Pre-conditioning Test Research Articles

The effect of spontaneous osteoarthritis on conditioned pain modulation in the canine model

Endogenous Pain Modulation (EPM) impairment is a significant contributor to chronic pain. Conditioned pain modulation (CPM) testing assesses EPM function. Osteoarthritic (OA) dogs are good translational models, but CPM has not been explored. Our aim was to assess EPM impairment in OA dogs compared to controls using CPM. We hypothesized that CPM testing would demonstrate EPM impairment in OA dogs compared to controls. Dogs with stifle/hip OA and demographically-matched controls were recruited. The pre-conditioning test stimulus, using mechanical/thermal quantitative sensory testing (MQST or TQST), were performed at the metatarsus. A 22N blunt probe (conditioning stimulus) was applied to the contralateral antebrachium for 2 minutes, followed by MQST or TQST (post-conditioning test stimulus). The threshold changes from pre to post-conditioning (∆MQST and ∆TQST) were compared between OA and control dogs. Twenty-four client-owned dogs (OA, n = 11; controls, n = 13) were recruited. The ∆MQST(p < 0.001) and ∆TQST(p < 0.001) increased in control dogs but not OA dogs (∆MQST p = 0.65; ∆TQST p = 0.76). Both ∆MQST(p < 0.001) and ∆TQST(p < 0.001) were different between the OA and control groups. These are the first data showing that EPM impairment is associated with canine OA pain. The spontaneous OA dog model may be used to test drugs that normalize EPM function.

Evaluation of effect of minocycline on rewarding potential and alcohol relapse in place preference model in mice

IntroductionMedical management for alcohol abuse has limitations. Alcohol consumption activates N-methyl-d-aspartate receptors and release of nitric oxide which can be inhibited by minocycline as it readily crosses blood brain barrier and may have effect on alcohol consumption. Thus, study objective is to evaluate the effect of minocycline on rewarding property, extinction and the reinstatement phenomenon induced by alcohol in a model of conditioned place preference (CPP) in mice. MethodologyTo evaluate rewarding effects of alcohol, CPP procedure consisted of 4 parts, including adaptation (day 1), pre-conditioning test (day 2), conditionings with alcohol (days 3, 5, 7 and 9) or saline (days 4, 6, 8 and 10) and postconditioning test (day 11) conducted on 11 consecutive days. The groups included were saline treated group (alcohol control), naltrexone – 1mg/kg (positive control), and minocycline in the doses of 10, 30 and 50mg/kg. To evaluate the effect of minocycline on alcohol relapse, CPP procedure consisted 6 parts, the first 4 were the same as enumerated above followed by extinction (days 12–16) and reinstatement phase (day 17). ResultsThe time spent in alcohol paired compartment by different groups, revealed that minocycline and naltrexone significantly attenuated alcohol-induced place preference compared to alcohol control (p<0.05). Pretreatment with minocycline and naltrexone blocked reinstatement of extinguished CPP. ConclusionMinocycline may have a role in attenuating the rewarding property of alcohol and prevent alcohol relapse.

GABAB receptor system modulates mitragynine-induced conditioned place preference in rats

