Adherence to All Steps of a Pain Management Protocol in Intensive Care Patients after Cardiac Surgery Is Hard to Achieve.

Purpose. To investigate adherence to our pain protocol considering analgesics administration, number and timing of pain assessments, and adjustment of analgesics upon unacceptably high (NRS ≥ 4) and low (NRS ≤ 1) pain scores. Material and Methods. The pain protocol for patients in the intensive care unit (ICU) after cardiac surgery consisted of automated prescriptions for paracetamol and morphine, automated reminders for pain assessments, a flowchart to guide interventions upon high and low pain scores, and reassessments after unacceptable pain. Results. Paracetamol and morphine were prescribed in all 124 patients. Morphine infusion was stopped earlier than protocolized in 40 patients (32%). During the median stay of 47 hours [IQR 26 to 74 hours], 702/706 (99%) scheduled pain assessments and 218 extra pain scores were recorded. Unacceptably high pain scores accounted for 96/920 (10%) and low pain scores for 546/920 (59%) of all assessments. Upon unacceptable pain additional morphine was administered in 65% (62/96) and reassessment took place in 15% (14/96). Morphine was not tapered in 273 of 303 (90%) eligible cases of low pain scores. Conclusions. Adherence to automated prescribed analgesics and pain assessments was good. Adherence to nonscheduled, flowchart-guided interventions was poor. Improving adherence may refine pain management and reduce side effects.

Examining the relationship between blast-induced mild traumatic brain injury and posttraumatic stress-related traits.

Emerging evidence suggests that mild traumatic brain injury (mTBI) resulting from blast exposure may contribute to the occurrence of posttraumatic stress disorder (PTSD) and related affective sequelae, such as anxiety and depression. Many studies have used survey techniques to describe blast exposure leading to comorbid mTBI and related persistent postconcussive symptoms (PPCS) with PTSD in military populations. Despite this, there is a lack of literature that examines possible biological mechanisms by which blast exposure contributes to the development of PTSD sequelae. This Mini-Review addresses the current literature on potential neurophysiological changes that may contribute to PTSD-like traits as a result of a single or multiple exposures to blast events. Evidence from clinical blast-induced mTBI populations and animal models of blast-induced mTBI was evaluated with an emphasis on behavioral and physiological symptoms similar to those seen in PTSD populations and models. From the analysis, we propose potential mechanisms that merit further investigation for better understanding of how blast exposures may produce a higher rate of comorbid PPCS, PTSD, and affective phenomena. An improved understanding of PTSD-like outcomes resulting from blast exposure will ultimately help facilitate the development of future treatments and contribute to a better understanding of PTSD sequelae that develop from physical trauma.

Selecting first-line bevacizumab-containing therapy for advanced breast cancer: TURANDOT risk factor analyses.

BACKGROUND: The randomised phase III TURANDOT trial compared first-line bevacizumab-paclitaxel (BEV-PAC) vs bevacizumab-capecitabine (BEV-CAP) in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). The interim analysis revealed no difference in overall survival (OS; primary end point) between treatment arms; however, progression-free survival (PFS) and objective response rate were significantly superior with BEV-PAC. We sought to identify patient populations that may be most appropriately treated with one or other regimen. METHODS: Patients with HER2-negative LR/mBC who had received no prior chemotherapy for advanced disease were randomised to either BEV-PAC (bevacizumab 10 mg kg(-1) days 1 and 15 plus paclitaxel 90 mg m(-2) days 1, 8 and 15 q4w) or BEV-CAP (bevacizumab 15 mg kg(-1) day 1 plus capecitabine 1000 mg m(-2) bid days 1-14 q3w). The study population was categorised into three cohorts: triple-negative breast cancer (TNBC), high-risk hormone receptor-positive (HR+) and low-risk HR+. High- and low-risk HR+ were defined, respectively, as having ⩾2 vs ⩽1 of the following four risk factors: disease-free interval ⩽24 months; visceral metastases; prior (neo)adjuvant anthracycline and/or taxane; and metastases in ⩾3 organs. RESULTS: The treatment effect on OS differed between cohorts. Non-significant OS trends favoured BEV-PAC in the TNBC cohort and BEV-CAP in the low-risk HR+ cohort. In all three cohorts, there was a non-significant PFS trend favouring BEV-PAC. Grade ⩾3 adverse events were consistently less common with BEV-CAP. CONCLUSIONS: A simple risk factor index may help in selecting bevacizumab-containing regimens, balancing outcome, safety profile and patient preference. Final OS results are expected in 2015 (ClinicalTrials.gov NCT00600340).

Effects of mild TBI from repeated blast overpressure on the expression and extinction of conditioned fear in rats.

Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are pressing medical issues for the Warfighter. Symptoms of mTBI can overlap with those of PTSD, suggesting the possibility of a causal or mediating role of mTBI in PTSD. To address whether mTBI can exacerbate the neurobiological processes associated with traumatic stress, we evaluated the impact of mTBI from a blast overpressure (BOP) on the expression of a conditioned fear. In the rat, conditioned fear models are used to evaluate the emotional conditioning processes that are known to become dysfunctional in PTSD. Rats were first trained on a variable interval (VI), food maintained, operant conditioning task that established a general measure of performance. Inescapable electric shock (IES) was paired with an audio-visual conditioned stimulus (CS) and followed 1day later by three daily exposures to BOP (75kPa). Subsequently, the CS alone was presented once every 7days for 2months, beginning 4days following the last BOP. The CS was presented during the VI sessions allowing a concurrent measure of performance. Treatment groups (n=10, each group) received IES+BOP, IES+sham-BOP, sham-IES+BOP or sham-IES+sham-BOP. As expected, pairing the CS with IES produced a robust conditioned fear that was quantified by a suppression of responding on the VI. BOP significantly decreased the expression of the conditioned fear. No systematic short- or long-term performance deficits were observed on the VI from BOP. These results show that mTBI from BOP can affect the expression of a conditioned fear and suggests that BOP caused a decrease in inhibitory behavioral control. Continued presentation of the CS produced progressively less response suppression in both fear conditioned treatments, consistent with extinction of the conditioned fear. Taken together, these results show that mTBI from BOP can affect the expression of a conditioned fear but not necessarily in a manner that increases the conditioned fear or extends the extinction process.

Remifentanil during cardiac surgery is associated with chronic thoracic pain 1 yr after sternotomy.

BACKGROUND: Chronic thoracic pain after cardiac surgery is a serious condition affecting many patients. The aim of this study was to identify predictors for chronic thoracic pain after sternotomy in cardiac surgery patients by analysing patient and perioperative characteristics. METHODS: A follow-up study was performed in 120 patients who participated in a clinical trial on pain levels in the early postoperative period after cardiac surgery. The presence of chronic thoracic pain was evaluated by a questionnaire 1 yr after surgery. Patients with and without chronic thoracic pain were compared. Associations were studied using multivariable logistic regression analysis. RESULTS: Questionnaires of 90 patients were analysed. Chronic thoracic pain was reported by 18 patients (20%). In the multivariable regression model, remifentanil during cardiac surgery, age below 69 yr, and a body mass index above 28 kg m(-2) were independent predictors for chronic thoracic pain {odds ratios 8.9 [95% confidence interval (CI) 1.6-49.0], 7.0 (95% CI 1.6-31.7), 9.1 (95% CI 2.1-39.1), respectively}. No differences were observed in patient and perioperative characteristics between patients receiving remifentanil (58%, n=52) compared with patients not receiving remifentanil (42%, n=38). The association between remifentanil and chronic thoracic pain appeared dose-dependent, both for total dose and for dose corrected for kilogram lean body mass and duration of surgery (P-value for trend: <0.01 and <0.005, respectively). CONCLUSIONS: In this follow-up study in cardiac surgery patients, intraoperative remifentanil was predictive for chronic thoracic pain in a dose-dependent manner. Randomized studies designed to evaluate the influence of intraoperative remifentanil on chronic thoracic pain are needed to confirm these results.

Efficacy of an intravenous bolus of morphine 2.5 versus morphine 7.5 mg for procedural pain relief in postoperative cardiothoracic patients in the intensive care unit: a randomised double-blind controlled trial.

As pain in the intensive care unit (ICU) is still common despite important progress in pain management, we studied the efficacy of an intravenous bolus of morphine 2.5 vs 7.5 mg for procedural pain relief in patients after cardiothoracic surgery in the ICU. In a prospective double-blind randomised study, 117 ICU patients after cardiothoracic surgery were included. All patients were treated according a pain titration protocol for pain at rest, consisting of continuous morphine infusions and paracetamol, applied during the entire ICU stay. On the first postoperative day, patients were randomised to intravenous morphine 2.5 (n=59) or 7.5 mg (n=58) 30 minutes before a painful intervention (turning of patient and/or chest drain removal). Pain scores using the numeric rating scale (Numeric Rating Scale, range 0 to 10) were rated at rest (baseline) and around the painful procedure. At rest (baseline), overall incidence of unacceptable pain (Numeric Rating Scale ≥4) was low (Numeric Rating Scale >4; 14 vs 17%, P=0.81) for patients allocated to morphine 2.5 and 7.5 mg respectively. For procedure-related pain, there was no difference in incidence of unacceptable pain (28 vs 22%, P=0.53) mean pain scores (2.6 [95% confidence interval 2.0 to 3.2] vs 2.7 [95% confidence interval 2.0 to 3.4]) between patients receiving morphine 2.5 and 7.5 mg respectively. In intensive care patients after cardiothoracic surgery with low pain levels for pain at rest, there was no difference in efficacy between intravenous morphine 2.5 mg or morphine 7.5 mg for pain relief during a painful intervention.

