic Irradiation of Earth and Mars by Flares and Explosions

(Abridged) We show that sizeable fractions of incident ionizing radiation from stochastic astrophysical sources can be redistributed to biologically and chemically important UV wavelengths, a significant fraction of which can reach the surface. This redistribution is mediated by secondary electrons, resulting from Compton scattering and X-ray photoabsorption, with energies low enough to excite atmospheric molecules and atoms, resulting in a rich aurora-like spectrum. We calculate the fraction of energy redistributed into biologically and chemically important wavelength regions for spectra characteristic of stellar flares and supernovae using a Monte-Carlo transport code written for this problem and then estimate the fraction of this energy that is transmitted from the atmospheric altitudes of redistribution to the surface for a few illustrative cases. Redistributed fractions are found to be of order 1%, even in the presence of an ozone shield. This result implies that planetary organisms will be subject to mutationally significant, if intermittent, fluences of UV-B and harder radiation even in the presence of a narrow-band UV shield like ozone. We also calculate the surficial transmitted fraction of ionizing radiation and redistributed ultraviolet radiation for two illustrative evolving Mars atmospheres whose initial surface pressures were 1 bar. Our results suggest that coding organisms on planets orbiting low-mass stars (and on the early Earth) may evolve very differently than on contemporary Earth, with diversity and evolutionary rate controlled by a stochastically varying mutation rate and frequent hypermutation episodes.Comment: 21 pages, 2 figures, accepted for publication in Origins of Life and Evolution of the Biospher

Transport of Ionizing Radiation in Terrestrial-like Exoplanet Atmospheres

(Abridged) The propagation of ionizing radiation through model atmospheres of terrestrial-like exoplanets is studied for a large range of column densities and incident photon energies using a Monte Carlo code we have developed to treat Compton scattering and photoabsorption. Incident spectra from parent star flares, supernovae, and gamma-ray bursts are modeled and compared to energetic particles in importance. We find that terrestrial-like exoplanets with atmospheres thinner than about 100 g cm^-2 transmit and reprocess a significant fraction of incident gamma-rays, producing a characteristic, flat surficial spectrum. Thick atmospheres (>~ 100 g cm^-2) efficiently block even gamma-rays, but nearly all incident energy is redistributed into diffuse UV and visible aurora-like emission, increasing the effective atmospheric transmission by many orders of magnitude. Depending on the presence of molecular UV absorbers and atmospheric thickness, up to 10% of the incident energy can reach the surface as UV reemission. For the Earth, between 2 x 10^-3 and 4 x 10^-2 of the incident flux reaches the ground in the biologically effective 200--320 nm range, depending on O_2/O_3 shielding. Finally, we suggest that transient atmospheric ionization layers can be frequently created at low altitudes. We conclude that these events can produce frequent fluctuations in atmospheric ionization levels and surficial UV fluxes on terrestrial-like planets.Comment: 59 pages, 15 figures; in press in Icarus; minor edits, no results change

Corticosterone Regulates Both Naturally Occurring and Cocaine‐Induced Dopamine Signaling by Selectively Decreasing Dopamine Uptake

Stressful and aversive events promote maladaptive reward‐seeking behaviors such as drug addiction by acting, in part, on the mesolimbic dopamine system. Using animal models, data from our laboratory and others show that stress and cocaine can interact to produce a synergistic effect on reward circuitry. This effect is also observed when the stress hormone corticosterone is administered directly into the nucleus accumbens (NAc), indicating that glucocorticoids act locally in dopamine terminal regions to enhance cocaine\u27s effects on dopamine signaling. However, prior studies in behaving animals have not provided mechanistic insight. Using fast‐scan cyclic voltammetry, we examined the effect of systemic corticosterone on spontaneous dopamine release events (transients) in the NAc core and shell in behaving rats. A physiologically relevant systemic injection of corticosterone (2 mg/kg i.p.) induced an increase in dopamine transient amplitude and duration (both voltammetric measures sensitive to decreases in dopamine clearance), but had no effect on the frequency of transient release events. This effect was compounded by cocaine (2.5 mg/kg i.p.). However, a second experiment indicated that the same injection of corticosterone had no detectable effect on the dopaminergic encoding of a palatable natural reward (saccharin). Taken together, these results suggest that corticosterone interferes with naturally occurring dopamine uptake locally, and this effect is a critical determinant of dopamine concentration specifically in situations in which the dopamine transporter is pharmacologically blocked by cocaine

