Theoretical Investigation of Linear Relationships between the Dihedral Torsion Angles and Diosmium Bond Distances in Diosmium Sawhorse Complexes.

Strong linear relationships between their Ceq-Os-Os-Ceq dihedral angles and their Os-Os bond distances in diosmium sawhorse complexes Os2(u-O2CR)2(CO)4L2 (L = CO and/or PR3) form two trendlines depending upon the presence or absence of terminal phosphines. These trends appear unrelated to the basicity of the bridging ligand or the number of phosphines. The mathematical derivation of the relationship between the O-Os-Os-O dihedral angle and the Os-Os bond distance shows how the other geometric parameters affect this relationship. Optimized density functional theory (DFT) structures reveal a similar strong linear correlation, where more electron-donating ligands render shorter Os-Os bond distances and larger dihedral angles, but these results form a single trendline. Computational scans of individual parameters show that the Os-Os bond responds strongly to changes in the dihedral angles, but the dihedral angles only respond weakly to changes in the Os-Os bond distance because the Os-Os-O bond angle links and modifies their direct coupling. Solid-state analysis of their structures, including DFT geometry optimizations, shows that phosphines protect the Os-Os bond distance from packing influences along the Os-Os axis, while in complexes without phosphines, packing compresses the Os-Os bond and the weak dihedral responses create the second trendline.

Kinetic and Computational Analysis of CO Substitution in a Dinuclear Osmium Carbonyl Complex: Intersection between Dissociative and Dissociative-Interchange Mechanisms.

The mechanism for the CO substitution reaction involving the diosmium carbonyl sawhorse complex Os2(µ-O2CH)2(CO)6, which contains an Os-Os single bond, two axial CO ligands, and four equatorial CO ligands, was investigated experimentally and theoretically. Kinetic measurements show 13CO axial substitution proceeding by a dissociative reaction that is first-order in the complex and zero-order in 13CO but with an unexpectedly negative entropy of activation. The corresponding electronic structure calculations yield an enthalpy of activation for axial CO dissociation that is much larger than that determined by the kinetic experiments, but in agreement with the complex's stability with respect to CO loss. Additional calculations yield a dissociative interchange transition state whose free energy, enthalpy, and entropy of activation are in good agreement with those obtained from the kinetic measurements for the apparently dissociative substitution. These results point to an exchange reaction mechanism that is surprisingly close to the poorly understood transition from a dissociative mechanism with a CO-loss intermediate to a dissociative interchange mechanism with a transition state involving both the entering and the leaving COs. The key to explain these findings is provided by the vibrational analysis, which shows very low energy wagging motions for the axial COs. Thus, the incoming CO only displaces the outgoing CO when the complex has an outgoing CO near the wag's turning point. This dissociative interchange mechanism predicted by the calculation explains the unexpected combination of kinetics and stability characteristics. Kinetics reveals that the reaction is first-order in the Os dimer with a negative Eyring entropy, while a stability study shows that the Os dimer's decomposition rate is several orders of magnitude slower than CO exchange.

Accumbens neuroimmune signaling and dysregulation of astrocytic glutamate transport underlie conditioned nicotine-seeking behavior.

Nicotine self-administration is associated with decreased expression of the glial glutamate transporter (GLT-1) and the cystine-glutamate exchange protein xCT within the nucleus accumbens core (NAcore). N-acetylcysteine (NAC) has been shown to restore these proteins in a rodent model of drug addiction and relapse. However, the specific molecular mechanisms driving its inhibitory effects on cue-induced nicotine reinstatement are unknown. Here, we confirm that extinction of nicotine-seeking behavior is associated with impaired NAcore GLT-1 function and expression and demonstrates that reinstatement of nicotine seeking rapidly enhances membrane fraction GLT-1 expression. Extinction and cue-induced reinstatement of nicotine seeking was also associated with increased tumor necrosis factor alpha (TNFα) and decreased glial fibrillary acidic protein (GFAP) expression in the NAcore. NAC treatment (100 mg/kg/day, i.p., for 5 d) inhibited cue-induced nicotine seeking and suppressed AMPA to NMDA current ratios, suggesting that NAC reduces NAcore postsynaptic excitability. In separate experiments, rats received NAC and an antisense vivo-morpholino to selectively suppress GLT-1 expression in the NAcore during extinction and were subsequently tested for cue-induced reinstatement of nicotine seeking. NAC treatment rescued NAcore GLT-1 expression and attenuated cue-induced nicotine seeking, which was blocked by GLT-1 antisense. NAC also reduced TNFα expression in the NAcore. Viral manipulation of the NF-κB pathway, which is downstream of TNFα, revealed that cue-induced nicotine seeking is regulated by NF-κB pathway signaling in the NAcore independent of GLT-1 expression. Ultimately, these results are the first to show that immunomodulatory mechanisms may regulate known nicotine-induced alterations in glutamatergic plasticity that mediate cue-induced nicotine-seeking behavior.

