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Detailed analysis of the upper airway has not been performed in children with obstructive sleep apnea. We used magnetic resonance imaging and automatic segmentation to delineate the upper airway in 20 children with obstructive sleep apnea and in 20 control subjects (age, 3.7 +/- 1.4 versus 3.9 +/- 1.7 years, respectively). We measured mean and minimal cross-sectional area, length, and volume of: (1) the total airway; (2) regions along the adenoid, tonsils, and where adenoid and tonsils overlap; and (3) 10 segments at 10% increments along the airway. The mean cross-sectional area of the total airway of the obstructive sleep apnea group was significantly smaller in comparison with the control group, 28.1 +/- 12.6 versus 47.1 +/- 18.2 mm2, respectively (p < 0.0005). Minimal cross-sectional area and airway volume were smaller in this group, 4.6 +/- 3.3 versus 15.7 +/- 12.7 mm2 (p < 0.0005), and 1,129 +/- 515 versus 1,794 +/- 846 mm3 (p < 0.005), respectively. Regional analysis suggested that the upper airway in children with obstructive sleep apnea is most restricted where adenoid and tonsils overlap. Segmental analysis demonstrated that the upper airway is restricted throughout the initial two-thirds of its length and that the narrowing is not in a discrete region adjacent to either the adenoid or tonsils, but rather in a continuous fashion along both. [ABSTRACT FROM AUTHOR]

This study identifies and characterizes symptoms of caffeine dependence in adolescents. Thirty-six adolescents who consumed caffeine daily and had some features of caffeine dependence on telephone screen were scheduled for outpatient evaluation. Evaluation included the Diagnostic Interview Schedule for Children-IV-Youth Version (DISC-IV) and modified DISC-IV questions that assessed caffeine dependence based on DSM-IV substance dependence criteria. Of 36 subjects, 41.7% (n=15) reported tolerance to caffeine, 77.8% (n=28) described withdrawal symptoms after cessation or reduction of caffeine intake, 38.9% (n=14) reported desire or unsuccessful attempts to control use, and 16.7% (n=6) endorsed use despite knowledge of physical or psychological problems associated with caffeine. There was no significant difference in the amount of caffeine consumed daily by caffeine dependent versus non-dependent teenagers. These findings are important due to the vast number of adolescents who drink caffeinated beverages. [ABSTRACT FROM AUTHOR]

Abstract Background Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are often linked to respiratory infections. However, it is unknown if COPD patients who experience frequent exacerbations have impaired humoral immunity. The aim of this study was to determine if antibodies specific for common respiratory pathogens are associated with AECOPD. Methods Plasma was obtained from COPD patients when clinically stable. AECOPD requiring hospitalisation were recorded. IgG1 antibodies to H. Influenzae outer membrane protein 6 (P6), pneumococcal surface protein C (PspC) and the VP1 viral capsid protein of rhinovirus were measured. Results COPD patients who had an AECOPD (n = 32) had significantly lower anti-VP1 IgG1 antibody levels when stable compared to COPD patients who did not have an AECOPD (n = 28, p = 0.024). Furthermore, the number of hospitalisations was inversely proportional to anti-VP1 antibody levels (r = −0.331, p = 0.011). In contrast, antibodies specific for P6 and PspC were present at similar concentrations between groups. Plasma IL-21, a cytokine important for B-cell development and antibody synthesis, was also lower in COPD patients who had an AECOPD, than in stable COPD patients (p = 0.046). Conclusion Deficient humoral immunity specific for rhinoviruses is associated with AECOPD requiring hospitalisation, and may partly explain why some COPD patients have an increased exacerbation risk following respiratory viral infections.

Abstract Background Rhinoviruses (RV) are key triggers in acute asthma exacerbations. Previous studies suggest that men suffer from infectious diseases more frequently and with greater severity than women. Additionally, the immune response to most infections and vaccinations decreases with age. Most immune function studies do not account for such differences, therefore the aim of this study was to determine if the immune response to rhinovirus varies with sex or age. Methods Blood mononuclear cells were isolated from 63 healthy individuals and grouped by sex and age (≤50 years old and ≥52 years old). Cells were cultured with rhinovirus 16 at a multiplicity of infection of 1. The chemokine IP-10 was measured at 24 h as an index of innate immunity while IFNγ and IL-13 were measured at 5 days as an index of adaptive immunity. Results Rhinovirus induced IFNγ and IL-13 was significantly higher in ≤50 year old women than in age matched men (p < 0.02 and p < 0.05) and ≥52 year old women (p < 0.02 and p > 0.005). There was no sex or age based difference in rhinovirus induced IP-10 expression. Both IFNγ and IL-13 were negatively correlated with age in women but not in men. Conclusions This study suggests that pre-menopausal women have a stronger adaptive immune response to rhinovirus infection than men and older people, though the mechanisms responsible for these differences remain to be determined. Our findings highlight the importance of gender and age balance in clinical studies and in the development of new treatments and vaccines.

Introduction: Effective monitoring of insect-pests is vital for safeguarding agricultural yields and ensuring food security. Recent advances in computer vision and machine learning have opened up significant possibilities of automated persistent monitoring of insect-pests through reliable detection and counting of insects in setups such as yellow sticky traps. However, this task is fraught with complexities, encompassing challenges such as, laborious dataset annotation, recognizing small insect-pests in low-resolution or distant images, and the intricate variations across insect-pests life stages and species classes., Methods: To tackle these obstacles, this work investigates combining two solutions, Hierarchical Transfer Learning (HTL) and Slicing-Aided Hyper Inference (SAHI), along with applying a detection model. HTL pioneers a multi-step knowledge transfer paradigm, harnessing intermediary in-domain datasets to facilitate model adaptation. Moreover, slicing-aided hyper inference subdivides images into overlapping patches, conducting independent object detection on each patch before merging outcomes for precise, comprehensive results., Results: The outcomes underscore the substantial improvement achievable in detection results by integrating a diverse and expansive in-domain dataset within the HTL method, complemented by the utilization of SAHI., Discussion: We also present a hardware and software infrastructure for deploying such models for real-life applications. Our results can assist researchers and practitioners looking for solutions for insect-pest detection and quantification on yellow sticky traps., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fotouhi, Menke, Prestholt, Gupta, Carroll, Yang, Skidmore, O’Neal, Merchant, Das, Kyveryga, Ganapathysubramanian, Singh, Singh and Sarkar.)

