Anxiogenic and aversive effects of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis in the rat: role of CRF receptor subtypes

Rationale Corticotropin-releasing factor (CRF) produces anxiety-like and aversive effects when infused directly into the various regions of the brain, including the bed nucleus of the stria terminalis (BNST). However, the CRF receptor subtypes within the BNST mediating these phenomena have not been established.Objectives We used selective CRF receptor antagonists to determine the receptor subtypes involved in the anxiogenic-like and aversive effects CRF in the BNST.Materials and methods Male Long–Evans rats were bilaterally infused with CRF (0.2 or 1.0 nmol) either alone or in combination with the CRF₁ receptor antagonist CP154,526 or the CRF₂ receptor antagonist anti-sauvagine 30 (AS30) before behavioral testing in the elevated plus maze or place conditioning paradigms.Results Intra-BNST administration of CRF produced a dose-dependent reduction in open arm entries and open arm time in the elevated plus maze, indicating an anxiogenic-like effect. These effects were inhibited by co-infusion of CP154,526 but not of AS30, indicating that the anxiogenic-like effects of CRF in the BNST are mediated by CRF₁ receptors. Place conditioning with intra-BNST administration of CRF produced a dose-dependent aversion to the CRF-paired environment that was prevented by co-infusion of either CP154,526 or AS30, indicating that both CRF receptor subtypes mediate the aversive effects of this peptide. Intra-BNST infusions of the CRF receptor antagonists alone produced no effects in either behavioral paradigm.Conclusions CRF₁ receptors in the BNST mediate the anxiogenic-like effects of CRF in this region, whereas both CRF₁ and CRF₂ receptor subtypes mediate the conditioned aversive effects of this peptide within the BNST.     

Loss of tolerance to morphine after a change in route of administration: control of within-session tolerance by interoceptive conditioned stimuli

Tolerance to morphine analgesia (tail-immersion test) was examined after manipulation of two aspects of a tolerance test: 1) the route of drug administration and 2) the time interval between the test dosing and the tolerance test. The intravenous (IV) and intraperitoneal (IP) routes were used, together with a novel test for tolerance in which the test morphine was infused IV just 2 min before measuring the opiate effect. The first experiment validated this test as an assay for tolerance by examining the log dose-response (LDR) curve changes produced by daily IP injection with 0, 20 or 200 mg/kg morphine; the IV test confirmed the expected parallel shift to the right and flattening of the LDR curve. In the second experiment, all rats of two groups were injected once daily for 3 weeks with 20 mg/kg morphine and with saline except that one group received the morphine IV (and saline IP), the other morphine IP (saline IV). The results indicated route-specific tolerance. On a test using 20 mg/kg given IV morphine, tolerance was significantly greater in rats treated with IV morphine than in those treated IP. However, a larger effect on tolerance was produced by a pretest application of 5 mg/kg morphine 30 min before the actual tolerance test. This manipulation was designed to prime short-term, adaptive processes hypothesized to occur within a normal tolerance test session as morphine is taking effect. The tolerance on the test increased (equivalent to 2 to 3 fold shift in the LDR curve) when the pretest morphine was given with the same route as the chronic morphine, regardless of treatment group. It was concluded that opiate tolerance may be modulated by conditioned stimuli produced by morphine acting through different routes. These interoceptive cues appear to modulate rapidly acquired and short-lived adaptive processes taking place within a given test session.     

Enhanced vulnerability to the rewarding effects of nicotine during the adolescent period of development

This study compared the rewarding and aversive effects of nicotine in adolescent, adult, and adult rats pre-exposed to nicotine during adolescence. Prior to conditioning, the rats were tested for their initial preference for either of 2 distinct compartments. Adolescent and adult rats then received various nicotine doses in their initially non-preferred side on one day and saline in the other side on alternate days. This 2-day procedure was repeated over 8 consecutive days. Following conditioning, rats were re-tested for their preference. Another cohort of adolescent and adult rats were conditioned with various doses of d-amphetamine. Nicotine produced CPP in an inverted U-shaped manner in both age groups. However, adolescents displayed a larger upward shift in CPP that was significant across a wider dose range relative to adults. There were no developmental differences to CPP produced by d-amphetamine. In a final study, adolescents were prepared with pumps that delivered nicotine for 14 days. These rats were conditioned later as adults using the same procedures used previously. Pre-exposure to nicotine during adolescence diminished the aversive effects produced by the highest nicotine dose in naïve adults. Taken together, these studies provide a basis for enhanced vulnerability to nicotine during adolescence.     