N-acetylcysteine yields sex-specific efficacy for cue-induced reinstatement of nicotine seeking.

Women report greater craving during certain phases of the menstrual cycle. As well, research indicates that pharmacotherapies for smoking may be less efficacious in women compared with men, which may be due to interactions with natural fluctuations in ovarian hormone levels. N-Acetylcysteine (NAC) is a glutamatergic compound that has shown some efficacy in treating substance use disorders and aids in the prevention of relapse. However, it is unclear whether NAC has sex-specific effectiveness for nicotine relapse treatment. Given that NAC has shown promise to reduce nicotine reinstatement in preclinical models using male rats, the exploration of potential sex differences in the efficacy of NAC is warranted. Using a rat model, we first investigated the ability of NAC treatment (100 mg/kg, ip) during nicotine withdrawal with extinction training to reduce cue-induced nicotine seeking in male and female rats. Next, we assessed whether NAC's effects were estrous cycle-dependent for female rats. Results show that following NAC treatment during extinction, reinstatement of nicotine seeking was significantly decreased in males but not females, indicating a sex-specific effect of NAC. Furthermore, for females, both vehicle- and NAC-treated groups significantly reinstated nicotine-seeking behavior compared with extinction, regardless of estrous cycle phase. These results suggest that NAC is inefficacious in reducing nicotine relapse in females regardless of estrous cycle phase at the dose evaluated here. These collective findings could have important clinical implications for use and efficacy of NAC as a pharmacotherapy for freely cycling women smokers.

Enabling social listening for cardiac safety monitoring: Proceedings from a drug information association-cardiac safety research consortium cosponsored think tank.

This white paper provides a summary of the presentations and discussions from a think tank on "Enabling Social Listening for Cardiac Safety Monitoring" trials that was cosponsored by the Drug Information Association and the Cardiac Safety Research Consortium, and held at the White Oak headquarters of the US Food and Drug Administration on June 3, 2016. The meeting's goals were to explore current methods of collecting and evaluating social listening data and to consider their applicability to cardiac safety surveillance. Social listening is defined as the act of monitoring public postings on the Internet. It has several theoretical advantages for drug and device safety. First, these include the ability to detect adverse events that are "missed" by traditional sources and the ability to detect adverse events sooner than would be allowed by traditional sources, both by affording near-real-time access to data from culturally and geographically diverse sources. Social listening can also potentially introduce a novel patient voice into the conversation about drug safety, which could uniquely augment understanding of real-world medication use obtained from more traditional methodologies. Finally, it can allow for access to information about drug misuse and diversion. To date, the latter 2 of these have been realized. Although regulators from the Food and Drug Administration and the United Kingdom's Medicines and Healthcare Products Regulatory Agency participated in the think tank along with representatives from industry, academia, and patient groups, this article should not be construed to constitute regulatory guidance.

Influence of developmental nicotine exposure on spike-timing precision and reliability in hypoglossal motoneurons.

Smoothly graded muscle contractions depend in part on the precision and reliability of motoneuron action potential generation. Whether or not a motoneuron generates spikes precisely and reliably depends on both its intrinsic membrane properties and the nature of the synaptic input that it receives. Factors that perturb neuronal intrinsic properties and/or synaptic drive may compromise the temporal precision and the reliability of action potential generation. We have previously shown that developmental nicotine exposure (DNE) alters intrinsic properties and synaptic transmission in hypoglossal motoneurons (XIIMNs). Here we show that the effects of DNE also include alterations in spike-timing precision and reliability, and spike-frequency adaptation, in response to sinusoidal current injection. Current-clamp experiments in brainstem slices from neonatal rats show that DNE lowers the threshold for spike generation but increases the variability of spike-timing mechanisms. DNE is also associated with an increase in spike-frequency adaptation and reductions in both peak and steady-state firing rate in response to brief, square wave current injections. Taken together, our data indicate that DNE causes significant alterations in the input-output efficiency of XIIMNs. These alterations may play a role in the increased frequency of obstructive apneas and altered suckling strength and coordination observed in nicotine-exposed neonatal humans.