Background: In a previous study in female rats, voluntary wheel running attenuated incubation of cocaine craving after 30 but not 3 days (Zlebnik and Carroll Zlebnik and Carroll, Psychopharmacology 232:3507-3413, 2015). The present study in male rats, using the same procedure, showed that wheel running reduced incubated craving after both 30 and 3 days of abstinence., Methods: Male rats self-administered i.v. cocaine (0.4 mg/kg) during 6-h sessions for 10 days. They were then moved from the operant chamber to a home cage with an attached running wheel or stationary wheel, for 6 h daily for a 3- or 30-day period when cocaine craving was hypothesized to incubate. Rats were then returned to the operant chamber for a 30-min test of cocaine seeking, or "craving," indicated by responses on the former "drug" lever was formerly associated with drug stimulus lights and responses (vs. no drug stimuli), and lever responding was compared to responses on the "inactive" that was illuminated and counted lever pressing., Results: Mean wheel revolutions were similar across the 3- and 30-day incubation groups, when both groups of rats were given access to wheel running vs. access to a stationary wheel in controls. Subsequently, when rats were tested in the operant chamber for "relapse" responding (drug-lever responding) on the lever formerly associated with drug access, cocaine craving was reduced by recent running wheel access (vs. stationary wheel access) in both the 3- and 30-day wheel exposure groups., Conclusion: Voluntary, self-initiated, and self-sustained physical exercise reduced cocaine craving after short- (3 days) and long-term (30 days) abstinence periods in male rats that previously self-administered cocaine. This was contrasted with reduction of cocaine seeking in females after 30-day, but not 3-day, incubation periods under the wheel running vs. stationary wheel conditions in a previous study (Zlebnik and Carroll Zlebnik and Carroll, Psychopharmacology 232:3507-3413, 2015). These initial findings suggest males may be more sensitive to incubated craving for cocaine than females., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Lung nodules or masses due to a variety of malignant or benign conditions such as opportunistic infections are observed after lung transplant. Malakoplakia is a rare complication in immunocompromised patients. Here we describe the clinical course and management of a lung transplant recipient with pulmonary malakoplakia and provide a review of the literature. To our knowledge, this is the first report of a case of pulmonary malakoplakia due to Escherichia coli infection in a lung allograft., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Drug addiction is a chronic relapsing disorder, as more than 80% of former drug users relapse within a year after quit attempts have ended. This review examines incubated craving that develops over long periods of weeks to months after addictive drug use ends, when rats are given a small priming exposure to the formerly used drug, and a large amount of drug seeking occurs, reflecting large increases in craving over time. Expanded craving occurs when not only the recently-used drug, but other related or unrelated drugs of abuse elicit drug seeking that leads to relapse behavior, including common drugs like caffeine or nicotine, Thus, expanded craving is an increase in the conditions that elicit relapse, such as, a variety of drugs, and it persists weeks after drug use ends. Incubated and expanded craving occur with several drugs of abuse, and these forms of craving, can last for weeks to months and end in relapse. Voluntary physical exercise, blocked incubated cocaine craving, and expanded heroin craving elicited by multiple conditions was reduced in female and male rats. This review examines voluntary physical exercise as a long-term, self-initiated, and self-sustainable treatment that reduces long-term drug craving leading to relapse., (Copyright © 2021. Published by Elsevier Inc.)

Background: Worldwide methamphetamine (METH) use has increased significantly over the last 10 years, and in the US, METH dependence has sky-rocketed among individuals with opioid use disorder. Of significant concern, METH use is gaining popularity among groups with susceptibility to developing severe substance use disorders, such as women and adolescents. Nevertheless, there is no established pharmacotherapy for METH addiction. Emerging evidence has identified the orexin/hypocretin system as an important modulator of reward-driven behavior and a potential target for the treatment of drug addiction and relapse. However, to date, there have been no investigations into the therapeutic efficacy of orexin/hypocretin receptor antagonists for METH-motivated behavior in adolescents or adults. In the present study, we examined the effects of selective antagonists of the orexin-1 (SB-334867, 20 mg/kg) and orexin-2 (TCS-OX2-29, 20 mg/kg) receptors on the reinstatement of METH seeking in both adolescent and adult male and female rats., Methods: Rats were trained to self-administer METH (0.05 mg/kg/inf, iv) during two 2-h sessions/day for 5 days. Following 20 sessions of extinction over 10 days, a within-subjects design was used to test for METH seeking precipitated by METH (1 mg/kg, ip) or METH cues after systemic pretreatment with SB-334867 or TCS-OX2-29., Results: SB-334867 reduced cue-induced reinstatement in males and females, regardless of age. Additionally, METH-induced METH seeking was attenuated by SB-334867 in adolescents and by TCS-OX2-29 in adults., Conclusion: Selective orexin/hypocretin receptor antagonists have significant therapeutic potential for diminishing METH-seeking behavior, although their treatment efficacy may be influenced by age., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Reliable seed yield estimation is an indispensable step in plant breeding programs geared towards cultivar development in major row crops. The objective of this study is to develop a machine learning (ML) approach adept at soybean ( Glycine max L. (Merr.)) pod counting to enable genotype seed yield rank prediction from in-field video data collected by a ground robot. To meet this goal, we developed a multiview image-based yield estimation framework utilizing deep learning architectures. Plant images captured from different angles were fused to estimate the yield and subsequently to rank soybean genotypes for application in breeding decisions. We used data from controlled imaging environment in field, as well as from plant breeding test plots in field to demonstrate the efficacy of our framework via comparing performance with manual pod counting and yield estimation. Our results demonstrate the promise of ML models in making breeding decisions with significant reduction of time and human effort and opening new breeding method avenues to develop cultivars., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Luis G. Riera et al.)

Unmanned aircraft system (UAS) is a particularly powerful tool for plant phenotyping, due to reasonable cost of procurement and deployment, ease and flexibility for control and operation, ability to reconfigure sensor payloads to diversify sensing, and the ability to seamlessly fit into a larger connected phenotyping network. These advantages have expanded the use of UAS-based plant phenotyping approach in research and breeding applications. This paper reviews the state of the art in the deployment, collection, curation, storage, and analysis of data from UAS-based phenotyping platforms. We discuss pressing technical challenges, identify future trends in UAS-based phenotyping that the plant research community should be aware of, and pinpoint key plant science and agronomic questions that can be resolved with the next generation of UAS-based imaging modalities and associated data analysis pipelines. This review provides a broad account of the state of the art in UAS-based phenotyping to reduce the barrier to entry to plant science practitioners interested in deploying this imaging modality for phenotyping in plant breeding and research areas., Competing Interests: The authors declare no competing interests., (Copyright © 2021 Wei Guo et al.)

The nitride salt [(PN) 2 Ti≡N{μ 2 -K(OEt 2 )}] 2 ( 1 ) (PN - = ( N -(2-P i Pr 2 -4-methylphenyl)-2,4,6-Me 3 C 6 H 2 ) can be oxidized with two equiv of I 2 or four equiv of ClCPh 3 to produce the phosphinimide-halide complexes (NPN')(PN)Ti(X) (X - = I ( 2 ), Cl ( 3 ); NPN' = N-(2-NP i Pr 2 -4-methylphenyl)-2,4,6-Me 3 C 6 H 2 2- ), respectively. In the case of 2 , H 2 was found to be one of the other products; whereas, HCPh 3 and Gomberg's dimer were observed upon the formation of 3 . Independent studies suggest that the oxidation of 1 could imply the formation of the transient nitridyl species [(PN) 2 Ti(≡N•)] ( A ), which can either oxidize the proximal phosphine atom to produce the Ti(III) intermediate [(NPN')(PN)Ti] ( B ) or, alternatively, engage in H atom abstraction to form the parent imido (PN) 2 Ti≡NH ( 4 ). The latter was independently prepared and was found to photochemically convert to the titanium-hydride, (NPN')(PN)Ti(H) ( 5 ). Isotopic labeling studies using (PN) 2 Ti≡ND ( 4 - d 1 ) as well as reactivity studies of 5 with a hydride abstractor demonstrate the presence of the hydride ligand in 5 . An alternative route to putative A was observed via a photochemically promoted incomplete reduction of the azide ligand in (PN) 2 Ti(N 3 ) ( 6 ) to 4 . This process was accompanied by some formation of 5 . Frozen matrix X-band EPR studies of 6 , performed under photolytic conditions, were consistent with species B being formed under these reaction conditions, originating from a low barrier N-insertion into the phosphine group in the putative nitridyl species A . Computational studies were also undertaken to discover the mechanism and plausibility of the divergent pathways (via intermediates A and B ) in the formation of 2 and 3 , and to characterize the bonding and electronic structure of the elusive nitrogen-centered radical in A .

