Effects of dopamine D1 and D2 receptor agonists and antagonists on bombesin-induced behaviors

Central administration of bombesin elicits excessive grooming and locomotor activity in rats. This grooming activity is one characterised by vigorous scratching of the face, nape and body flanks. Pretreatment with the D1 receptor antagonist SCH 23390 inhibited the expression of bombesin-induced activity with grooming being more inhibited than locomotion. Blockade of D2 receptors with eticlopride significantly attenuated the behavioral responses to bombesin. When SCH 23390 and eticlopride were administered concurrently, it was apparent that D1 blockade had a greater effect on grooming and D2 blockade a larger effect on locomotion. Stimulation of D1 receptors by SKF 38393 elicited non-stereotyped locomotor activity and a form of grooming behavior characterised by vigorous washing of the face and ventral body surfaces. Co-administration of bombesin and SKF 38393 resulted in a form of grooming which resembled that elicited by SKF 38393 alone. The specific D2 agonist PPHT elicited a form of locomotion characterised by a downward oriented head posture and slow ambulatory activity around the cage perimeter. Co-administration of PPHT and bombesin resulted in a complete suppression of bombesin-induced behaviors and was largely indistinguishable from activity observed under PPHT alone conditions. These data implicate both D1 and D2 receptor based mechanisms in the modulation/mediation of the behavioral effects of bombesin. Part of the bombesin-induced behavioral effects may be explained by (indirect) activation of (a) dopamine system(s).     

Short- and long-periods of neonatal maternal separation differentially affect anxiety and feeding in adult rats: gender-dependent effects

Environmental manipulations during early development can induce permanent alterations in hypothalamic-pituitary-adrenal (HPA) and behavioral responses to stressors. However, little is known about the impact of early life experiences on appetitive responses. The present investigation assessed the effects of brief handling/separation or protracted separation from the dams, on feeding and anxiety responses during development. During the first 3 weeks post-partum, Sprague-Dawley rat pups were exposed daily to either brief (15 min) handling/isolation (H), a more protracted (3 h) period of maternal separation (MS), or were not handled (NH). When tested on the elevated plus-maze (at 5-6 weeks) H groups displayed less anxiety than NH gender-matched controls. Surprisingly, so did the MS females. At weaning (Day 22), the MS rats weighed significantly less than both the H and NH animals; the difference between the H and MS was more robust and persisted throughout the experiment (D 62). The H animals of both genders, and the females of the MS group, consumed more of the palatable 'snack' than their NH counterparts. The feeding suppressant response to the various satiety peptides (bombesin, cholecystokinin, and amylin) was not affected by the early life experience, with exception of cholecystokinin (CCK) effects, which were more pronounced in H and MS males. These results suggest that early life events may contribute to anxiety and/or ingestive disorders such as anorexia nervosa, bulimia and obesity.     

The use of psychiatry‐focused simulation in undergraduate nursing education: A systematic search and review

Evidence on the use of simulation to teach psychiatry and mental health (including addiction) content is emerging, yet no summary of the implementation processes or associated outcomes exists. The aim of this study was to systematically search and review empirical literature on the use of psychiatry‐focused simulation in undergraduate nursing education. Objectives were to (i) assess the methodological quality of existing evidence on the use of simulation to teach mental health content to undergraduate nursing students, (ii) describe the operationalization of the simulations, and (iii) summarize the associated quantitative and qualitative outcomes. We conducted online database (MEDLINE, Embase, ERIC, CINAHL, PsycINFO from January 2004 to October 2015) and grey literature searches. Thirty‐two simulation studies were identified describing and evaluating six types of simulations (standardized patients, audio simulations, high‐fidelity simulators, virtual world, multimodal, and tabletop). Overall, 2724 participants were included in the studies. Studies reflected a limited number of intervention designs, and outcomes were evaluated with qualitative and quantitative methods incorporating a variety of tools. Results indicated that simulation was effective in reducing student anxiety and improving their knowledge, empathy, communication, and confidence. The summarized qualitative findings all supported the benefit of simulation; however, more research is needed to assess the comparative effectiveness of the types of simulations. Recommendations from the findings include the development of guidelines for educators to deliver each simulation component (briefing, active simulation, debriefing). Finally, consensus around appropriate training of facilitators is needed, as is consistent and agreed upon simulation terminology.     