Respiration-related discharge of hyoglossus muscle motor units in the rat.

Although respiratory muscle motor units have been studied during natural breathing, simultaneous measures of muscle force have never been obtained. Tongue retractor muscles, such as the hyoglossus (HG), play an important role in swallowing, licking, chewing, breathing, and, in humans, speech. The HG is phasically recruited during the inspiratory phase of the respiratory cycle. Moreover, in urethane anesthetized rats the drive to the HG waxes and wanes spontaneously, providing a unique opportunity to study motor unit firing patterns as the muscle is driven naturally by the central pattern generator for breathing. We recorded tongue retraction force, the whole HG muscle EMG and the activity of 38 HG motor units in spontaneously breathing anesthetized rats under low-force and high-force conditions. Activity in all cases was confined to the inspiratory phase of the respiratory cycle. Changes in the EMG were correlated significantly with corresponding changes in force, with the change in EMG able to predict 53-68% of the force variation. Mean and peak motor unit firing rates were greater under high-force conditions, although the magnitude of discharge rate modulation varied widely across the population. Changes in mean and peak firing rates were significantly correlated with the corresponding changes in force, but the correlations were weak (r(2) = 0.27 and 0.25, respectively). These data indicate that, during spontaneous breathing, recruitment of HG motor units plays a critical role in the control of muscle force, with firing rate modulation playing an important but lesser role.

Lessons Learned from the Design, Construction, and Commissioning of a Retrofitted Arthropod Containment Level 3 Insectary.

Arthropods are vectors for many pathogens that significantly harm human and animal health globally, and research into vector-borne diseases is of critical public health importance. Arthropods present unique risks for containment, and therefore insectary facilities are essential to the safe handling of arthropod-borne hazards. In 2018, the School of Life Sciences at Arizona State University (ASU) began the process to build a level 3 arthropod containment (ACL-3) facility. Even with the COVID-19 pandemic, it took more than 4 years for the insectary to be granted a Certificate of Occupancy. At the request of the ASU Environmental Health and Safety team, Gryphon Scientific, an independent team with biosafety and biological research expertise, studied the project lifecycle through the design, construction, and commissioning of the ACL-3 facility with the goal of identifying lessons learned from the delayed timeline. These lessons learned convey insight into best practices for assessing potential facility sites, anticipating challenges with retrofitted construction, preparing for commissioning, equipping the project team with necessary expertise and expectations, and supplementing the gaps in available containment guidance. Several unique mitigations designed by the ASU team to address research risks not specifically addressed in the American Committee of Medical Entomology Arthropod Containment Guidelines are also described. Completion of the ACL-3 insectary at ASU was delayed, but the team thoroughly assessed potential risks and enabled appropriate practices for the safe handling of arthropod vectors. These efforts will enhance future ACL-3 construction by helping to avoid similar setbacks and streamlining progress from concept to operation.

Identifying Barriers to Enrollment in Patient Pregnancy Registries: Building Evidence Through Crowdsourcing.