Aminotransferase levels in relation to short-term use of acetaminophen four grams daily in postoperative cardiothoracic patients in the intensive care unit.

A volunteer study suggested that taking paracetamol 4 g daily could result in elevated alanine aminotransferase plasma levels in a substantial proportion of healthy volunteers. The safety of this dose of paracetamol for acute postoperative pain remains controversial. This study aimed to examine the incidence of alanine aminotransferase elevations after short-term use of paracetamol 4 g daily, as part of the standard pain management protocol, for 93 consecutive patients after cardiothoracic surgery. Alanine aminotransferase levels and other liver function tests were measured preoperatively as baseline and once daily after surgery during the intensive care unit stay. Preoperative alanine aminotransferase levels of more than one time the upper limit of normal (ULN >40 U/l) was observed in 11% (n=10) of the patients but none of these baseline alanine aminotransferase levels exceeded three times the ULN (>3 x ULN). The average daily dose of paracetamol administered was 50 mg/kg (SD=16) after surgery. Postoperative alanine aminotransferase levels of >1 x ULN was observed in 17% (n=16), and 4% (n=4) exceeded >3 x ULN The other liver function tests of the latter four patients, including aspartate aminotransferase (range 173 to 5590 U/l), gamma-glutamyltransferase (range 56 to 103 U/l), lactate dehydrogenase (range 376 to 3518 U/l) and the International Normalised Ratio (range 2.0 to 6.6), were all abnormal. These four patients all had right ventricular failure or cardiogenic shock during the postoperative period which could explain the significant rises in alanine aminotransferase after surgery. In conclusion, the incidence of significant alanine aminotransferase elevations after using daily paracetamol as an analgesic agent for cardiac surgery, at a dose of 4 g per day, was low and mostly due to complications after surgery. Our results, albeit still very limited, provided some reassurance about the safety of paracetamol 4 g daily, as a supplementary analgesic agent for adult patients undergoing cardiac surgery.

Ge(1-x) Mn(x) clusters: central structural and magnetic building blocks of nanoscale wire-like self-assembly in a magnetic semiconductor.

Controlled nanoscale self-assembly of magnetic entities in semiconductors opens novel perspectives for the tailoring of magnetic semiconductor films and nanostructures with room temperature functionality. We report that a strongly directional self-assembly in growth direction in Mn-alloyed Ge is due to a stacking of individual Ge(1-x)Mn(x) clusters. The clusters represent the relevant entities for the magnetization of the material. They are formed of a core-shell structure displaying a Mn concentration gradient. While the magnetic moments seem to be carried by the shells of the clusters, their core is magnetically inactive.

Immune effects of decreasing low-molecular weight hemoglobin components of hemoglobin-based oxygen carriers (HBOC) in a swine model of severe controlled hemorrhagic shock.

Hemoglobin-based oxygen carriers (HBOCs) show potential as safe, efficacious, pre-hospital resuscitation fluids. The major criticism of HBOC-201 is its vasoactive property, attributed partially to low-molecular weight (low-MW) tetrameric/dimeric (TD) hemoglobin (Hb) in HBOC solution. Here we sought to determine whether resuscitation with decreasing concentrations of low-MW Hb component of HBOC affects immune responses in hemorrhagic swine. 28 anesthetized swine underwent a soft muscle crush and controlled hemorrhage of 55% blood volume, followed by resuscitation with HBOC containing 31%, 2%, or 0.4% low-MW Hb in four 10 ml/kg infusions at 20, 30, 45 and 60 minutes before hospital arrival at 75 minutes. IL-10, cell activation and adhesion markers and CD4:CD8 ratio remained unchanged in all 3 groups compared to baseline. Leukocyte apoptosis was equally elevated across all groups. Purification from 31% to 0.4% low-MW Hb in HBOC solution did not alter immune effects in a swine model of severe controlled hemorrhagic shock.

Innate immune responses in Swine resuscitated from severe traumatic hemorrhagic shock with hemoglobin-based oxygen carrier-201.

Hemoglobin-based oxygen carrier-201 transports oxygen and improves survival in swine with hemorrhagic shock, but has potential to be immune activating. Herein, we evaluated HBOC-201's immune effects in swine with more severe hemorrhagic shock due to soft tissue injury and 55% blood volume catheter withdrawal over 15 minutes followed by fluid resuscitation at 20 minutes with HBOC-201, Hextend, or no treatment (NON) before hospital arrival. Survival rates were similar with HBOC-201 and Hextend (p > 0.05), but were higher than in (p = 0.007). There were no significant group differences in blood cell count, percentages of leukocyte sub-populations and immunophenotype (CD4:CD8 ratio), adhesion markers expression (neutrophil CD11b; monocyte or neutrophil CD49d) and apoptosis. There was a trend to higher plasma IL-10 in HBOC-201 and groups vs. Hextend. We conclude that in swine with severe controlled HS and soft tissue injury, immune responses are similar with resuscitation with HBOC-201 and Hextend.