Relationships between individual sensitivity to CS- and cocaine-induced reinstatement in the rat

Rationale. Maintaining abstinence is highly challenging for cocaine ex-users. Exposure to drug conditioned stimuli (CS) and to low doses of cocaine can provoke craving in humans and reinstate self-administration (SA) behavior in animal models. Whether drug- and CS-induced reinstatement depend on the same biological substrates remains controversial. Objectives. We investigated the relationships between cocaine- and CS-induced SA reinstatement within the same individuals as a function of the duration of the withdrawal period after cessation of extended cocaine SA. Methods. Sprague-Dawley rats were trained for cocaine intravenous SA (0.8 mg/kg per infusion) during 74 sessions (2 h daily exposure to cocaine) and submitted to withdrawal. Five and 30 days after the end of SA, cocaine- and CS-induced reinstatement were tested. Results. Both after a short and a long withdrawal, CS- and cocaine-induced reinstatement were not related. Furthermore, cocaine-induced reinstatement measured after a short and a long withdrawal was positively related while CS-induced reinstatement was not. The sensitivity of an individual to cocaine-induced reinstatement is not related to its sensitivity to CS-induced reinstatement. Furthermore, vulnerability to cocaine-induced reinstatement is determined quickly after SA cessation and is a long lasting state, whilst vulnerability to CS-induced reinstatement develops quickly or slowly depending on the individual. Conclusions. These results support the view that cocaine and CS induce reinstatement through different mechanisms. They imply that reinstatement in drug abuse is a heterogeneous condition with some individuals being more sensitive to one factor than to the other. Research for effective anti-relapse therapies should take these elements into account.     

Pavlovian conditioning of discriminatively elicited eyeblink responses with short onset latency attributable to lengthened interstimulus intervals

Conditioned eyeblink responses were obtained in cats by pairing click (CS) with glabella tap (US) and electrical stimulation of the hypothalamus (HS). Hiss was used as a discriminative stimulus (DS). Onset latencies of conditioned responses (CRs) of 20–56 ms were obtained by using an interstimulus interval (ISI) of 570-10 ms between CS and US-HS. Longer latency (90–320 ms) blink CRs were obtained with ISIs of 340-240 and 340-10 ms. The timing of associatively learned movements has been thought to increase with lengthening of the intervals between CS and US presentation. The production of shorter latency CRs of this type by lengthening the ISI is a novel result and one unexpected from widely held beliefs.     

Effects of a mood-enhancing intervention on subjective well-being and cardiovascular parameters

Background: In spite of extensive evidence indicating that affective traits can influence health, conclusive studies on a potential preventive value of systematical mood improvement have been relatively sparse. In part, this may be due to the lack of appropriate and proven behavioral intervention methods.Purpose: The purpose of this study was to test a newly developed intervention method for its effectiveness to enhance cheerfulness and to improve aspects of psychological well-being and subjective health that may be advanced by increased levels of cheerfulness.Method: The key element of the “Cheerfulness Training,” which follows a behavioral therapy approach, is that imaginations of personal shortcomings, annoyances, and unpleasant situations are coupled with a self-induced positive affective state by conditioning processes.Results: Experimental findings demonstrated a pronounced enhancement of cheerfulness that was accompanied by reduced feelings of stress and improved psychological well-being and subjective health. Effects were stronger in participants with lower levels of trait seriousness.Conclusion: Findings indicate that the training is effective in enhancing cheerfulness and that successfully enhancing cheerfulness also promotes more general improvement of well-being. The authors would like to thank Brigitte Abels, Eva Kogler, Sylvia Lang, and Andrea Zitzenbacher for their valuable input and practical support that helped to develop, elaborate, and test the 1-2-H Cheerfulness Training. We would also like to thank Manuela Deimbacher, Michaela Klampfer, Ulrike Ofner, Kathrin Semlitsch, and Daniela Weinhappl for their involvement in data collection and data processing, and Sylvia Lang for acting as co-trainer.     