Mediastinal Mass Causing Spinal Cord Compression

A 4-year-old Cambodian male presented to the emergency room with 2 weeks of gradually increasing leg weakness until he could no longer stand. He was also reported to have a deformity on his back, intermittent fevers and cough. His physical exam was notable for a 2 cm × 1 cm bony protrusion at his T4 vertebrae, and 2/5 strength and positive Babinski reflexes in his lower extremities. A chest x-ray showed a 3.2 cm × 2.9 cm mass in the middle mediastinum extending to the posterior mediastinum. A purified protein derivative test was positive. A computed tomography scan showed findings consistent with pulmonary tuberculosis and a paravertebral mass with amorphous calcifications, which involved destruction of the T4-T5 vertebrae and evidence of cord compression. These findings were all consistent with tuberculous spondylitis (Pott''s disease).A 4-year-old male presented to a Cambodian emergency department with gradually increasing leg weakness for 2 weeks until he could no longer stand. He was also reported to have a deformity on his back for the past 2 months, and intermittent fevers and cough for several months. He retained control of his bowel and bladder function. On physical exam he was mildly tachypneic. His skin exam revealed a 2 cm × 1 cm bony protrusion at his T4 vertebrae (Figure 1). His neurological exam was significant for 2/5 strength, and positive Babinski reflexes in his lower extremities. He had normal sensation.Open in a separate windowFigure 1.Gibbus deformity representing wedged vertebrae as a result of vertebral body collapse.Workup included anteroposterior (Figure 2) and lateral chest x-rays, which showed a 3.2 cm × 2.9 cm mass in the middle mediastinum extending to the posterior mediastinum. The patient was promptly started on anti-tuberculosis (TB) treatment. A purified protein derivative test was positive. Three sputum samples were analyzed with the Xpert Mycobacterium tuberculosis/rifampin resistance (MTB/RIF) test and were all negative. A computed tomography scan done at an outside facility showed findings consistent with pulmonary tuberculosis as well as a paravertebral mass with amorphous calcifications, which involved destruction of the T4-T5 vertebrae and evidence of cord compression. These findings were all consistent with tuberculous spondylitis (Pott''s disease). After 1 month of treatment with anti-tuberculosis medication in conjunction with physical therapy, the patient had significantly improved. He remained afebrile, his cough had decreased in frequency, and he was able to stand with support.Open in a separate windowFigure 2.Anteroposterior chest x-ray demonstrating a mediastinal mass.Despite significant progress to reverse the TB epidemic, it was estimated that there were 500,000 cases of TB in the pediatric population and 64,000 deaths in 2011.¹ Tuberculosis can spread hematogenously to vertebral bodies, causing pain and eventual bony destruction.² A Gibbus deformity is a late finding in Pott''s disease³ and clinicians should keep TB high on the differential when presented with this finding in any TB-endemic area. Although microbiological confirmation is preferred, TB can be very difficult to isolate in children in the developing world due to lack of effective diagnostic tools, paucibacillary samples, and the difficulty of obtaining high-quality specimens from children. Even the new Xpert MTB/RIF test has only been shown to have 79.5% sensitivity for detection of confirmed TB from sputum, gastric, cerebrospinal fluid, and pleural fluid samples in a pediatric population from Vietnam.⁴Current management always includes medical management and can also include surgical management for patients with acute neurological deterioration.⁵ In a resource-limited setting without a neurosurgeon, it is important to promptly initiate TB treatment without waiting for the results of diagnostic studies, advanced imaging, or biopsy.     