BACKGROUND: Enrollment in pregnancy registries is challenging despite substantial awareness-raising activities, generally resulting in low recruitment owing to limited safety data. Understanding patient and physician awareness of and attitudes toward pregnancy registries is needed to facilitate enrollment. Crowdsourcing, in which services, ideas, or content are obtained by soliciting contributions from a large group of people using web-based platforms, has shown promise for improving patient engagement and obtaining patient insights. OBJECTIVE: This study aimed to use web-based crowdsourcing platforms to evaluate Belimumab Pregnancy Registry (BPR) awareness among patients and physicians and to identify potential barriers to pregnancy registry enrollment with the BPR as a case study. METHODS: We conducted 2 surveys using separate web-based crowdsourcing platforms: Amazon Mechanical Turk (a 14-question patient survey) and Sermo RealTime (a 11-question rheumatologist survey). Eligible patients were women, aged 18-55 years; diagnosed with systemic lupus erythematosus (SLE); and pregnant, recently pregnant (within 2 years), or planning pregnancy. Eligible rheumatologists had prescribed belimumab and treated pregnant women. Responses were descriptively analyzed. RESULTS: Of 151 patient respondents over a 3-month period (n=88, 58.3% aged 26-35 years; n=149, 98.7% with mild or moderate SLE; and n=148, 98% from the United States), 51% (77/151) were currently or recently pregnant. Overall, 169 rheumatologists completed the survey within 48 hours, and 59.2% (100/169) were based in the United States. Belimumab exposure was reported by 41.7% (63/151) patients, whereas 51.7% (75/145) rheumatologists had prescribed belimumab to <5 patients, 25.5% (37/145) had prescribed to 5-10 patients, and 22.8% (33/145) had prescribed to >10 patients who were pregnant or trying to conceive. Of the patients exposed to belimumab, 51% (32/63) were BPR-aware, and 45.5% (77/169) of the rheumatologists were BPR-aware. Overall, 60% (38/63) of patients reported belimumab discontinuation because of pregnancy or planned pregnancy. Among the 77 BPR-aware rheumatologists, 70 (91%) referred patients to the registry. Concerns among rheumatologists who did not prescribe belimumab during pregnancy included unknown pregnancy safety profile (119/169, 70.4%), and 61.5% (104/169) reported their patients' concerns about the unknown pregnancy safety profile. Belimumab exposure during or recently after pregnancy or while trying to conceive was reported in patients with mild (6/64, 9%), moderate (22/85, 26%), or severe (1/2, 50%) SLE. Rheumatologists more commonly recommended belimumab for moderate (84/169, 49.7%) and severe (123/169, 72.8%) SLE than for mild SLE (36/169, 21.3%) for patients trying to conceive recently or currently pregnant. Overall, 81.6% (138/169) of the rheumatologists suggested a belimumab washout period before pregnancy of 0-30 days (44/138, 31.9%), 30-60 days (64/138, 46.4%), or >60 days (30/138, 21.7%). CONCLUSIONS: In this case, crowdsourcing efficiently obtained patient and rheumatologist input, with some patients with SLE continuing to use belimumab during or while planning a pregnancy. There was moderate awareness of the BPR among patients and physicians.

Biosafety Practices When Working with Bats: A Guide to Field Research Considerations.

Introduction: Field work with bats is an important contribution to many areas of research in environmental biology and ecology, as well as microbiology. Work with bats poses hazards such as bites and scratches, and the potential for exposure to infectious pathogens such as rabies virus. It also exposes researchers to many other potential hazards inherent to field work, such as environmental conditions, delayed emergency responses, or challenging work conditions. Methods: This article discusses the considerations for a thorough risk assessment process around field work with bats, pre- and post-occupational health considerations, and delves into specific considerations for areas related to biosafety concerns-training, personal protective equipment, safety consideration in field methods, decontamination, and waste. It also touches on related legal and ethical issues that sit outside the realm of biosafety, but which must be addressed during the planning process. Discussion: Although the focal point of this article is bat field work located in northern and central America, the principles and practices discussed here are applicable to bat work elsewhere, as well as to field work with other animal species, and should promote careful considerations of how to safely conduct field work to protect both researchers and animals.

Developing Crowdsourced Training Data Sets for Pharmacovigilance Intelligent Automation.

INTRODUCTION: Machine learning offers an alluring solution to developing automated approaches to the increasing individual case safety report burden being placed upon pharmacovigilance. Leveraging crowdsourcing to annotate unstructured data may provide accurate, efficient, and contemporaneous training data sets in support of machine learning. OBJECTIVE: The objective of this study was to evaluate whether crowdsourcing can be used to accurately and efficiently develop training data sets in support of pharmacovigilance automation. MATERIALS AND METHODS: Pharmacovigilance experts created a reference dataset by reviewing 15,490 de-identified social media posts of narratives pertaining to 15 drugs and 22 medically relevant topics. A random sampling of posts from the reference dataset was published on Amazon Turk and its users (Turkers) were asked a series of questions about those same medical concepts. Accuracy, price elasticity, and time efficiency were evaluated. RESULTS: Accuracy of crowdsourced curation exceeded 90% when compared to the reference dataset and was completed in about 5% of the time. There was an increase in time efficiency with higher pay, but there was no significant difference in accuracy. Additionally, having a social media post reviewed by more than one Turker (using a voting system) did not offer significant improvements in terms of accuracy. CONCLUSIONS: Crowdsourcing is an accurate and efficient method that can be used to develop training data sets in support of pharmacovigilance automation. More research is needed to better understand the breadth and depth of possible uses as well as strengths, limitations, and generalizability of results.

