Long-Term Alcohol Drinking Reduces the Efficacy of Forced Abstinence and Conditioned Taste Aversion in Crossed High-Alcohol-Preferring Mice

BACKGROUND: Negative outcomes of alcoholism are progressively more severe as the duration of problem of alcohol use increases. Additionally, alcoholics demonstrate tendencies to neglect negative consequences associated with drinking and/or to choose to drink in the immediate presence of warning factors against drinking. The recently derived crossed high-alcohol-preferring (cHAP) mice, which volitionally drink to heavier intoxication (as assessed by blood ethanol [EtOH] concentration) than other alcohol-preferring populations, as well as spontaneously escalating their intake, may be a candidate to explore mechanisms underlying long-term excessive drinking. Here, we hypothesized that an extended drinking history would reduce the ability of 2 manipulations (forced abstinence [FA] and conditioned taste aversion [CTA]) to attenuate drinking. METHODS: Experiment 1 examined differences between groups drinking for either 14 or 35 days, half of each subjected to 7 days of FA and half not, to characterize the potential changes in postabstinence drinking resulting from an extended drinking history. Experiment 2 used a CTA procedure to assess stimulus specificity of the ability of an aversive flavorant to decrease alcohol consumption. Experiment 3 used this taste aversion procedure to assess differences among groups drinking for 1, 14, or 35 days in their propensity to overcome this aversion when the flavorant was mixed with either EtOH or water. RESULTS: Experiment 1 demonstrated that although FA decreased alcohol consumption in mice with a 14-day drinking history, it failed to do so in mice drinking alcohol for 35 days. Experiment 2 showed that the addition of a flavorant only suppressed alcohol drinking if an aversion to the flavorant was previously established. Experiment 3 demonstrated that an extended drinking history expedited extinction of suppressed alcohol intake caused by a conditioned aversive flavor. CONCLUSIONS: These data show that a history of long-term drinking in cHAP mice attenuates the efficacy of interventions that normally reduce drinking. Analogous to alcoholics who may encounter difficulties in limiting their intake, cHAP mice with long drinking histories are relatively insensitive to both abstinence and signals of harmful consequences. We propose that the cHAP line may be a valid model for adaptations that occur following the extended heavy alcohol drinking

Effects of Intoxicating Free-Choice Alcohol Consumption During Adolescence on Drinking and Impulsivity During Adulthood in Selectively Bred High Alcohol Preferring Mice

Background— Abuse of alcohol during adolescence continues to be a problem, and it has been shown that earlier onset of drinking predicts increased alcohol abuse problems later in life. High levels of impulsivity have been demonstrated to be characteristic of alcoholics, and impulsivity has also been shown to predict later alcohol use in teenage subjects, showing that impulsivity may precede the development of alcohol use disorders. These experiments examined adolescent drinking in a high-drinking, relatively impulsive mouse population, and assessed its effects on adult drinking and adult impulsivity. Methods— Experiment 1: Selectively bred High-Alcohol Preferring (HAPII) mice were given either alcohol (free choice access) or water only for two weeks during middle adolescence or adulthood. All mice were given free choice access to alcohol 30 days later, in adulthood. Experiment 2: Adolescent HAPII mice drank alcohol and water, or water alone, for two weeks, and were then trained to perform a delay discounting task as adults to measure impulsivity. In each experiment, effects of volitional ethanol consumption on later behavior were assessed. We expected adolescent alcohol exposure to increase subsequent drinking and impulsivity. Results— Mice consumed significant quantities of ethanol, reaching average blood ethanol concentrations (BECs) of 142 mg/dl (adolescent) or 154 mg/dl (adult) in Experiment 1. Adolescent mice in experiment 2 reached an average of 108 mg/dl. Mice exposed to alcohol in either adolescence or adulthood showed a transient increase in ethanol consumption, but we observed no differences in impulsivity in adult mice as a function of whether mice drank alcohol during adolescence. Conclusions— These findings indicate that HAPII mice drink intoxicating levels of alcohol during both adolescence and adulthood, and that this volitional intake has long-term effects on subsequent drinking behavior. Nonetheless, this profound exposure to alcohol during adolescence does not increase impulsivity in adulthood, indicating that long-term changes in drinking are mediated by mechanisms other than impulsivity

The seventh blind test of crystal structure prediction: structure generation methods.

Publication status: PublishedA seventh blind test of crystal structure prediction was organized by the Cambridge Crystallographic Data Centre featuring seven target systems of varying complexity: a silicon and iodine-containing molecule, a copper coordination complex, a near-rigid molecule, a cocrystal, a polymorphic small agrochemical, a highly flexible polymorphic drug candidate, and a polymorphic morpholine salt. In this first of two parts focusing on structure generation methods, many crystal structure prediction (CSP) methods performed well for the small but flexible agrochemical compound, successfully reproducing the experimentally observed crystal structures, while few groups were successful for the systems of higher complexity. A powder X-ray diffraction (PXRD) assisted exercise demonstrated the use of CSP in successfully determining a crystal structure from a low-quality PXRD pattern. The use of CSP in the prediction of likely cocrystal stoichiometry was also explored, demonstrating multiple possible approaches. Crystallographic disorder emerged as an important theme throughout the test as both a challenge for analysis and a major achievement where two groups blindly predicted the existence of disorder for the first time. Additionally, large-scale comparisons of the sets of predicted crystal structures also showed that some methods yield sets that largely contain the same crystal structures

The seventh blind test of crystal structure prediction: structure ranking methods.