Background: The rise in heroin addiction has heightened the need for novel and effective treatments. Physical exercise has been shown as an effective treatment for stimulant abuse in clinical and pre-clinical research. However, this treatment has not yet been tested on opioid addiction. This study examined the effects of physical activity (wheel running) on heroin-seeking in rats within a reinstatement paradigm (i.e., heroin relapse model)., Methods: Female and male rats were trained to self-administer intravenous heroin (0.015 mg/kg). Once trained, rats were placed into extinction (i.e., heroin abstinence) for 21 days with continuous access to a locked or unlocked running wheel. After extinction, rats were tested for drug- (heroin, caffeine, and yohimbine) and cue-primed reinstatement of heroin-seeking., Results: Females completed more wheel revolutions than males across all study phases. Access to an unlocked running wheel reduced extinction and reinstatement of heroin-seeking, with greater reductions in females than males across several reinstatement conditions. In the locked wheel group, female rats showed greater reinstatement of heroin-seeking than males across several priming conditions., Conclusions: Wheel running reduced heroin-seeking in male and female rats, with females showing a more robust effect during reinstatement. The locked wheel group allowed an examination of sex differences in heroin reinstatement, which revealed that females showed greater vulnerability to heroin reinstatement than males, but with no other sex differences observed in maintenance or extinction. Overall, the results indicate that voluntary physical exercise may be an effective treatment for heroin dependence in humans.

Introduction: Despite extensive efforts to develop effective smoking cessation interventions, 70-85% of American cigarette smokers who quit relapse within one year. Exercise has shown promise as an intervention; however, many results have been equivocal. This study explored how exercise is associated with smoking-related symptomatology, smoking behavior and impulsivity in male and female smokers., Methods: Participants were recruited throughout the United States using the on-line crowdsourcing platform, Amazon's Mechanical Turk. They completed a survey with self-report measures assessing exercise, smoking-related symptomatology, smoking behavior and impulsivity. Differences between men and women were tested using t- and chi-square tests. Regression analyses tested for associations between exercise and smoking-related symptomatology, smoking behavior and impulsivity., Results: Participants (N = 604) were, on average, 32 (SD = 6.2) years old, mostly Caucasian, with at least some college education and approximately half were women. Women exercised slightly less than men and had more negative affect, craving, physical symptoms and withdrawal. Women smoked more cigarettes per day, had greater nicotine dependency and more years of smoking. Positive affect was positively associated with exercise for both men and women; however, this association was significantly stronger in women. Negative affect and withdrawal were inversely associated with exercise for women only. Impulsivity was inversely associated with exercise for both men and women., Conclusion: Exercise was significantly associated with several smoking-related symptomatology, smoking behavior and impulsivity variables for both men and women, suggesting that exercise may be a useful intervention for smoking cessation. Future prospective research should determine how exercise directly impacts smoking cessation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Rationale: Previous work indicated that progesterone (PRO) reduced impulsive choice for cocaine in female but not male rats (Smethells et al. Psychopharmacology 233:2999-3008, 2016). Impulsive action, typically measured by responding for a reinforcer during a signaled period of nonavailability of natural reinforcers, predicts initiation and escalation of drug use in animals and humans. The present study examined impulsive action for cocaine using PRO in male and female rats trained on a go/no-go task., Objective: Rats were trained on a go/no-go task to respond for cocaine infusions (0.4 mg/kg/inf). During the "go" component, responding was reinforced on a VI 30-s schedule, whereas during the "no-go" component, withholding a response was reinforced on a differential reinforcement of other behavior (DRO) 30-s schedule. A response during the no-go component resets the DRO timer and served as a measure of impulsive action. After baseline responding was established, rats were pretreated with vehicle (VEH) or PRO (0.5 mg/kg), and DRO resets and responding during the go component for cocaine were compared in males vs. females., Results: DRO resets were significantly lower following PRO treatment compared to VEH in female, but not male, rats. Response rates and overall infusions during the go component were not significantly altered by PRO in either females or males., Conclusion: Treatment with PRO resulted in a sex-specific reduction in impulsive action for cocaine, while not affecting cocaine self-administration.

In this contribution we present reactivity studies of a rare example of a titanium salt, in the form of [μ 2 -K(OEt 2 )] 2 [(PN) 2 Ti[triple bond, length as m-dash]N] 2 ( 1 ) (PN - = N -(2-(diisopropylphosphino)-4-methylphenyl)-2,4,6-trimethylanilide) to produce a series of imide moieties including rare examples such as methylimido, borylimido, phosphonylimido, and a parent imido. For the latter, using various weak acids allowed us to narrow the p K a range of the NH group in (PN) 2 Ti[triple bond, length as m-dash]NH to be between 26-36. Complex 1 could be produced by a reductively promoted elimination of N 2 from the azide precursor (PN) 2 TiN 3 , whereas reductive splitting of N 2 could not be achieved using the complex (PN) 2 Ti[double bond, length as m-dash]N[double bond, length as m-dash]N[double bond, length as m-dash]Ti(PN) 2 ( 2 ) and a strong reductant. Complete N-atom transfer reactions could also be observed when 1 was treated with ClC(O) t Bu and OCCPh 2 to form NC t Bu and KNCCPh 2 , respectively, along with the terminal oxo complex (PN) 2 Ti[triple bond, length as m-dash]O, which was also characterized. A combination of solid state 15 N NMR (MAS) and theoretical studies allowed us to understand the shielding effect of the counter cation in dimer 1 , the monomer [K(18-crown-6)][(PN) 2 Ti[triple bond, length as m-dash]N], and the discrete salt [K(2,2,2-Kryptofix)][(PN) 2 Ti[triple bond, length as m-dash]N] as well as the origin of the highly downfield 15 N NMR resonance when shifting from dimer to monomer to a terminal nitride (discrete salt). The upfield shift of 15 N nitride resonance in the 15 N NMR spectrum was found to be linked to the K + induced electronic structural change of the titanium-nitride functionality by using a combination of MO analysis and quantum chemical analysis of the corresponding shielding tensors., (This journal is © The Royal Society of Chemistry 2016.)

In comparison to men, women initiate drug use at earlier ages and progress from initial use to addiction more rapidly. This heightened intake and vulnerability to drugs of abuse is regulated in part by estradiol, although the signaling mechanisms by which this occurs are not well understood. Recent findings indicate that within the nucleus accumbens core, estradiol induces structural plasticity via membrane-localized estrogen receptor α, functionally coupled to metabotropic glutamate receptor subtype 5 (mGluR5). Hence, we sought to determine whether mGluR5 activation was essential for estradiol-mediated enhancement of cocaine self-administration. Ovariectomized (OVX) female rats were allowed to freely self-administer cocaine under extended access conditions (6 h/d) for 10 consecutive days. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) or vehicle was administered before estradiol (or oil), on a 2 d on/2 d off schedule throughout the extended access period. MPEP treatment prevented the estradiol-dependent enhancement of cocaine self-administration in OVX females. In a separate experiment, potentiation of mGluR5 function with the positive allosteric modulator 3-cyano- N -(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (in the absence of estradiol treatment) failed to increase cocaine self-administration. These data suggest that mGluR5 activation is necessary for estradiol-mediated enhancement of responses to cocaine, but that direct mGluR5 activation is insufficient to mimic the female response to estradiol. Building on previous studies in male animals, these findings further highlight the therapeutic potential of mGluR5 antagonism in the treatment of addiction and suggest that there may be added therapeutic benefit in females., Competing Interests: Authors report no conflict of interest.