Event Abstract Back to Event GABAB receptor system modulates mitragynine-induced conditioned place preference in rats Nurul H. Mohammad Yusoff1*, Sharif M. Mansor1, Navaratnam Visweswaran1, Christian P. Muller2 and Zurina Hassan1* 1 Universiti Sains Malaysia, Centre for Drug Research, Malaysia 2 Friedrich-Alexander-University Erlangen-Nuremberg, Department of Psychiatry and Psychotherapy, Germany Many drugs of abuse produce rewarding effects, as evidenced by their ability to induce conditioned place preference (CPP). Mitragynine, the major active alkaloid of Mitragyna speciosa (Kratom) plant, has been reported to possess this response in animal model. Considering the role of GABAB receptor subtypes in mediating the rewarding properties of various classes of addictive drugs, the present study aims to examine the involvement of GABAB receptor system on acquisition and expression of mitragynine-induced CPP. An unbiased 3-chamber CPP paradigm was employed, which consisted of 3 phases; pre-conditioning (2 days), conditioning (8 days), and CPP test. Pre-conditioning test was performed to assess initial individual preference for each CPP chamber. Groups of rats were conditioned with mitragynine (10 mg/kg), combination of mitragynine and baclofen (1.25, 2.5 and 5.0 mg/kg) or vehicle paired with a distinctive chamber. On alternating days, rats were given vehicle and paired with another distinctive chamber. After 8 conditioning sessions, a preference (CPP) test was conducted whereby rats had full access to the entire apparatus under the influence of either baclofen (1.25, 2.5 and 5.0 mg/kg) or saline. Mitragynine-conditioned animals showed CPP as demonstrated by an increased amount of time spent in the drug-associated chamber during the CPP test relative to pre-conditioning test. The administration of baclofen (2.5 and 5.0 mg/kg) 30 min prior to mitragynine injection inhibited the acquisition of mitragynine-induced CPP. In addition, the administration of baclofen (2.5 and 5.0 mg/kg) to the mitragynine-conditioned animals 30 min prior to the CPP test blocked the expression of CPP responses. These findings showed that activation of GABAB receptors by baclofen suppressed the acquisition and expression of CPP effects produced by mitragynine. Mitragynine-induced CPP effects are dependent on the activity of GABAB receptor system during acquisition and expression phases. Acknowledgements Financial support was received from Higher Education Centre of Excellence (HiCoE) special funding (304/CDADAH/650527/K134) and FRGS (203/CDADAH/6711469) Keywords: Addiction, GABA, conditioned place preference, in vivo, rewarding effect Conference: 14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016. Presentation Type: O03: Postgraduate Travel Awardees Oral Session 3 Topic: 14th Meeting of the Asian-Pacific Society for Neurochemistry Citation: Mohammad Yusoff NH, Mansor SM, Visweswaran N, Muller CP and Hassan Z (2016). GABAB receptor system modulates mitragynine-induced conditioned place preference in rats. Conference Abstract: 14th Meeting of the Asian-Pacific Society for Neurochemistry. doi: 10.3389/conf.fncel.2016.36.00090 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Aug 2016; Published Online: 11 Aug 2016. * Correspondence: Ms. Nurul H Mohammad Yusoff, Universiti Sains Malaysia, Centre for Drug Research, Minden, Penang, Malaysia, hess_myz@yahoo.com Dr. Zurina Hassan, Universiti Sains Malaysia, Centre for Drug Research, Minden, Penang, Malaysia, zurina_hassan@usm.my Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Nurul H Mohammad Yusoff Sharif M Mansor Navaratnam Visweswaran Christian P Muller Zurina Hassan Google Nurul H Mohammad Yusoff Sharif M Mansor Navaratnam Visweswaran Christian P Muller Zurina Hassan Google Scholar Nurul H Mohammad Yusoff Sharif M Mansor Navaratnam Visweswaran Christian P Muller Zurina Hassan PubMed Nurul H Mohammad Yusoff Sharif M Mansor Navaratnam Visweswaran Christian P Muller Zurina Hassan Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Influence of Glass Transition Temperature of Underfill on the Stress Behavior and Reliability of Microjoints Within a Chip Stacking Architecture

In this study, the reliability performance of two capillary-type underfill materials with different glass transition temperatures (Tg) and coefficients of thermal expansion (CTE) were assessed for a chip stacking architecture. The microbumps for integrating four chips on a Si interposer were with a pitch size of 20 μm and composed of 5 μm Cu/3 μm Ni/5 μm Sn2.5Ag solder cap. A thermocompressive bonder was used to interconnect the microbumps at 280 °C for 15 s, and the microgaps between the chips and the interposer were then, respectively, sealed by the mentioned underfill materials to form a chip stacking architecture. Then, the reliability characteristics of the test vehicles were evaluated following the preconditioning and temperature cycling test (TCT). Furthermore, a numerical analysis model was established by ansys software to study the stress and strain contours of the microjoints sealed by different underfill materials. It was found that the lifetime of microjoints was highly related to the Tg points of underfills, an interfacial fracture was observed within the microjoints sealed by a lower Tg underfill after temperature cycling because the tensile strength damaged the Sn depletion zone as heated.

