Chemical stimulation of the lateral hypothalamus potentiated the sensitization to morphine in rats

Orexin plays a crucial role in drug-seeking behavior. The lateral hypothalamus (LH) is a central region that produces orexin, and its projections to the ventral tegmental area (VTA) play an important role in reward and addiction-related behaviors. In this study, we investigated the role of LH stimulation and the involvement of the orexin-1 receptor (Ox1r) in the VTA in relation to morphine sensitization. In all animals, cannulae were implanted unilaterally into the LH and VTA to inject different doses of carbachol (62.5, 125 and 250 nmol/0.5 μl saline) as a cholinergic agonist and SB334867 (1, 10 and 20 nmol/0.3 μl DMSO) as a selective Ox1r antagonist for three consecutive days (sensitization period) respectively. These drugs were injected five minutes before administration of an ineffective dose of morphine (0.5 mg/kg; sc) during the sensitization period. In all groups, the sensitization period occurred in a separate room from which the conditioning occurred. After this period, all groups exceeded five days under the conditioned place preference (CPP) paradigm without any treatment. For evaluation of morphine sensitization, place preference was induced by ineffective dose of morphine (0.5 mg/kg) and the CPP score was represented by the difference in time spent in drug- and saline-paired compartments. The results revealed that concurrent intra-LH administration of carbachol (125 nmol/0.5 μl saline) and an ineffective dose of morphine (0.5 mg/kg) significantly induce CPP. Additionally, the blockade of Ox1r in the VTA by SB334867 can attenuate the conditioning score induced by concurrent administration of carbachol and an ineffective dose of morphine. Our findings suggest that LH stimulation potentiates the effect of an ineffective dose of morphine, and induces morphine sensitization. It seems that the chemical stimulation of LH potentiates sensitization to morphine through the orexinergic system in the VTA in rats

Changes in apoptotic factors in hypothalamus and hippocampus after acute and subchronic stress induction during conditioned place preference paradigm

The hypothalamus (HYP) and hippocampus (HIP) are important regions involved in stress responses. These areas are also associated with reward processing. In this study, the effects of acute and subchronic stress on the changes in apoptotic factors (Bax/Bcl-2 ratio, caspase-3 activation and PARP degradation) in the HYP and HIP during conditioned place preference (CPP) paradigm were evaluated. Male Wistar rats were divided into two saline- and morphine-reated supergroups. Each supergroup contained control, acute stress (AS) and subchronic stress (SS) groups. In all groups, CPP paradigm was done and thereinafter alterations of apoptotic factors were measured by western blot. The results revealed that in the HYP, all mentioned factors increased significantly in saline- or morphine-treated animals during AS and SS. On the other hand, in the HIP, Bax/Bcl-2 ratio in saline-treated animals increased significantly during AS and SS, while in morphine-treated animals this ratio did not have any significant alteration during AS and was decreased during SS compared with morphine-control group. Caspase-3 and PARP increased during AS and SS in saline- or morphine-treated animals. For example, caspase-3 increased during AS and SS in morphine-treated animals by 2.4 folds and PARP (89 KDa) increased by 3.1 and 3.5 folds, respectively. Interestingly, the increase of apoptotic factors in morphine-treated animals was more considerable than that of saline-treated animals. These results strongly implied that AS and SS trigger apoptotic events in the HYP and HIP of saline- and/or morphine-treated animals as well as morphine reinforces the effect of stress on the induction of apoptosis

Activation of cannabinoid system in anterior cingulate cortex and orbitofrontal cortex modulates cost-benefit decision making

Despite the evidence for altered decision making in cannabis abusers, the role of the cannabinoid system in decision-making circuits has not been studied. Here, we examined the effects of cannabinoid modulation during cost-benefit decision making in the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC), key brain areas involved in decision making. We trained different groups of rats in a delay-based and an effort-based form of cost-benefit T-maze decision-making task. During test days, the rats received local injections of either vehicle or ACEA, a cannabinoid type-1 receptor (CB1R) agonist in the ACC or OFC. We measured spontaneous locomotor activity following the same treatments and characterized CB1Rs localization on different neuronal populations within these regions using immunohistochemistry. We showed that CB1R activation in the ACC impaired decision making such that rats were less willing to invest physical effort to gain high reward. Similarly, CB1R activation in the OFC induced impulsive pattern of choice such that rats preferred small immediate rewards to large delayed rewards. Control tasks ensured that the effects were specific for differential cost-benefit tasks. Furthermore, we characterized widespread colocalizations of CB1Rs on GABAergic axonal ends but few colocalizations on glutamatergic, dopaminergic, and serotonergic neuronal ends. These results provide first direct evidence that the cannabinoid system plays a critical role in regulating cost-benefit decision making in the ACC and OFC and implicate cannabinoid modulation of synaptic ends of predominantly interneurons and to a lesser degree other neuronal populations in these two frontal regions

Standards for Iranian Hospital Libraries: Why do Hospital Libraries Need to be Standardized?