Insulin Regulates the Unfolded Protein Response in Human Adipose Tissue

Endoplasmic reticulum (ER) stress is increased in obesity and is postulated to be a major contributor to many obesity-related pathologies. Little is known about what causes ER stress in obese people. Here, we show that insulin upregulated the unfolded protein response (UPR), an adaptive reaction to ER stress, in vitro in 3T3-L1 adipocytes and in vivo, in subcutaneous (sc) adipose tissue of nondiabetic subjects, where it increased the UPR dose dependently over the entire physiologic insulin range (from ∼35 to ∼1,450 pmol/L). The insulin-induced UPR was not due to increased glucose uptake/metabolism and oxidative stress. It was associated, however, with increased protein synthesis, with accumulation of ubiquitination associated proteins, and with multiple posttranslational protein modifications (acetylations, methylations, nitrosylations, succinylation, and ubiquitinations), some of which are potential causes for ER stress. These results reveal a new physiologic role of insulin and provide a putative mechanism for the development of ER stress in obesity. They may also have clinical and therapeutic implications, e.g., in diabetic patients treated with high doses of insulin.     

Evaluation of the effects of chronic mild stressors on hedonic and physiological responses: sex and strain compared

The chronic mild stress (CMS) paradigm was developed in order to simulate in animals the symptom of anhedonia, a major feature of depression. Typically, changes in hedonic status are interpreted from a decrease in either intake or preference for a mild sucrose solution. Although the incidence of clinical depression is significantly higher in women than in men, the study of this disorder in most animal models of depression has been based on the responses of male rodents. The purpose of this study was to compare the effects of 6 weeks of CMS administration among male and female rats of two rat strains, Sprague-Dawley (SD) and Long Evans (LE), with respect to physiological (body, adrenal gland, and spleen weight) and biochemical (plasma corticosterone levels) indices of stress as well as evaluations of 1 and 24 h sucrose intake and preference. Estrous cycle was tracked throughout the study. Overall, our results indicate a slower rate of weight gain in animals, greater in males, exposed to the chronic stressor regime. Furthermore, CMS is shown to disrupt estrous cycling, predominantly in the Long Evans strain of rats. The main behavioral finding was a significant reduction in 24 h sucrose intake in female treated groups, which was not accompanied by alterations in preference. Corticosterone levels were elevated in CMS-treated animals relative to the singly housed control groups, but exposure to a subsequent stressor was not influenced by the stress history. Taken together, the effects of chronic stressor exposure are evident, based on physiological and biochemical indices, although none of the measures distinguished any striking gender specific reactions. The usefulness of sucrose intake or preference as behavioral indices of CMS-induced anhedonia in males and females is modest at best.     

S-adenosylmethionine concentrations in diagnosis of Pneumocystis carinii pneumonia

Pneumocystis carinii is unable to synthesise S-adenosylmethionine and thus scavenges this intermediate. We aimed to test whether measurement of concentrations of this metabolic intermediate in plasma could provide a new method for rapid diagnosis of Pneumocystis carinii pneumonia (PCP). We measured S-adenosylmethionine plasma concentrations in 12 healthy controls, 16 patients with confirmed or suspected PCP, and 36 patients with other infections. Median concentration in healthy controls was 106 nmol/L (range 86-128), but the protein was undetectable in eight patients with histologically proven and seven with suspected PCP, and was 8 nmol/L in another confirmed case (p<0.0001). In 36 patients with other infections, S-adenosylmethionine concentrations were much the same as in controls: 18 had bacterial pneumonia, two tuberculosis, five cryptococcal meningitis, three had other infections, and eight had asymptomatic HIV-1 infection. After treatment for PCP, S-adenosylmethionine concentrations rose rapidly in all but one patient who died of the disease. Measurement of plasma S-adenosylmethionine concentrations could prove useful for diagnosis of PCP and assessment of patients' response to treatment.     