Efficacy Of a Pharmacokinetics-Directed IV Busulfan (Bu), Plus Cyclophosphamide (Cy) and Etoposide (E) Preparative Regimen With Autologous Hematopoietic Stem Cell Transplantation For Lymphoma: Final Report Of a Multi-Center Phase 2 Study In North America

BackgroundBu-based conditioning regimens are commonly used prior to autologous hematopoietic stem cell transplantation (ASCT) for lymphoma, but clinical results of an intravenous (IV) Bu-based regimen have been limited to single center studies. This multi-center, single-arm, Phase 2 study prospectively evaluated the safety and efficacy of the IV BuCyE regimen in lymphoma patients undergoing ASCT. MethodsThe primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), transplant-related mortality (TRM) and overall response rate. TRM was defined as a death after transplant due to any cause other than disease progression. Subjects underwent first ASCT for Hodgkin lymphoma (HL) and B-cell non-Hodgkin lymphoma (NHL) that relapsed after initial therapy, was initially refractory to an anthracycline-based chemotherapy, or for high-risk NHL histology in first complete remission (CR) [International Prognostic Index (IPI) score of 4-5, or mantle cell lymphoma (MCL)]. Eligible subjects achieved CR or partial remission (PR) following salvage chemotherapy. The study initially enrolled subjects of 18-80 years, but the protocol was amended to reduce the upper age limit to 65 years due to a high TRM rate at post-transplant 100 days for the subjects >65 years. Therefore, we report safety for all the subjects undergoing ASCT (n=203) and efficacy from those 65 years old or younger (n=186). IV Bu doses were individually adjusted based on pre-conditioning test PK results; the area under the concentration-time curve of Bu was targeted to 20,000 mM*min. Bu was given as a 3-hour infusion once daily from Days -8 through Day -5. E (1.4 g/m2) was administered on Day -4, followed by 2.5 g/m2/day of Cy on Days -3 and -2. ResultsA total of 207 subjects with HL (n=66) or NHL (n=141) were enrolled from 32 centers in the US and Canada between February 2010 and April 2012. Four subjects did not proceed with ASCT due to insurance or eligibility issues; the remaining 203 underwent ASCT. The final TRM rates at Day 100 for all subjects (n=203), for those older than 65 year old (n=17), and for those 65 years old or younger (n=186) were 4.5% (95% confidence intervals (CI) 2.1-8.3%), 23.5% (95% CI; 6.8-49.9%) and 2.7% (95% CI: 0.9-6.2%), respectively. The most common grade (Gr) 3 or 4 adverse events (CTCAE v3.0) observed from Day -8 through Day 100 were febrile neutropenia (Gr 3: 58.1%; Gr 4: 3.0%), stomatitis (Gr 3: 40.9%; no Gr 4), nausea (Gr 3: 8.9%; no Gr 4), and hypophosphatemia (Gr 3:6.9%; Gr 4: 1.0%). There was no instance of seizure or hepatic veno-occlusive disease (VOD) meeting the Baltimore criteria.Efficacy was analyzed for 186 subjects ≤65 years old with HL (n=65) or NHL (n=121), which included diffuse large B-cell lymphoma (DLBCL; n=63), MCL (n=29) and follicular lymphoma (FL; n=23). The median age was 49 year old (range: 19-65); 36 % were female, 87% were white, 76% had a Karnofsky Score ≥90. Majority of the patients had CR2 or higher, or PR at transplant except that 19 MCL patients and three DLBCL patients with IPI score 4 had CR1. In addition, five patients (3 for NHL; 2 for HL) who had refractory disease to initial chemotherapy and required salvage therapy to achieve CR1 also enrolled this study. With median 20 months follow-up, the estimated 2-year PFS was 33% for HL and 58%, 77%, and 43% for DLBCL, MCL, and FL respectively [Fig. 1]. The estimated 2-year OS was 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL respectively [Fig. 2 [Display omitted] [Display omitted] ]. ConclusionsIV BuCyE regimen provided good early disease control with acceptable safety profiles in B-cell NHL lymphoma patients 65 year old or younger, but there were early declines in PFS in HL patients. Additional comparisons of PFS and OS from the BuCyE regimen with a pre-specified, matched-control group of approximately 800 matched cases (1:4 ratio) obtained from the Center for International Blood and Marrow Transplant Research registry data who received carmustine, E, cytarabine, and melphalan (BEAM) conditioning regimen are underway, and updated results will be presented. Disclosures:Off Label Use: Busulfan, Cyclophosphamide and VP-16 for Autologous Hematopoietic Stem Cell Transplantation. Costa:Otsuka: Research Funding. Freytes:Otsuka America Pharmaceutical: Research Funding, Travel funds for scientific presentation Other. Armstrong:Otsuka: Employment. Smith:Otsuka Pharmacetical Development & Commercialization: Employment. Elekes:Otsuka Pharmaceutical: Employment. Kato:Otsuka Pharmaceutical Development & Commercialization, Inc: Employment.