Publication status: PublishedA seventh blind test of crystal structure prediction has been organized by the Cambridge Crystallographic Data Centre. The results are presented in two parts, with this second part focusing on methods for ranking crystal structures in order of stability. The exercise involved standardized sets of structures seeded from a range of structure generation methods. Participants from 22 groups applied several periodic DFT-D methods, machine learned potentials, force fields derived from empirical data or quantum chemical calculations, and various combinations of the above. In addition, one non-energy-based scoring function was used. Results showed that periodic DFT-D methods overall agreed with experimental data within expected error margins, while one machine learned model, applying system-specific AIMnet potentials, agreed with experiment in many cases demonstrating promise as an efficient alternative to DFT-based methods. For target XXXII, a consensus was reached across periodic DFT methods, with consistently high predicted energies of experimental forms relative to the global minimum (above 4 kJ mol-1 at both low and ambient temperatures) suggesting a more stable polymorph is likely not yet observed. The calculation of free energies at ambient temperatures offered improvement of predictions only in some cases (for targets XXVII and XXXI). Several avenues for future research have been suggested, highlighting the need for greater efficiency considering the vast amounts of resources utilized in many cases

The seventh blind test of crystal structure prediction: structure ranking methods

A seventh blind test of crystal structure prediction has been organized by the Cambridge Crystallographic Data Centre. The results are presented in two parts, with this second part focusing on methods for ranking crystal structures in order of stability. The exercise involved standardized sets of structures seeded from a range of structure generation methods. Participants from 22 groups applied several periodic DFT-D methods, machine learned potentials, force fields derived from empirical data or quantum chemical calculations, and various combinations of the above. In addition, one non-energy-based scoring function was used. Results showed that periodic DFT-D methods overall agreed with experimental data within expected error margins, while one machine learned model, applying system-specific AIMnet potentials, agreed with experiment in many cases demonstrating promise as an efficient alternative to DFT-based methods. For target XXXII, a consensus was reached across periodic DFT methods, with consistently high predicted energies of experimental forms relative to the global minimum (above 4 kJ mol−1 at both low and ambient temperatures) suggesting a more stable polymorph is likely not yet observed. The calculation of free energies at ambient temperatures offered improvement of predictions only in some cases (for targets XXVII and XXXI). Several avenues for future research have been suggested, highlighting the need for greater efficiency considering the vast amounts of resources utilized in many cases

Abstracts of the 3rd Annual Graduate Entry Research in Medicine Conference

This book contains the abstracts of the papers presented at The 3rd Annual Graduate Entry Research in Medicine Conference (GERMCON 2020) Organized by Warwick Medical School, University of Warwick in collaboration with Swansea University Medical School, Swansea University, Wales, UK held on 12–18 October 2020. This was especially important for Graduate Entry Medical (GEM) students, who have less opportunity and time to engage in research due to their accelerated medical degree. Conference Title: 3rd Annual Graduate Entry Research in Medicine ConferenceConference Acronym: GERMCON 2020Conference Date: 12–18 October 2020Conference Location: Online (Virtual Mode)Conference Organizer: Warwick Medical School, University of Warwick, UKCo-organizer: Swansea University Medical School, Swansea University, Wales, UK Other Abstract Book of GERMCON: Abstracts of the 4th Annual Graduate Entry Research in Medicine Conferenc

The seventh blind test of crystal structure prediction: structure ranking methods

A seventh blind test of crystal structure prediction has been organized by the Cambridge Crystallographic Data Centre. The results are presented in two parts, with this second part focusing on methods for ranking crystal structures in order of stability. The exercise involved standardized sets of structures seeded from a range of structure generation methods. Participants from 22 groups applied several periodic DFT-D methods, machine learned potentials, force fields derived from empirical data or quantum chemical calculations, and various combinations of the above. In addition, one non-energy-based scoring function was used. Results showed that periodic DFT-D methods overall agreed with experimental data within expected error margins, while one machine learned model, applying system-specific AIMnet potentials, agreed with experiment in many cases demonstrating promise as an efficient alternative to DFT-based methods. For target XXXII, a consensus was reached across periodic DFT methods, with consistently high predicted energies of experimental forms relative to the global minimum (above 4 kJ mol−1 at both low and ambient temperatures) suggesting a more stable polymorph is likely not yet observed. The calculation of free energies at ambient temperatures offered improvement of predictions only in some cases (for targets XXVII and XXXI). Several avenues for future research have been suggested, highlighting the need for greater efficiency considering the vast amounts of resources utilized in many cases.</p

The seventh blind test of crystal structure prediction: structure generation methods

A seventh blind test of crystal structure prediction was organized by the Cambridge Crystallographic Data Centre featuring seven target systems of varying complexity: a silicon and iodine-containing molecule, a copper coordination complex, a near-rigid molecule, a cocrystal, a polymorphic small agrochemical, a highly flexible polymorphic drug candidate, and a polymorphic morpholine salt. In this first of two parts focusing on structure generation methods, many crystal structure prediction (CSP) methods performed well for the small but flexible agrochemical compound, successfully reproducing the experimentally observed crystal structures, while few groups were successful for the systems of higher complexity. A powder X-ray diffraction (PXRD) assisted exercise demonstrated the use of CSP in successfully determining a crystal structure from a low-quality PXRD pattern. The use of CSP in the prediction of likely cocrystal stoichiometry was also explored, demonstrating multiple possible approaches. Crystallographic disorder emerged as an important theme throughout the test as both a challenge for analysis and a major achievement where two groups blindly predicted the existence of disorder for the first time. Additionally, large-scale comparisons of the sets of predicted crystal structures also showed that some methods yield sets that largely contain the same crystal structures