Effects of bupropion on nicotine self-administration and food-maintained responding in rats

Over the past 40 years various behavioral techniques and pharmaceutical adjuncts have been developed to aid in smoking cessation. The continued need for the development of new and more effective pharmaceutical adjuncts for smoking cessation is evident by the large number of individuals continuing to smoke despite their knowledge of the significant health risks associated with tobacco use. Bupropion recently has been found to be a useful pharmaceutical agent in furthering smoking abstinence, but the long-term effectiveness of the drug is mediocre at best. In order to gain a better understanding of how bupropion affects smoking, the current studies investigated the effects of bupropion in a rodent model of nicotine self-administration. In the nicotine study, subjects self-administered nicotine (0.03 mg/kg/inf) under a fixed-ratio 3 (FR3) 60 s timeout (TO) schedule of reinforcement. The effects of bupropion on food-maintained responding using two levels of food deprivation (food-deprived and food-satiated) were used to assess the specificity of the effects of the drug on nicotine self-administration. Once subjects acquired stable rates of responding, they were pretreated 15 min prior to 60 min sessions with various doses of bupropion (0, 10, 30, 56 mg/kg, IP). The 30 mg/kg dose of bupropion resulted in an increase in nicotine intake while the drug dose-dependently decreased food-maintained behavior under deprivation conditions. When more comparable rates of behavior in the food-satiated group were investigated, bupropion had similar effects on nicotine and food-maintained responding. The current studies indicate that response rate must be considered when evaluating selective effects of drugs. The findings that bupropion can increase moderate rates of nicotine self-administration at doses that decrease higher rates of responding maintained by food suggest that adding alternative reinforcers to the environment of individuals attempting to quit could affect the drug’s ability to sustain abstinence

The NMDA receptor GluN2C subunit controls cortical excitatoryinhibitory balance, neuronal oscillations and cognitive function

Despite strong evidence for NMDA receptor (NMDAR) hypofunction as an underlying factor for cognitive disorders, the precise roles of various NMDAR subtypes remains unknown. The GluN2Ccontaining NMDARs exhibit unique biophysical properties and expression pattern, and lower expression of GluN2C subunit has been reported in postmortem brains from schizophrenia patients. We found that loss of GluN2C subunit leads to a shift in cortical excitatory-inhibitory balance towards greater inhibition. Specifically, pyramidal neurons in the medial prefrontal cortex (mPFC) of GluN2C knockout mice have reduced mEPSC frequency and dendritic spine density and a contrasting higher frequency of mIPSCs. In addition a greater number of perisomatic GAD67 puncta was observed suggesting a potential increase in parvalbumin interneuron inputs. At a network level the GluN2C knockout mice were found to have a more robust increase in power of oscillations in response to NMDAR blocker MK- 801. Furthermore, GluN2C heterozygous and knockout mice exhibited abnormalities in cognition and sensorimotor gating. Our results demonstrate that loss of GluN2C subunit leads to cortical excitatoryinhibitory imbalance and abnormal neuronal oscillations associated with neurodevelopmental disorders

Multi-Messenger Gravitational Wave Searches with Pulsar Timing Arrays: Application to 3C66B Using the NANOGrav 11-year Data Set

When galaxies merge, the supermassive black holes in their centers may form binaries and, during the process of merger, emit low-frequency gravitational radiation in the process. In this paper we consider the galaxy 3C66B, which was used as the target of the first multi-messenger search for gravitational waves. Due to the observed periodicities present in the photometric and astrometric data of the source of the source, it has been theorized to contain a supermassive black hole binary. Its apparent 1.05-year orbital period would place the gravitational wave emission directly in the pulsar timing band. Since the first pulsar timing array study of 3C66B, revised models of the source have been published, and timing array sensitivities and techniques have improved dramatically. With these advances, we further constrain the chirp mass of the potential supermassive black hole binary in 3C66B to less than $(1.65\pm0.02) \times 10^9~{M_\odot}$ using data from the NANOGrav 11-year data set. This upper limit provides a factor of 1.6 improvement over previous limits, and a factor of 4.3 over the first search done. Nevertheless, the most recent orbital model for the source is still consistent with our limit from pulsar timing array data. In addition, we are able to quantify the improvement made by the inclusion of source properties gleaned from electromagnetic data to `blind' pulsar timing array searches. With these methods, it is apparent that it is not necessary to obtain exact a priori knowledge of the period of a binary to gain meaningful astrophysical inferences.Comment: 14 pages, 6 figures. Accepted by Ap