HuD Regulates mRNA-circRNA-miRNA Networks in the Mouse Striatum Linked to Neuronal Development and Drug Addiction.

The RNA-binding protein HuD (a.k.a., ELAVL4) is involved in neuronal development and synaptic plasticity mechanisms, including addiction-related processes such as cocaine conditioned-place preference (CPP) and food reward. The most studied function of this protein is mRNA stabilization; however, we have recently shown that HuD also regulates the levels of circular RNAs (circRNAs) in neurons. To examine the role of HuD in the control of coding and non-coding RNA networks associated with substance use, we identified sets of differentially expressed mRNAs, circRNAs and miRNAs in the striatum of HuD knockout (KO) mice. Our findings indicate that significantly downregulated mRNAs are enriched in biological pathways related to cell morphology and behavior. Furthermore, deletion of HuD altered the levels of 15 miRNAs associated with drug seeking. Using these sets of data, we predicted that a large number of upregulated miRNAs form competing endogenous RNA (ceRNA) networks with circRNAs and mRNAs associated with the neuronal development and synaptic plasticity proteins LSAMP and MARK3. Additionally, several downregulated miRNAs form ceRNA networks with mRNAs and circRNAs from MEF2D, PIK3R3, PTRPM and other neuronal proteins. Together, our results indicate that HuD regulates ceRNA networks controlling the levels of mRNAs associated with neuronal differentiation and synaptic physiology.

microRNA regulation related to the protective effects of environmental enrichment against cocaine-seeking behavior.

BACKGROUND: MicroRNAs (miRNAs) are "master post-transcriptional regulators" of gene expression. Here we investigate miRNAs involved in the incentive motivation for cocaine elicited by exposure to cocaine-associated cues. METHODS: We conducted NanoString nCounter analyses of microRNA expression in the nucleus accumbens shell of male rats that had been tested for cue reactivity in a previous study. These rats had been trained to self-administer cocaine while living in isolate housing, then during a subsequent 21-day forced abstinence period they either stayed under isolate housing or switched to environmental enrichment (EE), as this EE intervention is known to decrease cocaine seeking. This allowed us to create groups of "high" and "low" cocaine seekers using a median split of cocaine-seeking behavior. RESULTS: Differential expression analysis across high- and low-seekers identified 33 microRNAs that were differentially expressed in the nucleus accumbens shell. Predicted mRNA targets of these microRNAs are implicated in synaptic plasticity, neuronal signaling, and neuroinflammation signaling, and many are known addiction-related genes. Of the 33 differentially-expressed microRNAs, 8 were specifically downregulated in the low-seeking group and another set of 8 had expression levels that were significantly correlated with cocaine-seeking behavior. CONCLUSION: These findings not only confirm the involvement of previously identified microRNAs (e.g., miR-212, miR-495) but also reveal novel microRNAs (e.g., miR-3557, miR-377) that alter, or are altered by, processes associated with cocaine-seeking behavior. Further research examining the mechanisms involved in these microRNA changes and their effects on signaling may reveal novel therapeutic targets for attenuating drug craving.

5-HT1B receptor agonist attenuates cocaine self-administration after protracted abstinence and relapse in rats.