Safety of PK-Guided IV Bu Cy VP-16 Preparative Regimen Prior to Autologous Hematopoietic Stem Cell Transplantation for Lymphoma: Findings From a Multi-Center Phase II Study in North America

AbstractAbstract ▪813▪This icon denotes a clinically relevant abstract Background:Published reports indicate that oral or intravenous (IV) busulfan in combination with cyclophosphamide and VP-16 (BuCyVP-16) is an effective conditioning regimen with acceptable safety profile for lymphoma patients prior to autologous hematopoietic stem cell transplantation (ASCT). Since the therapeutic window of Bu is narrow, it is important to standardize the systemic exposure during conditioning. Although the IV formulation of Bu eliminates the problem of variable drug absorption, unpredictable systemic exposure can still occur due to interpatient differences in Bu clearance. Therefore, tighter control of systemic Bu exposure using pharmacokinetics (PK) may lead to improved efficacy and further decrease in toxicity. The aim of this multi-center, single-arm, Phase II study was to prospectively evaluate the safety and efficacy of IV BuCyVP-16 regimen in lymphoma patients undergoing ASCT, after optimizing Bu exposure using PK-directed dosing. Methods:Patients with chemosensitive, relapsed or primary-refractory Hodgkin and B-cell non-Hodgkin lymphoma undergoing the first ASCT received a test dose of IV Bu (0.8 mg/kg) given as a 2-hour infusion 11 to 14 days before transplant. Bu exposure was determined as area under the concentration-time curve (AUC) using six serial blood samples after the test dose administration. Doses for the conditioning regimen were then calculated to result in total AUC (conditioning + test) of 20,000 mM*min. One-fourth of the resulting calculated Bu dose was given as a 3-hour infusion on Day -8, followed by a second, confirmatory PK analysis. The same daily Bu dose was administered on the next 3 days, unless the confirmatory PK analysis showed that this would result in total AUC outside the target range (>24,000 mM*min or <16,000 mM*min), in which case the subsequent dosing was further adjusted. VP-16 (1.4 g/m2) was administered on Day -4, followed by 2.5 g/m2/day of Cy on Days -3 and -2. Transplant-related mortality (TRM), defined by death from any cause other than disease progression, was monitored throughout the trial. After median 2 years of follow-up, the outcomes will be compared with a BEAM regimen control group from the CIBMTR registry, using pre-specified matching criteria. Results:A total of 202 subjects with Hodgkin (n=65) and non-Hodgkin lymphoma (n=137) were enrolled from 32 centers in the US and Canada.196 subjects had both test PK and confirmatory PK results. Test PK demonstrated that 36.2% (n=71) of the patients had exposure outside of expected range (1,250 μM*min ± 20%): higher AUC (>1,500 μM*min) in five patients (2.6 %) and lower AUC (<1,000 μM*min) in 66 (33.7%). These would have been dosed outside the total target AUC range if dose was not individualized based on test PK. Mean Bu clearances were comparable between test and Day -8 PK, 3.04 ± 0.48 ml/min/kg and 3.03 ± 0.49 ml/min/kg, respectively. Accordingly, 94.9 % of patients (n=186) fell within the target range (AUC, 20,000 μM*min ± 20%), using consistent doses on Days -8 through -5. The other ten patients (5.1%) required dose alteration for the last two days of conditioning due to clearance changes between test PK and confirmatory PK (Day -8): a dose reduction in eight patients (4.1%) and a dose increase in two (1.0%).An early subset-analysis by age