The NANOGrav 12.5-Year Data Set: Polarimetry and Faraday Rotation Measures from Observations of Millisecond Pulsars with the Green Bank Telescope

In this work, we present polarization profiles for 23 millisecond pulsars observed at 820 MHz and 1500 MHz with the Green Bank Telescope as part of the NANOGrav pulsar timing array. We calibrate the data using Mueller matrix solutions calculated from observations of PSRs B1929+10 and J1022+1001. We discuss the polarization profiles, which can be used to constrain pulsar emission geometry, and present both the first published radio polarization profiles for nine pulsars and the discovery of very low intensity average profile components ("microcomponents") in four pulsars. Using the Faraday rotation measures, we measure for each pulsar and use it to calculate the Galactic magnetic field parallel to the line of sight for different lines of sight through the interstellar medium. We fit for linear and sinusoidal trends in time in the dispersion measure and Galactic magnetic field and detect magnetic field variations with a period of one year in some pulsars, but overall find that the variations in these parameters are more consistent with a stochastic origin.Comment: 35 pages, 21 figures. Accepted to Ap

Bayesian Solar Wind Modeling with Pulsar Timing Arrays

Using Bayesian analyses we study the solar electron density with the NANOGrav 11-year pulsar timing array (PTA) dataset. Our model of the solar wind is incorporated into a global fit starting from pulse times-of-arrival. We introduce new tools developed for this global fit, including analytic expressions for solar electron column densities and open source models for the solar wind that port into existing PTA software. We perform an ab initio recovery of various solar wind model parameters. We then demonstrate the richness of information about the solar electron density, $n_E$, that can be gleaned from PTA data, including higher order corrections to the simple $1/r^2$ model associated with a free-streaming wind (which are informative probes of coronal acceleration physics), quarterly binned measurements of $n_E$ and a continuous time-varying model for $n_E$ spanning approximately one solar cycle period. Finally, we discuss the importance of our model for chromatic noise mitigation in gravitational-wave analyses of pulsar timing data and the potential of developing synergies between sophisticated PTA solar electron density models and those developed by the solar physics community.Comment: 22 pages, 7 figures, Submitted to Ap

An unusual pulse shape change event in PSR J1713+0747 observed with the Green Bank Telescope and CHIME

The millisecond pulsar J1713+0747 underwent a sudden and significant pulse shape change between April 16 and 17, 2021 (MJDs 59320 and 59321). Subsequently, the pulse shape gradually recovered over the course of several months. We report the results of continued multi-frequency radio observations of the pulsar made using the Canadian Hydrogen Intensity Mapping Experiment (CHIME) and the 100-meter Green Bank Telescope (GBT) in a three-year period encompassing the shape change event, between February 2020 and February 2023. As of February 2023, the pulse shape had returned to a state similar to that seen before the event, but with measurable changes remaining. The amplitude of the shape change and the accompanying TOA residuals display a strong non-monotonic dependence on radio frequency, demonstrating that the event is neither a glitch (the effects of which should be independent of radio frequency, $\nu$) nor a change in dispersion measure (DM) alone (which would produce a delay proportional to $\nu^{-2}$). However, it does bear some resemblance to the two previous "chromatic timing events" observed in J1713+0747 (Demorest et al. 2013; Lam et al. 2016), as well as to a similar event observed in PSR J1643-1224 in 2015 (Shannon et al. 2016).Comment: 19 pages, 8 figures. Submitted to ApJ. Data available at https://doi.org/10.5281/zenodo.723645

An Unusual Pulse Shape Change Event in PSR J1713+0747 Observed with the Green Bank Telescope and CHIME

The millisecond pulsar J1713+0747 underwent a sudden and significant pulse shape change between 2021 April 16 and 17 (MJDs 59320 and 59321). Subsequently, the pulse shape gradually recovered over the course of several months. We report the results of continued multifrequency radio observations of the pulsar made using the Canadian Hydrogen Intensity Mapping Experiment and the 100 m Green Bank Telescope in a 3 yr period encompassing the shape change event, between 2020 February and 2023 February. As of 2023 February, the pulse shape had returned to a state similar to that seen before the event, but with measurable changes remaining. The amplitude of the shape change and the accompanying time-of-arrival residuals display a strong nonmonotonic dependence on radio frequency, demonstrating that the event is neither a glitch (the effects of which should be independent of radio frequency, ν) nor a change in dispersion measure alone (which would produce a delay proportional to ν−2). However, it does bear some resemblance to the two previous "chromatic timing events" observed in J1713+0747, as well as to a similar event observed in PSR J1643−1224 in 2015