The objective of developing the National Standard for Hospital Libraries (NSHL) is to present an efficient tool to replace scientific methods with traditional ones. The standards should be designed to be used as a comprehensive guide for librarians working in hospitals in various fields. Various standards are currently being developed for national, public, and academic libraries. Despite the activity of more than 200 educational and medical centers and a large number of public and private medical centers in Iran, there was no comprehensive standard that could meet this group of libraries' expectations. Therefore, the development of a standard for hospital libraries began based on national research. Finally, this standard was prepared in four chapters, including mission and organization, strategic planning, resources management, and service management. This standard was handed over to the Iranian National Standards Organization and the Deputy for Research and Technology of the Ministry of Health and Medical Education to be available to users and stakeholders. The NSHL is a comprehensive guideline for establishing and developing hospital libraries and applies to all public and private hospital libraries, both

Time-domain Classification of the Brain Reward System: Analysis of Natural- and Drug-Reward Driven Local Field Potential Signals in Hippocampus and Nucleus Accumbens

Addiction is a major public health concern characterized by compulsive reward-seeking behavior. The excitatory glutamatergic signals from the hippocampus (HIP) to the Nucleus accumbens (NAc) mediate learned behavior in addiction. Limited comparative studies have investigated the neural pathways activated by natural and unnatural reward sources. This study has evaluated neural activities in HIP and NAc associated with food (natural) and morphine (drug) reward sources using local field potential (LFP). We developed novel approaches to classify LFP signals into the source of reward and recorded regions by considering the time-domain feature of these signals. Proposed methods included a validation step of the LFP signals using autocorrelation, Lyapunov exponent and Hurst exponent to assess the meaningful stability of these signals (lack of chaos). By utilizing the probability density function (PDF) of LFP signals and applying Kullback-Leibler divergence (KLD), data were classified to the source of the reward. Also, HIP and NAc regions were visually separated and classified using the symmetrized dot pattern technique, which can be applied in real-time to ensure the deep brain region of interest is being targeted accurately during LFP recording. We believe our method provides a computationally light and fast, real-time signal analysis approach with real-world implementation.Comment: 12 pages, 7 figures first two authors contributed equally to this wor

Blockade of the Naloxone-induced Aversion in Morphine-conditioned Wistar Rats by L-Arginine Intra-central Amygdala

AbstractObjective(s)Single injection of naloxone, a selective antagonist of morphine, prior to the drug conditioning testing was used to investigate on morphine dependence.Materials and MethodsConditioning to morphine (2.5-10 mg/kg, s.c.) was established in adult male Wistar rats (weighing 200-250 g) using an unbiased procedure. Nitric oxide agents were microinjected into the central amygdala prior to naloxone-paired place conditioning testing.ResultsThe results showed that morphine produced a significant dose-dependent place preference in animals. Naloxone (0.1-0.4 mg/kg, i.p.) injections pre-testing of the response to morphine (7.5 mg/kg, s.c.) caused a significant aversion at the higher doses (0.4 mg/kg, i.p.). This response was reversed by microinjection of L-arginine (0.3-3 µg/rat, intra-central amygdala) prior to naloxone on the day of the testing. The response to L-arginine was blocked by pre-injection of NG-nitro-L-arginine methyl ester (L-NAME) (intra-central amygdala).ConclusionA single injection of naloxone on the test day of morphine place conditioning may simply reveal the occurrence of morphine dependence in rats, and that the nitric oxide in the central amygdala most likely plays a key role in this phenomenon

Delay-Dependent Impairments in Memory and Motor Functions After Acute Methadone Overdose in Rats

Methadone is used as a substitution drug for the treatment of opioid dependence and chronic pain. Despite its widespread use and availability, there is a serious concern with respect to the relative safety of methadone. The purpose of this study was to characterize how acute methadone overdose affects the cognitive and motor performance of naïve healthy rats. The methadone overdose was induced by administering an acute toxic dose of methadone (15 mg/kg; ip; the equivalent dose of 80% of LD50) to adolescent rats. Resuscitation using a ventilator pump along with a single dose of naloxone (2 mg/kg; ip) was administered following the occurrence of apnea. The animals which were successfully resuscitated divided randomly into three apnea groups that evaluated either on day 1, 5, or 10 post-resuscitation (M/N-Day 1, M/N-Day 5, and M/N-Day 10 groups) in the Y-maze and novel object memory recognition tasks as well as pole and rotarod tests. The data revealed that a single toxic dose of methadone had an adverse effect on spontaneous behavior. In addition, Recognition memory impairment was observed in the M/N-Day 1, 5, and 10 groups after methadone-induced apnea. Further, descending time in the M/N-Day 5 group increased significantly in comparison with its respective Saline control group. The overall results indicate that acute methadone-overdose-induced apnea produced delay-dependent cognitive and motor impairment. We suggest that methadone poisoning should be considered as a possible cause of delayed neurological disorders, which might be transient, in some types of memory or motor performance in naïve healthy rats