in June 2011 revealed that 4 of 18 subjects older than 65 years suffered TRM. Consequently, the protocol was amended to lower the inclusion age limit to 65. The final TRM at day 100 was 4/18 (22.2% [95%CI; 6.4–47.6%]) for patients older than 65 years and 5/184 (2.7% [95%CI; 0.9–6.2%]) for those 65 years old or younger. PK results indicated no extraordinary Bu exposure in TRM cases. The most frequently observed grade ≥ 3 adverse events (CTCAE ver. 3.0) were febrile neutropenia 55.1 % (Grade 3: 52.2%; Grade 4: 2.9%; no Grade 5), stomatitis 37.7% (all Grade 3 events) and nausea 9.7% (all Grade 3 events). No case of hepatic veno-occlusive disease (HVOD) meeting Baltimore criteria was reported. Conclusions:A pre-conditioning test dose estimated individual PK parameters and accurately predicted Day-8 PK in 95% of the subjects. This strategy personalized the dosing for optimal Bu exposure preventing the Bu overexposure or underexposure that would have occurred in over a third of patients. The toxicity of PK-guided IV BuCyVP-16 preparative regimen was low for patients younger than 66 years of age. This approach resulted in no incidence of HVOD. Disclosures:Costa:Otsuka: Research Funding. Off Label Use: Off label use of busulfan in non hodgkin and hodgkin lymphoma. Waller:Outsuka: Research Funding. Freytes:Otsuka Pharmaceuticals: Research Funding. Shea:Otsuka : Research Funding. Rodriguez:Otsuka: Consultancy, Research Funding, Speakers Bureau; Millennium: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; SOBI: Consultancy, Speakers Bureau. Sun:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Armstrong:Otsuka: Employment. Smith:Otsuka America Pharmaceuticals Inc: Consultancy. Elekes:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Kato:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Vaughan:Pierre Fabre: Honoraria.

RF Sensitivity of Multi Chip Package Development by Using Embedded Resistor in Package Substrate

Recently, mobile age is blooming and makes change of 21st century. Especially multi chip package – MCP- is located center position of this flash era. Moreover, radio frequency –RF- sensitivity determines the product quality and life, therefore we try to develop the RF sensitivity of MCP in wireless circumstance. In this study, MCP comprised NAND Flash memory, Mobile DRAM, and a substrate, we focused on the substrate, changed substrate design and performance by using resistor embedded into 1 layer of substrate. The purpose of adaption of embedded resistor is in order to control the slew rate of signal channel of DRAM. NiCr thin film was used for the resistor in substrate. NiCr material presents superior temperature coefficient of resistance –TCR- to thick film material. NiCr coated on Cu foil and this foil laminated by conventional substrate manufacturing method. Embedded resistor applied on signal line as 3 kinds; 1. Signal and signal strobe line by 50 Ohm, 2.Signal strobe line by 50 Ohm, and 3. Signal and signal strobe line by 20 Ohm. In case of 3, result showed 0.5 dBm increment of RF sensitivity in full strength mode, also we got the same performance at half strength mode. Embedded resistor formed substrate did not affect the reliability of MCP, from the results of reliability test; pre-conditioning test, thermo-cyclic, temperature humidity, HAST, un-Bias HAST, and hot temperature storage test. This study showed signal waveform of DRAM is significantly effective in RF sensitivity for MCP. Passive component, resistor, made change of slew rate and revealed increase of sensitivity level finally.