BACKGROUND: The 5-HT1B receptor (5-HT1BR) agonist, CP94253, enhances cocaine intake during maintenance of self-administration (SA) but attenuates intake after 21 days of forced abstinence in male rats. AIMS: We examined whether CP94253 attenuates cocaine intake in female rats after a period of abstinence, and if these attenuating effects persist or revert to enhancing cocaine intake during resumption (i.e. relapse) of daily cocaine SA. METHODS: Male and female rats trained to lever press on a fixed ratio 5 schedule of cocaine reinforcement underwent ⩾21 days of forced abstinence. They were then tested for the effects of CP94253 (5.6 mg/kg, SC) or vehicle on cocaine SA. During the test session, rats had 1-h access to the training dose of cocaine (0.75 mg/kg, IV) followed by 1-h access to a lower cocaine dose (0.075 mg/kg, IV). Rats then resumed cocaine SA for 15 days to mimic relapse and were retested as done previously. Subsequently, rats underwent abstinence again (21-60 days) and were tested for CP94253 effects on locomotion and cue reactivity (i.e. responding for light/tone cues previously paired with cocaine infusions). RESULTS: Regardless of sex, CP94253 decreased cocaine intake after abstinence and during resumption of SA and decreased cue reactivity while having no effect on locomotion. CONCLUSIONS: CP94253 decreases cocaine intake and cocaine seeking in both males and females even after resumption of cocaine SA. These findings suggest that the inhibitory effects of CP94253 observed after abstinence are long-lasting, and therefore, 5-HT1BR agonists may have clinical efficacy as anti-relapse medications for cocaine use disorders.

Semi-automated risk estimation using large databases: quinolones and Clostridium difficile associated diarrhea.

PURPOSE: The availability of large databases with person time information and appropriate statistical methods allow for relatively rapid pharmacovigilance analyses. A semi-automated method was used to investigate the effect of fluoroquinolones on the incidence of C. difficile associated diarrhea (CDAD). METHODS: Two US databases, an electronic medical record (EMR) and a large medical claims database for the period 2006-2007 were evaluated using a semi-automated methodology. The raw EMR and claims datasets were subject to a normalization procedure that aligns the drug exposures and conditions using ontologies; Snowmed for medications and MedDRA for conditions. A retrospective cohort design was used together with matching by means of the propensity score. The association between exposure and outcome was evaluated using a Poisson regression model after taking into account potential confounders. RESULTS: A comparison between quinolones as the target cohort and macrolides as the comparison cohort produced a total of 564,797 subjects exposed to a quinolone in the claims data and 233,090 subjects in the EMR. They were matched with replacement within six strata of the propensity score. Among the matched cohorts there were a total of 488 and 158 outcomes in the claims and the EMR respectively. Quinolones were found to be twice more likely to be significantly associated with CDAD than macrolides adjusting for risk factors (IRR 2.75, 95%CI 2.18-3.48). CONCLUSIONS: Use of a semi-automated method was successfully applied to two observational databases and was able to rapidly identify a potential for increased risk of developing CDAD with quinolones.

5-Methyl-4-(5-methyl-3-oxo-2-phenyl-2,3-di-hydro-1H-pyrazol-4-yl)-2-phenyl-1H-pyrazol-3(2H)-one.

The title compound, C20H18N4O2, known as bis-pyrazolone, was crystallized from dimethyl sulfoxide. The structure has ortho-rhom-bic (Pbca) symmetry at 150 K, and displays both intra- and inter-molecular hydrogen bonding through C-H⋯O and N-H⋯O contacts, respectively. None of the phenyl and pyrazolone rings in the mol-ecule are coplanar. The dihedral angle between the pyrazolone rings is 66.18 (5)°.

Bis(µ4-adamantane-1,3-di-carboxyl-ato-1κO 1:2κO 1':3κO 3:4κO 3')octa-carbonyl-1κ2 C,2κ2 C,3κ2 C,4κ2 C-tetra-kis-[tris-(4-methyl-phen-yl)phosphane]-1κP,2κP,3κP,4κP-tetra-osmium(I)(2 Os-Os).

The title complex, [{Os2(CO)4(C21H21P)2}2(C12H14O4)2], is a centrosymmetric mol-ecular loop consisting of two Os-Os sawhorse units linked by two adamantane di-carboxyl-ato bridges. It was synthesized by the microwave-mediated reaction between Os3(CO)12 and adamantane-1,3-di-carb-oxy-lic acid. In contrast to the related complex [{Os2(CO)6}2(µ4-adamantane-1,3-di-acetate)2], the metal-metal axes within each mol-ecule are oriented parallel rather than perpendicular to one another. The crystal structure exhibits cavities that contain residual electron density peaks, but it was not possible to unambiguously identify the solvent therein. The contribution of the disordered solvent mol-ecules to the scattering was removed using the SQUEEZE (Spek (2015 ▸). Acta Cryst. C71, 9-18) routine in PLATON [Spek (2020 ▸). Acta Cryst. E76, 1-11]. These solvent mol-ecules are not considered in the given chemical formula and other crystal data.