Trends in HIV/AIDS morbidity and mortality in Eastern Mediterranean countries, 1990–2015: findings from the Global Burden of Disease 2015 study

OBJECTIVES: We used the results of the Global Burden of Disease 2015 study to estimate trends of HIV/AIDS burden in Eastern Mediterranean Region (EMR) countries between 1990 and 2015. METHODS: Tailored estimation methods were used to produce final estimates of mortality. Years of life lost (YLLs) were calculated by multiplying the mortality rate by population by age-specific life expectancy. Years lived with disability (YLDs) were computed as the prevalence of a sequela multiplied by its disability weight. RESULTS: In 2015, the rate of HIV/AIDS deaths in the EMR was 1.8 (1.4–2.5) per 100,000 population, a 43% increase from 1990 (0.3; 0.2–0.8). Consequently, the rate of YLLs due to HIV/AIDS increased from 15.3 (7.6–36.2) per 100,000 in 1990 to 81.9 (65.3–114.4) in 2015. The rate of YLDs increased from 1.3 (0.6–3.1) in 1990 to 4.4 (2.7–6.6) in 2015. CONCLUSIONS: HIV/AIDS morbidity and mortality increased in the EMR since 1990. To reverse this trend and achieve epidemic control, EMR countries should strengthen HIV surveillance, and scale up HIV antiretroviral therapy and comprehensive prevention services

The global burden of tuberculosis: results from the Global Burden of Disease Study 2015

Background: An understanding of the trends in tuberculosis incidence, prevalence, and mortality is crucial to tracking of the success of tuberculosis control programmes and identification of remaining challenges. We assessed trends in the fatal and non-fatal burden of tuberculosis over the past 25 years for 195 countries and territories. Methods: We analysed 10 691 site-years of vital registration data, 768 site-years of verbal autopsy data, and 361 site-years of mortality surveillance data using the Cause of Death Ensemble model to estimate tuberculosis mortality rates. We analysed all available age-specific and sex-specific data sources, including annual case notifications, prevalence surveys, and estimated cause-specific mortality, to generate internally consistent estimates of incidence, prevalence, and mortality using DisMod-MR 2.1, a Bayesian meta-regression tool. We assessed how observed tuberculosis incidence, prevalence, and mortality differed from expected trends as predicted by the Socio-demographic Index (SDI), a composite indicator based on income per capita, average years of schooling, and total fertility rate. We also estimated tuberculosis mortality and disability-adjusted life-years attributable to the independent effects of risk factors including smoking, alcohol use, and diabetes. Findings: Globally, in 2015, the number of tuberculosis incident cases (including new and relapse cases) was 10·2 million (95% uncertainty interval 9·2 million to 11·5 million), the number of prevalent cases was 10·1 million (9·2 million to 11·1 million), and the number of deaths was 1·3 million (1·1 million to 1·6 million). Among individuals who were HIV negative, the number of incident cases was 8·8 million (8·0 million to 9·9 million), the number of prevalent cases was 8·9 million (8·1 million to 9·7 million), and the number of deaths was 1·1 million (0·9 million to 1·4 million). Annualised rates of change from 2005 to 2015 showed a faster decline in mortality (–4·1% [–5·0 to –3·4]) than in incidence (–1·6% [–1·9 to –1·2]) and prevalence (–0·7% [–1·0 to –0·5]) among HIV-negative individuals. The SDI was inversely associated with HIV-negative mortality rates but did not show a clear gradient for incidence and prevalence. Most of Asia, eastern Europe, and sub-Saharan Africa had higher rates of HIV-negative tuberculosis burden than expected given their SDI. Alcohol use accounted for 11·4% (9·3–13·0) of global tuberculosis deaths among HIV-negative individuals in 2015, diabetes accounted for 10·6% (6·8–14·8), and smoking accounted for 7·8% (3·8–12·0). Interpretation: Despite a concerted global effort to reduce the burden of tuberculosis, it still causes a large disease burden globally. Strengthening of health systems for early detection of tuberculosis and improvement of the quality of tuberculosis care, including prompt and accurate diagnosis, early initiation of treatment, and regular follow-up, are priorities. Countries with higher than expected tuberculosis rates for their level of sociodemographic development should investigate the reasons for lagging behind and take remedial action. Efforts to prevent smoking, alcohol use, and diabetes could also substantially reduce the burden of tuberculosis