Background: Previous research has found that rats behaviorally screened for high (vs. low) wheel running were more vulnerable to cocaine abuse. To assess the extent to which a genetic component is involved in this drug-abuse vulnerability, rats selectively bred for high or low voluntary running (HVR or LVR, respectively) were examined for differences in cocaine seeking in the present study., Methods: Female rats were trained to lever press for food and then were assessed for differences in acquisition of cocaine (0.4mg/kg; i.v.) self-administration across 10 sessions. Once acquired, rats self-administered cocaine for a 14-day maintenance phase, followed by a 14-day extinction phase when cocaine was no longer available. Subsequently, reinstatement of cocaine seeking was examined with priming injections of cocaine (5, 10 & 15mg/kg), caffeine (30mg/kg), yohimbine (2.5mg/kg) and cocaine-paired cues., Results: A greater percentage of LVR rats met the acquisition criteria for cocaine self-administration and in fewer sessions than HVR rats. No differences in responding for cocaine were observed between phenotypes during maintenance. However, during extinction LVR rats initially responded at higher rates and persisted in cocaine seeking for a greater number of sessions. No phenotype differences were observed following drug and cue-primed reinstatement of cocaine seeking., Conclusions: In general, LVR rats were more sensitive to the reinforcing effects of cocaine than HVR rats during periods of transition into and out of cocaine self-administration. Thus, LVR rats sometimes showed a greater vulnerability cocaine seeking than HVR rats., Competing Interests: Declaration of Interest Conflict of Interest No conflict declared., (Published by Elsevier Ireland Ltd.)

Impulsivity, or a tendency to act without anticipation of future consequences, is associated with drug abuse. Impulsivity is typically separated into two main measures, impulsive action and impulsive choice. Given the association of impulsivity and drug abuse, treatments that reduce impulsivity have been proposed as an effective method for countering drug addiction. Progesterone has emerged as a promising treatment, as it is associated with decreased addiction-related behaviors and impulsive action. The goal of the present study was to determine the effects of progesterone (PRO) on impulsive action for food: a Go/No-Go task. Female and male rats responded for sucrose pellets during a Go component when lever pressing was reinforced on a variable-interval 30-s schedule. During the alternate No-Go component, withholding a lever press was reinforced on a differential reinforcement of other (DRO) behavior 30-s schedule, where a lever press reset the DRO timer. Impulsive action was operationally defined as the inability to withhold a response during the No-Go component (i.e. the number of DRO resets). Once Go/No-Go behavior was stable, responding between rats treated with PRO (0.5mg/kg) or vehicle was examined. Progesterone significantly decreased the total number of DRO resets in both males and females, but it did not affect VI responding for sucrose pellets. This suggests that PRO decreases motor impulsivity for sucrose pellets without affecting motivation for food. Thus, PRO may reduce motor impulsivity, a behavior underlying drug addiction., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The importance of studying sex as a biological variable in biomedical research is becoming increasingly apparent. There is a particular need in preclinical studies of addiction to include both sexes, as female animals are often excluded from studies, leaving large gaps in our knowledge of not only sex differences and potential prevention and treatment strategies but also with regard to the basic neurobiology of addiction. This review focuses on methodology that has been developed in preclinical studies to examine sex differences in the behavioral aspects and neurobiological mechanisms related to addiction across the full range of the addiction process, including initiation (acquisition), maintenance, escalation, withdrawal, relapse to drug seeking and treatment. This review also discusses strategic and technical issues that need to be considered when comparing females and males, including the role of ovarian hormones and how sex differences interact with other major vulnerability factors in addiction, such as impulsivity, compulsivity and age (adolescent versus adult). Novel treatments for addiction are also discussed, such as competing non-drug rewards, repurposed medications such as progesterone and treatment combinations. Practical aspects of conducting research comparing female and male animals are also considered. Making sex differences a point of examination requires additional effort and consideration; however, such studies are necessary given mounting evidence demonstrating that the addiction process occurs differently in males and females. These studies should lead to a better understanding of individual differences in the development of addiction and effective treatments for males and females., (© 2016 Society for the Study of Addiction.)

A family of Co(II) complexes supported by the bulky, dianionic bis(pyrrolyl)pyridine pincer ligand pyrr2py [pyrr2py(2-) = 3,5-(t)Bu2-bis(pyrrolyl)pyridine] are reported in this work. These compounds include 1-OEt2, 1·toluene, and 1-N3Ad (Ad = 1-adamantyl), the latter which is prepared via addition of N3Ad to 1-OEt2 [1 = (pyrr2py)Co]. While complexes 1-OEt2 and 1-N3Ad are four-coordinate systems having a Co(II) ion confined in a cis-divacant octahedral geometry, complex 1·toluene possesses a Co(II) ion in a T-shaped environment where the toluene is interstitial and intercalated between two (pyrr2py)Co molecules. Complex 1-N3Ad is notable in that the organic azide binds to the metal through γ-N in a κ(1) fashion. Photolysis of 1-N3Ad results in N2 extrusion and formation of C-H insertion product [(pyrrpypyrrNHAd)Co] (2). We propose complex 2 form via insertion of the nitrene (NAd) into one (t)Bu C-H bond, thus resulting in a pincer ligand having a pendant secondary amine. Complexes 1-OEt2, 1·toluene, and 1-N3Ad and C-H insertion product 2 have been structurally characterized, and in the case of 1-OEt2, we also present electrochemical data.

Background: In previous studies, female monkeys self-administered more oral phencyclidine (PCP) than males, and PCP intake differed by phase of menstrual cycle., Objectives: The purpose of this study was to examine sex and hormonal influences on oral cocaine self-administration in male and female rhesus monkeys in the follicular vs. luteal phases of the menstrual cycle, with concurrent access to an alternative nondrug reward, saccharin (SACC) vs. water., Materials and Methods: Concurrent access to cocaine (0.2, 0.4, and 0.8 mg/ml) and SACC or water was available from two drinking spouts under concurrent fixed-ratio (FR) 2, 4, and 8 schedules during daily 3-h sessions., Results: Cocaine deliveries were similar in males and females in the females' luteal phase, but cocaine deliveries were higher in females during the follicular phase than the luteal phase and compared to males. When SACC was available, cocaine deliveries were reduced in females in the follicular phase of the cycle, and cocaine intake (mg/kg) was reduced in males and in females' follicular and luteal phases., Conclusions: Access to concurrent SACC (vs. water) reduced cocaine intake (mg/kg) in males and in females during both menstrual phases, and the magnitude of the reduction in cocaine intake was greatest during the females' follicular phase. Thus, a nondrug alternative reward, SACC, is a viable alternative treatment for reducing cocaine's rewarding effects on male and female monkeys, and reductions in cocaine seeking were optimal in the females' luteal phase.