1,1,2,2,2,3,3,3-Octa-carbonyl-1,1,2,3-tetra-kis-(1,3,5-tri-aza-7-phosphatri-cyclo-[3.3.1.13,7]decane-κP)-triangulo-triosmium(0).

The title compound, [Os3(C6H12N3P)4(CO)8], crystallizes in the ortho-rhom-bic space group Pbca with Z = 8. The mol-ecule consists of a triangular triosmium(0) core surrounded by eight carbonyl ligands and four 1,3,5-tri-aza-7-phosphatri-cyclo-[3.3.1.13,7]decane (or PTA) ligands. One Os atom is coordinated by two PTA ligands and two CO ligands, while the other two Os atoms are each bonded to a single PTA ligand and three CO ligands. There is a small disorder associated with the Os3 unit so that a minor orientation has an occupancy of 2.17 (4)%. The title compound represents the first structurally characterized triangular Os3 carbonyl cluster with four monodentate tertiary phosphane ligands.

Nicotine reduction does not alter essential value of nicotine or reduce cue-induced reinstatement of nicotine seeking.

Reduction of nicotine content in tobacco products is a regulatory control strategy intended to decrease smoking dependence, and is hypothesized to produce gradual reductions of nicotine intake. Rats were initially trained to self-administer 0.06 mg/kg/infusion nicotine (Phase 1), which was followed by a threshold procedure to determine nicotine demand via a behavioral economics (BE) paradigm (Phase 2). Rats then either self-administered the training dose (high dose group), or were switched to a low dose of nicotine (0.001 mg/kg/infusion; low dose group) in Phase 3. Both groups then underwent a second threshold procedure and demand curves were re-determined (Phase 4). In Phase 5, responding for nicotine was extinguished over the course of 21 sessions. Cue-induced reinstatement was then evaluated (Phase 6). Rats in the low dose group maintained a steady amount of infusions, and thus, did not compensate for nicotine reduction. Rats in the low dose group also showed similar demand elasticity and nicotine seeking (Phase 6) compared to the high dose group, indicating that nicotine reduction did not decrease nicotine demand or seeking. Further, both groups displayed resistance to extinction, indicating that nicotine reduction did not facilitate extinction learning. These results suggest that although compensation of intake does not occur, decreasing the dose of nicotine does not alter nicotine reinforcement value or relapse vulnerability. Further, these results indicate persistence of nicotine-motivated behavior after self-administration of a low nicotine dose. Translationally, these results suggest that alternative strategies may be needed to achieve positive smoking cessation outcomes.

Environmental enrichment during forced abstinence from cocaine self-administration opposes gene network expression changes associated with the incubation effect.

Environmental enrichment (EE) is a robust intervention for reducing cocaine-seeking behaviors in animals when given during forced abstinence. However, the mechanisms that underlie these effects are not well-established. We investigated the adult male rat transcriptome using RNA-sequencing (RNA-seq) following differential housing during forced abstinence from cocaine self-administration for either 1 or 21 days. Enriched, 21-day forced abstinence rats displayed a significant reduction in cocaine-seeking behavior compared to rats housed in isolation. RNA-seq of the nucleus accumbens shell revealed hundreds of differentially regulated transcripts between rats of different forced abstinence length and housing environment, as well as within specific contrasts such as enrichment (isolated 21 days vs. enriched 21 days) or incubation (isolated 1 day vs. isolated 21 days). Ingenuity Pathway Analysis affirmed several pathways as differentially enriched based on housing condition and forced abstinence length including RELN, the Eif2 signaling pathway, synaptogenesis and neurogenesis pathways. Numerous pathways showed upregulation with incubation, but downregulation with EE, suggesting that EE may prevent or reverse changes in gene expression associated with protracted forced abstinence. The findings reveal novel candidate mechanisms involved in the protective effects of EE against cocaine seeking, which may inform efforts to develop pharmacological and gene therapies for treating cocaine use disorders. Furthermore, the finding that EE opposes multiple pathway changes associated with incubation of cocaine seeking strongly supports EE as a therapeutic intervention and suggests EE is capable of preventing or reversing the widespread dysregulation of signaling pathways that occurs during cocaine forced abstinence.