Evidence for Pavlovian conditioning of cocaine-induced responses linked to emotional behavioral effects

The pairing of cocaine treatments with a specific test environment typically leads to cocaine-conditioned drug effects. In this study, we first pre-exposed rats 10 times to an open-field environment to establish an habituation asymptote in locomotor activity prior to the initiation of cocaine treatments. Two groups ( N=10) equated for locomotion, grooming, central zone penetrations and rearing behavior were used. One group received five pairings of cocaine (10.0 mg/kg) and the second group five pairings of saline injections with placements in the open-field environment. Subsequently, both groups received a saline test to detect possible cocaine-conditioned behavioral effects. During the cocaine treatment phase, cocaine enhanced locomotion and central zone penetrations but decreased rearing and grooming. On the conditioning test, the cocaine group exhibited enhanced central zone penetrations and decreased grooming as compared to the saline group. There were no group differences in locomotion or rearing. When within group comparisons were performed between behavioral responses on the pre-conditioning test vs. the conditioning test, the saline group scores were essentially unchanged. In contrast, the cocaine group exhibited higher central zone penetrations and decreased grooming without changes in locomotion or rearing. In that a cocaine conditioning test can also be viewed as a cocaine withdrawal test, two additional experiments were conducted using an unpaired conditioning protocol to test for withdrawal effects without conditioning. These results indicated that the central zone and grooming effects observed in the conditioning protocol were not withdrawal effects. Altogether, these findings provide support for Pavlovian conditioning of cocaine-induced changes in emotion-related behavioral responses.

Differential effects of agents acting at various sites of the NMDA receptor complex in a place preference conditioning model

A conditioned place preference paradigm was used to assess the potential rewarding properties of the uncompetitive NMDA receptor antagonist, MK-801 (dizolcipine), the two competitive NMDA receptor antagonists, CGP 37849 ( d l-( E)-2-amino-4-methyl-5-phosphono-3-pentonoic acid) and its ( R)-enantiomer CGP 40116, as well as the partial agonist at strychnine-insensitive glycine receptors, ACPC (1-aminocyclopropanecarboxylic acid). MK-801 (0.3 mg/kg), CGP 37849 (1.25–10 mg/kg) and CGP 40116 (1.25–10 mg/kg), administered in association with either the initially non-preferred or initially preferred side of the two-arm chamber, caused a significant increase in the time spent on that side in a post-conditioning test. In contrast, ACPC did not support the conditioned place preference. Thus, the time spent on the drug-associated side following conditioning with ACPC (50–400 mg/kg) did not significantly differ from that measured in the pre-conditioning test, irrespective of whether it was associated with the initially non-preferred black side or the initially preferred white side. These results are consistent with both clinical and pre-clinical data demonstrating differences in psychopharmacological properties among compounds acting at the multiple, allosteric regulatory sites on the NMDA receptor complex. Moreover, these results indicate that the abuse potential of ACPC, which acts as a functional NMDA receptor antagonist, may be lower than that of either uncompetitive or competitive NMDA receptor antagonists.