Rationale: Impulsive choice, or an inability to delay immediate gratification, has been strongly linked to the development and persistence of drug abuse. Indeed, delaying drug use itself may underlie drug addiction and relapse. Thus, employing treatments that are efficacious in reducing impulsive choice (atomoxetine; ATO) or drug-seeking behavior (progesterone; PRO) may be an effective means of treating drug addiction., Objective: The current study assessed sex differences in the effects of PRO, ATO, and their combination in a delay discounting paradigm for cocaine and for sucrose pellets., Method: Male and female rats chose between a small-immediate or a large-delayed (0, 7.5, 15, 30, 60 s) outcome in an impulsive choice procedure for sucrose pellets (1 vs. 3 pellets) or for iv cocaine infusions (0.3 vs. 0.9 mg/kg). Following baseline assessment of impulsive choice, rats received daily treatment of vehicle (VEH), PRO (0.5 mg/kg), ATO (1.5 mg/kg), or a combination (PRO + ATO) until a second assessment of impulsive choice was determined., Results: Compared to the VEH group, females were less impulsive for cocaine following PRO or the PRO + ATO combined treatment, whereas males were less impulsive for cocaine following ATO. No treatment effects were observed on impulsive choice for sucrose pellets., Conclusions: The present results indicate that impulsive choice for cocaine is reduced by PRO in females and by ATO in males. These findings suggest both treatments may be an effective intervention in treating cocaine abuse, but that their effectiveness differs by sex.

Tobacco use is the largest cause of preventable mortality in the western world. Even after treatment, relapse rates for tobacco are high, and more effective pharmacological treatments are needed. Progesterone (PRO), a female hormone used in contraceptives, reduces stimulant use but its effects on tobacco addiction are unknown. Varenicline (VAR) is a commonly used medication that reduces tobacco use. The present study examined sex differences in the individual vs. combined effects of PRO and VAR on reinstatement of nicotine-seeking behavior in a rat model of relapse. Adult female and male Wistar rats self-administered nicotine (NIC, 0.03mg/kg/infusion) for 14days followed by 21days of extinction when no cues or drug were present. Rats were then divided into 4 treatment groups: control (VEH+SAL), PRO alone (PRO+SAL), VAR alone (VEH+VAR) and the combination (PRO+VAR). Reinstatement of nicotine-seeking behavior induced by priming injections of NIC or caffeine (CAF), presentation of cues (CUES), and the combination of drugs and cues (e.g. NIC+CUES, CAF+CUES) were tested after extinction. Male and female rats did not differ in self-administration of nicotine or extinction responding, and both showed elevated levels of responding to the CAF+CUES condition. However, males, but not females, reinstated active lever-pressing to the NIC+CUES condition, and that was attenuated by both VAR and VAR+PRO treatment. Thus, males were more sensitive to NIC+CUE-induced reinstatement than females, and VAR alone and VAR combined with PRO effectively reduced nicotine relapse., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Two repurposed medications have been proposed to treat cocaine abuse. Progesterone, a gonadal hormone, and atomoxetine, a medication commonly used to treat attention deficit/hyperactivity disorder, have both been separately shown to reduce cocaine self-administration and reinstatement (i.e., relapse). The goal of the present study was to examine sex differences in the individual effects of PRO and ATO as well as the combination PRO+ATO treatment on cocaine (COC), caffeine (CAF), and/or cue-primed reinstatement of cocaine-seeking. Adult male and female Wistar rats lever-pressed under a FR 1 schedule for cocaine infusions (0.4mg/kg/inf). After 14 sessions of stable responding in daily 2-h sessions, rats underwent a 21-day extinction period when no drug or drug-related stimuli were present. Rats were then separated into four groups that received PRO (0.5mg/kg) alone (PRO+SAL), ATO (1.5mg/kg) alone (VEH+ATO), control (VEH+SAL) or combination (PRO+ATO) treatments prior to the reinstatement condition. Reinstatement of cocaine-seeking to cues and/or drug injections of cocaine or caffeine was tested after extinction. During maintenance, females self-administered more cocaine than males, but no sex differences were seen during extinction. Females showed greater cocaine-seeking than males after a CAF priming injection. Individual treatment with ATO did not decrease reinstatement under any priming condition; however, the combination treatment decreased cocaine-seeking under the COC+CUES priming condition in males, and both PRO alone and the combination treatment decreased cocaine-seeking in the CAF+CUES condition in females. Overall, PRO alone was only effective in reducing reinstatement in females, while the combination treatment was consistently effective in reducing reinstatement in both sexes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A promising approach in treating cocaine abuse is to metabolize cocaine in the blood using a mutated butyrylcholinesterase (BChE) that functions as a cocaine hydrolase (CocH). In rats, a helper-dependent adenoviral (hdAD) vector-mediated delivery of CocH abolished ongoing cocaine use and cocaine-primed reinstatement of drug-seeking for several months. This enzyme also metabolizes ghrelin, an effect that may be beneficial in maintaining healthy weights. The effect of a single hdAD-CocH vector injection was examined in rats on measures of anxiety, body weight, cocaine self-administration, and cocaine-induced locomotor activity. To examine anxiety, periadolescent rats were tested in an elevated-plus maze. Weight gain was then examined under four rodent diets. Ten months after CocH-injection, adult rats were trained to self-administer cocaine intravenously and, subsequently, cocaine-induced locomotion was tested. Viral gene transfer produced sustained plasma levels of CocH for over 13 months of testing. CocH-treated rats did not differ from controls in measures of anxiety, and only showed a transient reduction in weight gain during the first 3 weeks postinjection. However, CocH-treated rats were insensitive to cocaine. At 10 months postinjection, none of the CocH-treated rats initiated cocaine self-administration, unlike 90% of the control rats. At 13 months postinjection, CocH-treated rats showed no cocaine-induced locomotion, whereas control rats showed a dose-dependent enhancement of locomotion. CocH vector produced a long-term blockade of the rewarding and behavioral effects of cocaine in rats, emphasizing its role as a promising therapeutic intervention in cocaine abuse., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Rats selectively bred for high (HiS) or low (LoS) saccharin intake are a well-established model of drug-abuse vulnerability, with HiS rats being more likely to consume sweets and cocaine than LoS rats. Still, the nature of these differences is poorly understood. This study examined whether the motivational consequences of cocaine exposure are differentially expressed in HiS and LoS rats by measuring intracranial self-stimulation (ICSS) thresholds following acute injections of cocaine (10 mg/kg). Reductions in ICSS thresholds following cocaine injection were greater in HiS rats than in LoS rats, suggesting that the reward-enhancing effects of cocaine are greater in the drug-vulnerable HiS than LoS rats. Higher cocaine-induced reward, indicated by lower ICSS thresholds, may explain the higher rates of drug consumption in sweet-preferring animal models, providing a clue to the etiology of cocaine addiction in vulnerable populations.