热休克蛋白在条件化噪声对强噪声致豚鼠听力损伤防护中的作用

目的：研究热休克蛋白在条件化噪声防护强噪声所致豚鼠听力损伤中的作用。方法：取杂色，耳廓反射正常，鼓膜完整的豚鼠40只，分为正常对照组（NG），条件化噪声组（CG），高强度噪声暴露组（HG），条件化噪声加高强度噪声暴露组（CHG）。所用低强度噪声（条件化噪声）为80dB SPL，高强度噪声为115dB SPL。噪声暴露后取下耳蜗，应用抗热休克蛋白70（HSP70）的单抗作免疫组化研究，对照组仅作免疫组化研究。结果：单纯给予条件化噪声暴露后，豚鼠耳蜗毛细胞HSP70染色与对照组比较无增强，而高强度噪声呼先条件化噪声再高强度噪声暴露后豚鼠的耳蜗毛蜗细胞HSP70染色强度均增高，CHG组的耳蜗毛细胞HSP70染色强度比HG组的强。结论：热休克蛋白在条件化噪声防护强噪声所致豚鼠听力损伤中起一定作用。     

Environment-specific tolerance to nicotine

Research has shown that tolerance to the behavioral effects of numerous drugs is mediated by learning. The present study was designed to test whether animals develop tolerance to the antinociceptive effects of nicotine, and whether these effects are also learned. Rats were given dally injections of nicotine in the same environment. After each injection, the latency of tail withdrawal from a hot water bath was measured. This was continued until they were tolerant to the drug: i.e., their response latencies did not differ from animals repeatedly given saline. The role of learning in nicotine tolerance was assessed by changing the environment in which they received nicotine on the day after tolerance was achieved. When the drug environment was changed, the animals recovered the full dose effect of nicotine on tail-flick latencies. These results show that tolerance develops to nicotine's antinociceptive effects, and that this tolerance also may be influenced by learning.     

Propensity Score Analysis of Conditioning Intensity in Peripheral Blood Haploidentical Hematopoietic Cell Transplantation

T cell replete HLA-haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide was originally described using a reduced-intensity conditioning (RIC) regimen. Given that myeloablative conditioning (MAC) is more effective at preventing disease relapse, we compared outcomes of patients receiving MAC and RIC regimens. We evaluated overall survival (OS), disease-free survival (DFS), relapse, nonrelapse mortality (NRM), and graft-versus-host disease (GVHD) of 148 patients that underwent haplo-HCT with either MAC (n?=?61) or RIC (n?=?87). Propensity score adjustment (PSA) was used to balance baseline characteristics between groups and more effectively compare outcomes based on conditioning intensity. After the PSA analysis, relapse was significantly decreased with MAC (hazard ratio [HR], .47; 95% confidence interval [CI], .31 to .70), but was associated with higher NRM (HR, 1.74; 95% CI, 1.13 to 2.67). OS and DFS were not significantly different between groups (HRs for MAC versus RIC were .87 [95% CI, .64 to 1.18] and .90 [95% CI, .68 to 1.18] for OS and DFS, respectively). Rates of acute and chronic GVHD were not significantly different between groups. This analysis suggests that both MAC and RIC regimens are effective in haplo-HCT and that MAC regimens may result in less relapse in selected patients. These results need to be verified in a larger registry study.     

Current Allogeneic Hematopoietic Stem Cell Transplantation for Pediatric Acute Lymphocytic Leukemia: Success,Failure and Future Perspectives—A Single-Center Experience, 2008 to 2016

Hematopoietic stem cell transplantation (HSCT) is the only curative option for a subset of patients with high-risk or relapsed acute lymphoblastic leukemia (ALL). Given evolving practices, it is important to continually evaluate outcomes for pediatric ALL following HSCT. Outcomes after HSCT are influenced by the type of donor used as this determines the degree and method of T cell depletion used and, consequently, specific transplant-related morbidities. We retrospectively analyzed HSCT data from our center for transplants performed between January 2008 and May 2016, comparing outcomes among different donor types. One hundred and twenty-four pediatric patients underwent HSCT from a matched sibling donor (MSD; n?=?48), an unrelated matched donor (UMD; n?=?56), or a haploidentical donor (n?=?20). We observed a similar 3-year event-free survival (EFS) for MSD recipients (of .64) and for UMD recipients (.62), but a significantly lower EFS for recipients of haploidentical transplants (.35; P?=?.01). Relapse was the main cause of HSCT failure and was significantly higher in the haploidentical donor group (.47 versus .19 for MSD and .24 for UMD; P?=?.02). Treatment-related mortality was evenly distributed among the donor groups (.17, .16, and .15 for the MSD, UMD, and haploidentical groups, respectively). Rates of infection-related mortality were lower than previously reported. Relapse is the main obstacle for successful HSCT in the contemporary era, and this effect is most evident in recipients of haploidentical donor grafts. Newer methods to improve graft-versus-leukemia effect are being evaluated and will need to be incorporated into the management of high-risk patients.