Multimessenger Gravitational-wave Searches with Pulsar Timing Arrays:Application to 3C 66B Using the NANOGrav 11-year Data Set

When galaxies merge, the supermassive black holes in their centers may form binaries and emit low-frequency gravitational radiation in the process. In this paper, we consider the galaxy 3C 66B, which was used as the target of the first multimessenger search for gravitational waves. Due to the observed periodicities present in the photometric and astrometric data of the source, it has been theorized to contain a supermassive black hole binary. Its apparent 1.05-year orbital period would place the gravitational-wave emission directly in the pulsar timing band. Since the first pulsar timing array study of 3C 66B, revised models of the source have been published, and timing array sensitivities and techniques have improved dramatically. With these advances, we further constrain the chirp mass of the potential supermassive black hole binary in 3C 66B to less than (1.65 ± 0.02) × 109 M o˙ using data from the NANOGrav 11-year data set. This upper limit provides a factor of 1.6 improvement over previous limits and a factor of 4.3 over the first search done. Nevertheless, the most recent orbital model for the source is still consistent with our limit from pulsar timing array data. In addition, we are able to quantify the improvement made by the inclusion of source properties gleaned from electromagnetic data over "blind"pulsar timing array searches. With these methods, it is apparent that it is not necessary to obtain exact a priori knowledge of the period of a binary to gain meaningful astrophysical inferences

The NANOGrav Nine-year Data Set:Observations, Arrival Time Measurements, and Analysis of 37 Millisecond Pulsars

We present high-precision timing observations spanning up to nine years for 37 millisecond pulsars monitored with the Green Bank and Arecibo radio telescopes as part of the North American Nanohertz Observatory for Gravitational Waves (NANOGrav) project. We describe the observational and instrumental setups used to collect the data, and methodology applied for calculating pulse times of arrival; these include novel methods for measuring instrumental offsets and characterizing low signal-to-noise ratio timing results. The time of arrival data are fit to a physical timing model for each source, including terms that characterize time-variable dispersion measure and frequency-dependent pulse shape evolution. In conjunction with the timing model fit, we have performed a Bayesian analysis of a parameterized timing noise model for each source, and detect evidence for excess low-frequency, or "red," timing noise in 10 of the pulsars. For 5 of these cases this is likely due to interstellar medium propagation effects rather than intrisic spin variations. Subsequent papers in this series will present further analysis of this data set aimed at detecting or limiting the presence of nanohertz-frequency gravitational wave signals

The NANOGrav 11-year Data Set: High-precision Timing of 45 Millisecond Pulsars

We present high-precision timing data over time spans of up to 11 years for 45 millisecond pulsars observed as part of the North American Nanohertz Observatory for Gravitational Waves (NANOGrav) project, aimed at detecting and characterizing low-frequency gravitational waves. The pulsars were observed with the Arecibo Observatory and/or the Green Bank Telescope at frequencies ranging from 327 MHz to 2.3 GHz. Most pulsars were observed with approximately monthly cadence, and six high-timing-precision pulsars were observed weekly. All were observed at widely separated frequencies at each observing epoch in order to fit for time-variable dispersion delays. We describe our methods for data processing, time-of-arrival (TOA) calculation, and the implementation of a new, automated method for removing outlier TOAs. We fit a timing model for each pulsar that includes spin, astrometric, and (for binary pulsars) orbital parameters; time-variable dispersion delays; and parameters that quantify pulse-profile evolution with frequency. The timing solutions provide three new parallax measurements, two new Shapiro delay measurements, and two new measurements of significant orbital-period variations. We fit models that characterize sources of noise for each pulsar. We find that 11 pulsars show significant red noise, with generally smaller spectral indices than typically measured for non-recycled pulsars, possibly suggesting a different origin. A companion paper uses these data to constrain the strength of the gravitational-wave background