Rationale: Consistent sex differences are observed in human drug addiction, with females often exceeding males on drug intake. However, there is still a need for animal models for some aspects of addiction such as acquisition of drug self-administration and the subsequent development of drug-seeking., Objectives: The present study examined sex differences in the acquisition and maintenance of self-administration of two widely used stimulants, cocaine and nicotine., Methods: Male and female rats self-administered cocaine (0.4 mg/kg/infusion) or nicotine (0.03 mg/kg/infusion) daily under a fixed-ratio 1 (FR 1) schedule until acquisition criteria were met (maximum of 30 sessions). The self-administration criterion for cocaine was ≥20 infusions in a 2-h session and ≥5 infusions in a 1-h session for nicotine. Sex differences were assessed by examining the percentage of rats that met acquisition criteria, the number of sessions to meet criteria, and the number of infusions earned during the maintenance phase., Results: A significantly higher percentage of male rats acquired both cocaine and nicotine self-administration than females, and males met acquisition criteria in fewer sessions. However, after criteria were met, females self-administered more cocaine than males during the first 5 days of maintenance. There were no sex differences in nicotine infusions post-acquisition., Conclusions: Differences in acquisition amongst sexes can reveal factors that are integral to initiation of drug use, an often overlooked phase of drug addiction.

The purpose of this review is to discuss recent findings related to sex differences in behavioral dyscontrol that lead to drug addiction, and clinical implications for humans are discussed. This review includes research conducted in animals and humans that reveals fundamental aspects of behavioral dyscontrol. The importance of sex differences in aspects of behavioral dyscontrol, such as impulsivity and compulsivity, is discussed as major determinants of drug addiction. Behavioral dyscontrol during adolescence is also an important consideration, as this is the time of onset for drug addiction. These vulnerability factors additively increase drug-abuse vulnerability, and they are integral aspects of addiction that covary and interact with sex differences. Sex differences in treatments for drug addiction are also reviewed in terms of their ability to modify the behavioral dyscontrol that underlies addictive behavior. Customized treatments to reduce behavioral dyscontrol are discussed, such as (1) using natural consequences such as non-drug rewards (e.g., exercise) to maintain abstinence, or using punishment as a consequence for drug use, (2) targeting factors that underlie behavioral dyscontrol, such as impulsivity or anxiety, by repurposing medications to relieve these underlying conditions, and (3) combining two or more novel behavioral or pharmacological treatments to produce additive reductions in drug seeking. Recent published work has indicated that factors contributing to behavioral dyscontrol are an important target for advancing our knowledge on the etiology of drug abuse, intervening with the drug addiction process and developing novel treatments.

Background: Recent research has demonstrated that aerobic exercise can attenuate craving for drugs of abuse and reduce escalation and reinstatement of drug-seeking behavior in animal models. The present study examined the effects of aerobic exercise on the development of the incubation of cocaine-seeking behavior or the progressive increase in cocaine seeking over a protracted withdrawal period from cocaine self-administration., Methods: Female rats were trained to self-administer cocaine (0.4 mg/kg/inf) during daily 6-h sessions for 10 days. Subsequently, access to cocaine and cocaine-paired cues was discontinued during a 3- or 30-day withdrawal period when rats had access to either a locked or unlocked running wheel. At the end of the withdrawal period, rats were reintroduced to the operant conditioning chamber and reexposed to cocaine-paired cues to examine cocaine-seeking behavior under extinction conditions., Results: Rats with access to a locked running wheel during 30 days of withdrawal had significantly greater cue-induced cocaine-seeking behavior than rats that had access to an unlocked running wheel for 30 days. Further, there was robust incubation of cocaine seeking in rats with access to a locked running wheel as cocaine seeking was notably elevated at 30 vs. 3 days of withdrawal. However, cocaine-seeking behavior did not differ between rats with access to an unlocked running wheel for 30 vs. 3 days, indicating that incubation of cocaine seeking was suppressed following access to exercise for 30 days., Conclusion: Aerobic exercise during extended withdrawal from cocaine self-administration decreased incubation of cue-induced cocaine-seeking behavior and may reduce vulnerability to relapse.

Investigations into animal models of drug withdrawal have largely found that emotional signs of withdrawal (e.g. anxiety, anhedonia, and aversion) in adolescents are experienced earlier and less severely than in their adult counterparts. The majority of these reports have examined withdrawal from ethanol or nicotine. To expand our knowledge about the emotional withdrawal state in adolescent rats, we used potentiation of the acoustic startle reflex after an acute dose of morphine (10 mg/kg, subcutaneously) as a measure of opiate withdrawal. Startle was measured at four time points after morphine injection (2, 3, 4, and 5 h) in 28-day-old and 90-day-old male and female rats. The results of this experiment revealed that peak potentiation of the startle reflex occurred at 3 h in the adolescent rats and at 5 h in the adult rats, and that the magnitude of withdrawal was larger in the adults. No sex differences were observed. Overall, these results affirm that, similar to withdrawal from ethanol and nicotine, opiate withdrawal signs are less severe in adolescent than in adult rats.

The Ti(III) azido complex (PN)2Ti(N3) (PN(-) = (N-(2-(diisopropylphosphino)-4-methylphenyl)-2,4,6-trimethylanilide), can be reduced with KC8 to afford the nitride salt [μ2-K(OEt2)]2[(PN)2Ti≡N]2 in excellent yield. While treatment of the dimer with 18-crown-6 yields a mononuclear nitride, complete encapsulation of the alkali metal with cryptand provides the terminally bound nitride as a discrete salt [K(2,2,2-Kryptofix)][(PN)2Ti≡N]. All complexes reported here have been structurally confirmed and also spectroscopically, and the Ti-Nnitride bonding has been probed theoretically via DFT-based methods.

Rationale: The relationship between impulsive choice and cocaine use in humans has been well established, although the causal role between these variables is complex. To disentangle this relationship, studies using rats have focused on how acute or chronic cocaine alters impulsive choice. A predominance of studies has focused on chronic cocaine regimens, but few have assessed acute cocaine's effects on impulsive choice., Objective: The current study assessed if acute cocaine administrations alter delay discounting of rats in two common impulsive choice procedures., Method: Baseline delay discounting rates were determined in female rats using both an increasing- and adjusting-delay procedure. Once stable, a range of acute cocaine injections (2, 5, and 15 mg/kg i.p.) was administered prior to both procedures., Results: Baseline delay discounting rates were positively correlated between the increasing- and adjusting-delay procedures. Acute administrations of cocaine produced a dose-dependent decrease in preference for the large alternative in the increasing-delay procedure but had no effect in the adjusting-delay procedure., Conclusions: The concordance of delay discounting rates across the two choice procedures suggests that both quantify the same underlying components of impulsive choice. However, manipulations that disrupt large alternative preference may not be readily detected under the adjusting-delay procedure unless control conditions are employed.

Adolescence is a transitional phase marked by a heightened vulnerability to substances of abuse. It has been hypothesized that both increased sensitivity to reward and decreased sensitivity to aversive events may drive drug-use liability during this phase. To investigate possible age-related differences in sensitivity to the aversive consequences of drug use, adolescent and adult rats were compared on self-administration of cocaine before, during, and after a 10-day period in which an aversive agent, histamine, was added to the cocaine solution. Adult and adolescent female rats were trained to self-administer intravenous cocaine (0.4 mg/kg/infusion) over 10 sessions (2 h/session; 2 sessions/day). Histamine (4 mg/kg/infusion) was then added directly into the cocaine solution for the next 10 sessions. Finally, the cocaine/histamine solution was replaced with a cocaine-only solution, and rats continued to self-administer cocaine (0.4 mg/kg) for 20 sessions. Compared with adolescent rats, adult rats showed a greater decrease in cocaine self-administration when it was punished with intravenous histamine compared with their baseline cocaine self-administration rates. These results suggest that differences in the sensitivity to negative consequences of drug use may partially explain developmental differences in drug use vulnerability.