Central monoamine activity following acute and repeated systemic interleukin-2 administration

Interleukin-2 (IL-2), together with other cytokines, may be involved in communication between the immune system and the CNS. Moreover, IL-2 alterations have been implicated in psychiatric disorders, and IL-2 immunotherapy may engender neuropsychiatric and cognitive disturbances. Given the presumed relationship between mood disturbances and monoamine activity, the present investigation was undertaken to determine the central monoamine alterations associated with acute and repeated systemic IL-2 administration in mice. Acute, systemic IL-2 (0.55-17.6 x 10(3) IU) did not influence plasma adrenocorticotropic hormone or corticosterone levels, but increased the utilization of norepinephrine (NE) within the paraventricular nucleus of the hypothalamus. In contrast to the effects of acute IL-2 administration, when administered repeatedly (for 7 days), IL-2 increased NE utilization within the median eminence plus arcuate nucleus and in the hippocampus, and to a lesser extent in the central amygdala and medial prefrontal cortex. These changes in utilization were accompanied by increased levels of NE within the median eminence plus arcuate nucleus and central amygdala, and reduced NE within the locus coeruleus. As well, serotonin (5-hydroxytryptamine; 5-HT) levels were altered within the hippocampus and prefrontal cortex, and dopamine turnover was reduced within the caudate and substantia nigra. The finding of altered central neurotransmitter activity needs to be considered in the context of the marked cognitive/memory impairments, as well as the neuropsychiatric symptoms, which are associated with IL-2 immunotherapy in humans.     

Central monoamine activity in genetically distinct strains of mice following a psychogenic stressor: effects of predator exposure

The effects of psychogenic stressors, rat exposure and fox urine odor, on central monoamine functioning was assessed in two inbred strains of mice, BALB/cByJ and C57BL/6ByJ, thought to be differentially reactive to stressors. These stressors markedly increased NE utilization, as reflected by MHPG accumulation, in the locus coeruleus, hippocampus, prefrontal cortex and central amygdala. Likewise, the 5-HT metabolite, 5-HIAA, was elevated in hippocampus, prefrontal cortex and central amygdala, and to some extent DOPAC accumulation was increased in the prefrontal cortex. In most brain regions, the neurochemical effects of the stressors were comparable in the two mouse strains. However, central amygdala 5-HIAA elevations as well as DOPAC increases in the prefrontal cortex elicited by fox odor were greater in C57BL/6ByJ than in BALB/cByJ mice. Although BALB/cByJ mice are more behaviorally reactive than C57BL/6ByJ mice, and also show greater corticosterone elevations in response to neurogenic and systemic stressors, it was previously shown that differential corticosterone changes were not elicited by a predator exposure. Taken together with earlier findings, it appears that despite greater behavioral reactivity/anxiety, the strain-specific neurochemical changes elicited may be situation-specific such that the profile apparent in response to neurogenic and systemic stressors may not be evident in response to predator-related threats.     

Differential involvement of amygdaloid CRH system(s) in the salience and valence of the stimuli

Anxiety is a heterogeneous term encompassing not only state or trait characteristics but also a wide range of pathologies such as generalized anxiety disorders, phobias, panic and obsessive–compulsive disorders, acute stress disorder, and posttraumatic stress disorder. Given that diverse forms of anxiety exist, numerous animal models have been developed, which are considered to be useful in identifying mechanisms underlying anxiety states. Examples of such animal models include paradigms that assess the behavioral response to neurogenic (or painful stimuli) or psychogenic stressors or to cues that had previously been associated with painful stimuli. The present report presents data regarding the impact of stressors on corticotropin-releasing hormone (CRH), and relates these to changes in anxiety-like states. Specifically, we demonstrate that (1) psychogenic stressors influence the in vivo release of CRH at the central nucleus of the amygdala (CeA); (2) although CRH changes within the CeA are exquisitely sensitive to stressors, they are also elicited by positive stimuli; and (3) while treatment with diazepam attenuates behavioral signs of anxiety, the CRH release associated with a stressor is unaffected by the treatment. The position is offered that although release of CRH within the CeA is increased under stressful conditions, it is not a necessary condition for the consequent behavioral expression of anxiety-like reactions, at least not in minimally threatening situations. We suggest that the CRH responses at the CeA may be involved in a preparatory capacity and, as such, may accompany a range of emotionally significant stimuli, be they appetitive or aversive.