Putting pharmaceuticals into the wider context of challenges to fish populations in rivers

The natural range of fish species in our rivers is related to flow, elevation, temperature, local habitat and connectivity. For over 2000 years, humans have altered to varying degrees the river habitat. In the past 200 years, we added to the environmental disruption by discharging poorly treated sewage, nutrients and industrial waste into our rivers. For many rivers, the low point arrived during the period of 1950s–1970s, when rapid economic development overrode environmental concerns and dissolved oxygen concentrations dropped to zero. In these more enlightened times, gross river pollution is a thing of the past in the Developed World. However, persistent legacy chemical contaminants can be found in fish long after their discharge ceased. Changes in habitat quality and morphology caused and continue to cause the disappearance of fish species. The range of fish stressors has now increased as temperatures rise, and non-native fish introductions bring new diseases. The threat from pharmaceuticals to fish populations remains hypothetical, and no studies have yet linked change in fish populations to exposure

Corticosterone Acts in the Nucleus Accumbens to Enhance Dopamine Signaling and Potentiate Reinstatement of Cocaine Seeking

Stressful life events are important contributors to relapse in recovering cocaine addicts, but the mechanisms by which they influence motivational systems are poorly understood. Studies suggest that stress may “set the stage” for relapse by increasing the sensitivity of brain reward circuits to drug-associated stimuli. We examined the effects of stress and corticosterone on behavioral and neurochemical responses of rats to a cocaine prime after cocaine self-administration and extinction. Exposure of rats to acute electric footshock stress did not by itself reinstate drug-seeking behavior but potentiated reinstatement in response to a subthreshold dose of cocaine. This effect of stress was not observed in adrenalectomized animals, and was reproduced in nonstressed animals by administration of corticosterone at a dose that reproduced stress-induced plasma levels. Pretreatment with the glucocorticoid receptor antagonist RU38486 did not block the corticosterone effect. Corticosterone potentiated cocaine-induced increases in extracellular dopamine in the nucleus accumbens (NAc), and pharmacological blockade of NAc dopamine receptors blocked corticosterone-induced potentiation of reinstatement. Intra-accumbens administration of corticosterone reproduced the behavioral effects of stress and systemic corticosterone. Corticosterone treatment acutely decreased NAc dopamine clearance measured by fast-scan cyclic voltammetry, suggesting that inhibition of uptake2-mediated dopamine clearance may underlie corticosterone effects. Consistent with this hypothesis, intra-accumbens administration of the uptake2 inhibitor normetanephrine potentiated cocaine-induced reinstatement. Expression of organic cation transporter 3, a corticosterone-sensitive uptake2 transporter, was detected on NAc neurons. These findings reveal a novel mechanism by which stress hormones can rapidly regulate dopamine signaling and contribute to the impact of stress on drug intake

Developmental trends in voice onset time: some evidence for sex differences

This study reports on an investigation into the voice onset time (VOT) patterns of the plosives /p b t d/ in a group of 30 children aged 7 (n = 10), 9 (n = 10) and 11 (n = 10) years. Equal numbers of girls and boys participated in the study. Each child named a series of letter objects to elicit /p b t d/ in a syllable onset position with a fixed vowel context. VOT data were examined for age, sex and plosive differences with the following hypotheses: Firstly, that there would be sex differences in the VOT patterns of preadolescent children. Secondly, that the sex differences in VOT patterns would be linked to age and development, and that these would eventually become marked by the age of 11 years, by which time adult-like VOT values should have been achieved. Finally, that the extent of sex and age differences would be dependent upon the plosive being investigated. Results indicated patterns of decrease with age in the VOT values of /p b/ for the boys, with some evidence of increases in the VOT values of /t/ for the girls. In addition, 'voiced' and 'voiceless' cognates showed a more marked bimodal distribution in the girls' VOT patterns. This bimodal distribution was investigated by examining the degree of difference between the VOT values of voiced and voiceless cognate pairs /p b/ and /t d/, and examining the effects of age, sex and cognate pair. These results indicated that more marked sex differences in the 'voiced'/'voiceless' contrast emerged between the data of the 9- and 11-year-olds, a pattern, which was more marked for the alveolar plosives. These preliminary results confirmed all three hypotheses. The findings are presented and discussed both within a developmental and sociophonetic framework