Background: Neutropenic patients often become febrile and require frequent temperature monitoring. Monitoring core body temperature is considered the gold standard for accuracy. Taking oral temperature is the recommended noninvasive practice when core body temperature cannot be obtained; however, neutropenic patients often, for various reasons, are unable to tolerate an oral probe., Objectives: The purpose of this article is to determine the equivalence of temperatures taken via temporal artery, axillary, and oral methods, and to determine the best alternative to the oral method in the adult hematology/oncology population., Methods: A repeated measures equivalence design was used. A convenience sample of 40 data sets (N = 33 inpatients) was tested on a hematology/oncology inpatient unit in a National Cancer Institute-designated comprehensive cancer center in the southeastern United States. A Latin squares design was employed with three possible sequences of measurement. Demographic data were analyzed using descriptive statistics, and equivalence was tested using the two one-sided tests method. Acceptance criterion for difference between methods was set at 0.2°F from the oral method., Findings: The temporal method is a potential noninvasive alternative to the oral method for the adult hematology/oncology population.

Rationale: Sweet preference is a marker of vulnerability to substance use disorders, and rats selectively bred for high (HiS) vs. low saccharin (LoS) intake display potentiated drug-seeking behaviors. Recent work indicated that LoS rats were more responsive to the negative effects of drugs in several assays., Objective: The current study used the intracranial self-stimulation (ICSS) procedure to investigate the anhedonic component of morphine withdrawal in male HiS and LoS rats., Methods: Rats were administered morphine (10mg/kg) or saline for 8 days. To evaluate withdrawal effects, reward thresholds were measured 24 and 28h following the 8th morphine injection (spontaneous withdrawal) and again for 4 days following daily acute morphine and naloxone (1mg/kg) administration (precipitated withdrawal)., Results: 24h following the final morphine injection, reward thresholds in LoS rats were significantly elevated compared to reward thresholds in LoS controls, indicating spontaneous withdrawal. This effect was not observed in HiS rats. LoS rats also showed greater elevations of reward thresholds on several days during naloxone-precipitated withdrawal compared to their HiS counterparts., Conclusions: LoS rats were more sensitive to morphine withdrawal-mediated elevations in ICSS thresholds than HiS rats. While these differences were generally modest, our data suggest that severity of the negative affective component of opiate withdrawal may be influenced by genotypes related to addiction vulnerability., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Aerobic exercise and the attention-deficit/hyperactivity disorder medication, atomoxetine (ATO), are two monotherapies that have been shown to suppress reinstatement of cocaine-seeking in an animal model of relapse. The present study investigated the effects of combining wheel running and ATO versus each treatment alone on cocaine-seeking precipitated by cocaine and cocaine-paired cues in rats with differing susceptibility to drug abuse (i.e., high vs. low impulsive)., Methods: Rats were screened for high (HiI) or low impulsivity (LoI) based on their performance on a delay-discounting task and then trained to self-administer cocaine (0.4 mg/kg/inf) for 10 days. Following 14 days of extinction, both groups were tested for reinstatement of cocaine-seeking precipitated by cocaine or cocaine-paired cues in the presence of concurrent running wheel access (W), pretreatment with ATO, or both (W+ATO)., Results: HiI rats acquired cocaine self-administration more quickly than LoI rats. While both individual treatments and W+ATO significantly attenuated cue-induced cocaine seeking in HiI and LoI rats, only W+ATO was effective in reducing cocaine-induced reinstatement compared with vehicle treatment. There were dose-dependent and phenotype-specific effects of ATO with HiI rats responsive to the low but not high ATO dose. Floor effects of ATO and W on cue-induced reinstatement prevented the assessment of combined treatment effects., Conclusions: These findings demonstrated greater attenuation of cue- versus cocaine-induced reinstatement by ATO and W alone and recapitulate impulsivity phenotype differences in both acquisition of cocaine self-administration and receptivity to treatment.

Cocaine use results in anhedonia during withdrawal, but it is not clear how this emotional state interacts with an individual's vulnerability for addiction. Rats selectively bred for high (HiS) or low (LoS) saccharin intake are a well-established model of drug abuse vulnerability, with HiS rats being more likely to consume sweets and drugs of abuse such as cocaine and heroin (Carroll et al., 2002) than LoS rats. This study examined whether the motivational consequences of cocaine withdrawal are differentially expressed in HiS and LoS rats. HiS and LoS rats were trained to respond for a sucrose reward on a progressive ratio (PR) schedule of reinforcement and breakpoints were measured during and after chronic, continuous exposure to cocaine (30 mg/kg/day). Cocaine, but not saline, treatment resulted in lower breakpoints for sucrose during withdrawal in LoS rats only. These results suggest anhedonia during withdrawal is more pronounced in the less vulnerable LoS rats. Fewer motivational deficits during withdrawal may contribute to greater drug vulnerability in the HiS line., (Published by Elsevier Inc.)

Background: Previous research indicates that individual differences in traits such as impulsivity, avidity for sweets, and novelty reactivity are predictors of several aspects of drug addiction. Specifically, rats that rank high on these behavioral measures are more likely than their low drug-seeking counterparts to exhibit several characteristics of drug-seeking behavior. In contrast, initial work suggests that the low drug-seeking animals are more reactive to negative events (e.g., punishment and anxiogenic stimuli). The goal of this study was to compare high and low impulsive rats on reinstatement of cocaine-seeking behavior elicited by cocaine (COC) and by negative stimuli such as the stress-inducing agent yohimbine (YOH) or a high dose of caffeine (CAFF). An additional goal was to determine whether treatment with allopregnanolone (ALLO) would reduce reinstatement (or relapse) of cocaine-seeking behavior under these priming conditions., Methods: Female rats were selected as high (HiI) or low (LoI) impulsive using a delay-discounting task. After selection, they were allowed to self-administer cocaine for 12 days. Cocaine was then replaced with saline, and rats extinguished lever responding over 16 days. Subsequently, rats were pretreated with either vehicle control or ALLO, and cocaine seeking was reinstated by injections of COC, CAFF, or YOH., Results: While there were no phenotype differences in maintenance and extinction of cocaine self-administration or reinstatement under control treatment conditions, ALLO attenuated COC- and CAFF-primed reinstatement in LoI but not HiI rats., Conclusions: Overall, the present findings suggest that individual differences in impulsive behavior may influence efficacy of interventions aimed to reduce drug-seeking behavior., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Individually, both treatment with progesterone and concurrent access to an exercise wheel reduce cocaine self-administration under long-access conditions and suppress cocaine-primed reinstatement in female rats. In the present study, wheel running and progesterone (alone and combined) were assessed for their effects on reinstatement of cocaine-seeking primed by yohimbine, cocaine, and cocaine-paired cues., Methods: Male and female rats were implanted with an intravenous catheter and allowed to self-administer cocaine (0.4 mg/kg/inf, iv) during 6-h sessions for 10 days. Subsequently, the groups of male and female rats were each divided into two groups that were given concurrent access to either a locked or unlocked running wheel under extinction conditions for 14 days. Next, all four groups were tested in a within-subjects design for reinstatement of cocaine-seeking precipitated by separate administration of cocaine-paired stimuli, yohimbine, or cocaine or the combination of yohimbine + cocaine-paired stimuli or cocaine + cocaine-paired stimuli. These priming conditions were tested in the presence of concurrent wheel access (W), pretreatment with progesterone (P), or both (W + P)., Results: In agreement with previous results, females responded more for cocaine than males during maintenance. Additionally, concurrent wheel running attenuated extinction responses and cocaine-primed reinstatement in females but not in males. Across all priming conditions, W + P reduced reinstatement compared to control conditions, and for cocaine-primed reinstatement in male rats, the combined W + P treatment was more effective than W or P alone., Conclusion: Under certain conditions, combined behavioral (exercise) and pharmacological (progesterone) interventions were more successful at reducing cocaine-seeking behavior than either intervention alone.