Popcorn phenomena in a ball grid array package

Plastic ball grid array packages can be an alternative to the fine-pitch plastic quad flat package with many I/O's, due to its advantages, such as small footprint and high density interconnect, improved module assembly yield, superior thermal and electrical performances to plastic quad flat packages, etc. In spite of these many advantages, there are several concerns which hinder the plastic ball grid array package from the widespread use. One of them is the package cracking by popcorn phenomena. For the purpose of studying the popcorn phenomena, plastic ball grid array packages with 129 I/O's were tested under the pre-conditioning test conditions. Observations using scanning acoustic tomography and optical microscopy were carried out to investigate the existence of delaminations and cracks in the package, and the cracking patterns after IR reflow. Package deformations and thermomechanical stress distributions in the package were calculated by the finite element method (FEM). Three types of substrates were tried to prove that open thermal viaholes under die pad could prevent popcorn cracking during IR reflow. From the experiments and the observations, it was concluded that package cracking, which was caused by the expansion of moisture concentrated at the die adhesive layer, could be prevented using open thermal viahole under die pad. The open thermal viaholes acted as vent holes, through which the expanded water vapor could escape without causing popcorn cracking. The die-attach process using UV tape was effective in the assembly of the packages with open thermal viaholes.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

SCH 23390 blocks drug-conditioned place-preference and place-aversion: anhedonia (lack of reward) or apathy (lack of motivation) after dopamine-receptor blockade?

The influence of the D1 antagonist SCH 23390 on the motivational properties of rewarding (morphine, nicotine and diazepam) and aversive (naloxone, phencyclidine and picrotoxin) drugs was studied in the rat in a two-compartment place-conditioning paradigm, which included a pre-conditioning test for spontaneous place-preference. The specific D1 dopamine-receptor antagonist SCH 23390 (0.05 mg/kg SC), paired with both compartments or, separately, with the preferred or with the non-preferred compartment, failed to affect the spontaneous unconditioned preference of the animal. Pairing of morphine (1.0 mg/kg SC), nicotine (0.6 mg/kg SC) or diazepam (1.0 mg/kg IP) with the less preferred compartment induced significant preference for that compartment. Pairing of SCH 23390 (0.05 mg/kg SC) with both compartments completely blocked the place-preference induced by morphine, nicotine and diazepam. Naloxone (0.8 mg/kg SC), phencyclidine (2.5 mg/kg SC) or picrotoxin (2.0 mg/kg IP) paired with the preferred compartment elicited place-aversion. Pairing of SCH 23390 (0.05 mg/kg SC) with both compartments abolished also the place-aversion induced by naloxone, phencyclidine and picrotoxin. The results indicate that blockade of dopamine transmission blocks the motivational properties of rewarding as well as aversive stimuli. It is suggested that neuroleptics rather than simply blocking the rewarding impact of positive reinforcers (anhedonia, lack of pleasure) exert a more general influence on conditioned behaviour by blocking the affective impact of negative as well as positive reinforcers (apathy, lack of motivation).

Thermolability in sheep induced by habituation to cold

1. 1.|Sixty-two shorn Scottish Blackface sheep were conditioned by daily repeated acute cold exposure in a climate chamber and were tested before and after these treatments for their thermolability (passive lowering of rectal temperature) in response to a gradual mild cold exposure (test cool). 2. 2.|Rectal temperature declined progressively during successive conditioning exposures. During the post-conditioning test cool thermolability was significantly greater than at the first, pre-conditioning test cool. This increase in thermolability was termed cold habituation. 3. 3.|The standard conditioning treatment comprised 6–8 daily exposures each lasting 1.5 h. This treatment caused an average voluntary decline of 1.7°C in rectal temperature during the post-conditioning test cool compared with 0.8°C at the pre-conditioning test cool. The maximum individual response was a decline of 3.5°C after treatment. At the first test cool, 58% of sheep showed some thermolability: at the second test cool, after the standard conditioning treatment, 97% showed thermolability: at the initial thermolability and the increase in thermolability after treatment were not correlated. 4. 4.|Other treatments involving conditioning exposures which were milder or longer, more frequent or more numerous, or which proressively increased or decreased in severity were less effective in inducing habituation than the standard treatment. 5. 5.|Control sheep which were confined in a climate chamber at thermoneutrality, but otherwise treated like the experimental groups, showed no habituation. Thermolability was therefore increased by cold exposure, not by non-specific psychological adjustment to other aspects of the experimental environment.