A new pharmacokinetic approach treating cocaine addiction involves rapidly metabolizing cocaine before it reaches brain reward centers using mutated human butyrylcholinesterase (BChE) or cocaine hydrolase (CocH). Recent work has shown that helper-dependent adenoviral (hdAD) vector-mediated plasma CocH reduced the locomotor-activating effects of cocaine and prevented reinstatement of cocaine-seeking behavior up to 6 months in rats. The present study investigated whether hdAD-CocH could decrease ongoing intravenous cocaine (0.4 mg/kg) self-administration. The hdAD-CocH vector was injected into self-administering rats, and after accumulation of plasma CocH, there was a dramatic reduction in cocaine infusions earned under a fixed ratio 1 schedule of reinforcement that lasted for the length of the study (>2 months). Pretreatment with the selective BChE and CocH inhibitor iso-OMPA (1.5 mg/kg) restored cocaine intake; therefore, the decline in self-administration was likely due to rapid CocH-mediated cocaine metabolism. Direct measurements of cocaine levels in plasma and brain samples taken after the conclusion of behavioral studies provided strong support for this conclusion. Further, rats injected with hdAD-CocH did not experience a deficit in operant responding for drug reinforcement and self-administered methamphetamine (0.05 mg/kg) at control levels. Overall, these outcomes suggest that viral gene transfer can yield plasma CocH levels that effectively diminish long-term cocaine intake and may have potential treatment implications for cocaine-dependent individuals seeking to become and remain abstinent.

Emerging evidence from human and animal studies suggests that exercise is a highly effective treatment for drug addiction. However, most work has been done in behavioral models, and the effects of exercise on the neurobiological substrates of addiction have not been identified. Specifically, it is unknown whether prior exercise exposure alters neuronal activation of brain reward circuitry in response to drugs of abuse. To investigate this hypothesis, rats were given 21 days of daily access to voluntary wheel running in a locked or unlocked running wheel. Subsequently, they were challenged with a saline or cocaine (15 mg/kg, i.p.) injection and sacrificed for c-Fos immunohistochemistry. The c-Fos transcription factor is a measure of cellular activity and was used to quantify cocaine-induced activation of reward-processing areas of the brain: nucleus accumbens (NAc), caudate putamen (CPu), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). The mean fold change in cocaine-induced c-Fos cell counts relative to saline-induced c-Fos cell counts was significantly higher in exercising compared to control rats in the NAc core, dorsomedial and dorsolateral CPu, the prelimbic area, and the OFC, indicating differential cocaine-specific cellular activation of brain reward circuitry between exercising and control animals. These results suggest neurobiological mechanisms by which voluntary wheel running attenuates cocaine-motivated behaviors and provide support for exercise as a novel treatment for drug addiction., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Reported are complexes of the formula Fe(dithiolate)(CO) 2 (diphos) and their use to prepare homo- and heterobimetallic dithiolato derivatives. The starting iron dithiolates were prepared by a one-pot reaction of FeCl 2 and CO with chelating diphosphines and dithiolates, where dithiolate = S 2 (CH 2 ) 2 2- (edt 2- ), S 2 (CH 2 ) 3 2- (pdt 2- ), S 2 (CH 2 ) 2 (C(CH 3 (Me 2 ) 2- (Me 2 pdt 2- ) and diphos = cis -C 2 H 2 (PPh 2 ) 2 (dppv), C 2 H 4 (PPh 2 ) 2 (dppe), C 6 H 4 (PPh 2 ) 2 (dppbz), C 2 H 4 [P(C 6 H 11 ) 2 ] 2 (dcpe). The incorporation of 57 Fe into such building block complexes commenced with the conversion of 57 Fe into 57 Fe 2 I 4 ( i PrOH) 4 , which then was treated with K 2 pdt, CO, and dppe to give 57 Fe(pdt)(CO) 2 (dppe). NMR and IR analyses show that these complexes exist as mixtures of all-cis and trans-CO isomers, edt 2- favoring the former and pdt 2- the latter. Treatment of Fe(dithiolate)(CO) 2 (diphos) with the Fe(0) reagent (benzylideneacetone)Fe(CO) 3 gave Fe 2 (dithiolate)(CO) 4 (diphos), thereby defining a route from simple ferrous salts to models for hydrogenase active sites. Extending the building block route to heterobimetallic complexes, treatment of Fe(pdt)(CO) 2 (dppe) with [(acenaphthene)Mn(CO) 3 ] + gave [(CO) 3 Mn(pdt)Fe(CO) 2 (dppe)] + ([ 3d (CO)] + ). Reduction of [ 3d (CO)] + with BH 4 - gave the C s -symmetric μ-hydride (CO) 3 Mn(pdt)(H)Fe(CO)(dppe) (H 3d ). Complex H 3d is reversibly protonated by strong acids, the proposed site of protonation being sulfur. Treatment of Fe(dithiolate)(CO) 2 (diphos) with CpCoI 2 (CO) followed by reduction by Cp 2 Co affords CpCo(dithiolate)Fe(CO)(diphos) ( 4 ), which can also be prepared from Fe(dithiolate)(CO) 2 (diphos) and CpCo(CO) 2 . Like the electronically related (CO) 3 Fe(pdt)Fe(CO)(diphos), these complexes undergo protonation to afford the μ-hydrido complexes [CpCo(dithiolate)HFe(CO)(diphos)] + . Low-temperature NMR studies indicate that Co is the kinetic site of protonation.

A key feature of substance use disorders is continued drug consumption despite aversive consequences. This has been modeled in the animal laboratory by pairing drug self-administration with electric shock, thereby punishing drug intake (Deroche-Gamonet et al. 2004). In the present experiments, we examined the effects of punishment on i.v. cocaine self-administration by adding histamine to the cocaine solution with three different animal models of high and low vulnerability to drug abuse: rats selectively bred for high (HiS) and low (LoS) saccharin consumption, rats selected for high (HiI) and low (LoI) impulsivity, and sex differences. Animals were allowed to self-administer cocaine (0.4 mg/kg/infusion) to establish a baseline of operant responding. Histamine (4.0mg/kg/infusion) was then added directly into the cocaine solution and its consequent effects on self-administration were compared to baseline. The histamine+cocaine solution was then replaced with a cocaine-only solution, and the rats' operant responding was again compared to baseline. Concurrent histamine exposure was effective in reducing cocaine consumption in all groups of rats; however, LoS and female rats took longer to return to baseline levels of cocaine consumption after histamine was removed compared to HiS and male rats. These data suggest that the reduction of drug self-administration by aversive consequences may differ in groups that vary in drug use vulnerability . Such results may inform pharmacological strategies that enhance the negative aspects of drug consumption., (© 2013.)