Clustering in a precipitate-free GeMn magnetic semiconductor.

We present the first study relating structural parameters of precipitate-free Ge0.95Mn0.05 films to magnetization data. Nanometer-sized clusters--areas with increased Mn content on substitutional lattice sites compared to the host matrix--are detected in transmission electron microscopy analysis. The films show no overall spontaneous magnetization at all down to 2 K. The TEM and magnetization results are interpreted in terms of an assembly of superparamagnetic moments developing in the dense distribution of clusters. Each cluster individually turns ferromagnetic below an ordering temperature which depends on its volume and Mn content.

Effect of hyperbaric oxygen treatment on nitric oxide and oxygen free radicals in rat brain.

Oxygen (O(2)) at high pressures acts as a neurotoxic agent leading to convulsions. The mechanism of this neurotoxicity is not known; however, oxygen free radicals and nitric oxide (NO) have been suggested as contributors. This study was designed to follow the formation of oxygen free radicals and NO in the rat brain under hyperbaric oxygen (HBO) conditions using in vivo microdialysis. Male Sprague-Dawley rats were exposed to 100% O(2) at a pressure of 3 atm absolute for 2 h. The formation of 2,3-dihydroxybenzoic acid (2, 3-DHBA) as a result of perfusing sodium salicylate was followed as an indicator for the formation of hydroxyl radicals. 2,3-DHBA levels in hippocampal and striatal dialysates of animals exposed to HBO conditions were not significantly different from controls. However, rats treated under the same conditions showed a six- and fourfold increase in nitrite/nitrate, break down products of NO decomposition, in hippocampal and striatal dialysates, respectively. This increase was completely blocked by the nitric oxide synthase (NOS) inhibitor L-nitroarginine methyl ester (L-NAME). Using neuronal NOS, we determined the NOS O(2) K(m) to be 158 +/- 28 (SD) mmHg, a value which suggests that production of NO by NOS would increase approximately four- to fivefold under hyperbaric O(2) conditions, closely matching the measured increase in vivo. The increase in NO levels may be partially responsible for some of the detrimental effects of HBO conditions.

Acute cold stress leading to elevated corticosterone neither enhances synaptic efficacy nor impairs LTP in the dentate gyrus of freely moving rats.

Exposure to stress has previously been found to impair long-term potentiation (LTP) in the hippocampus. Exposure to stress has also been proposed to induce an LTP-like effect. We examined the effect of acute cold stress on synaptic transmission, neuronal excitability, and LTP induction in the medial perforant path-granule cell synapse of freely moving rats. After obtaining baseline recordings of evoked field potentials at room temperature (23 degrees C), rats were transferred to an environmental cage maintained at 4 degrees C (cold group) or 23 degrees C (control group) and, 90 min later, high-frequency stimulation (HFS) was applied to the medial perforant path. Serum corticosterone measured in trunk blood from rats without implanted electrodes was significantly elevated in cold exposed (28. 7 microg/dl) rats relative to control (6.6 microg/dl). Despite increased corticosterone levels indicative of stress activation, cold exposed rats exhibited LTP of the fEPSP slope and population spike of similar magnitude and time course as controls. In addition, there was no stress-specific effect on the fEPSP slope or population spike and no effect on paired-pulse plasticity. Surprisingly, despite extensive cage acclimation, transferring rats to the environmental cage was associated with a reduction in population spike amplitude and an enhancement in paired-pulse facilitation. The results show that acute cold stress leading to elevated serum corticosterone levels neither induces LTP-like increases in synaptic efficacy nor impairs tetanus-evoked LTP in the dentate gyrus of freely moving rats. Thus, impaired working memory during cold stress is not due to an inability of perforant path synapses to express LTP.

Cold-induced perturbation of cutaneous blood flow in the rat tail: a model of nonfreezing cold injury.

Cold-induced alteration of cutaneous blood flow, measured with laser-Doppler flowmetry, was studied in a rat tail model of nonfreezing cold injury (NFCI). The NFCI-inducing condition consisted of prolonged tail immersion in 1 degree water. Before exposure to the injury condition, tail blood flow (laser Doppler flux) during brief 3 degrees immersion showed cold-induced cycles of vasoconstriction followed by cold-induced vasodilation (CIVD). Tail temperature exhibited cyclic patterns similar to blood flow in response to cold water immersion. Cold exposures to 1 degree for 1 or 3 hr induced no systematic change; however, cold exposures of 6 or 9 hr induced profound and long-lasting blood flow and temperature deviations. Following the cold injury condition, CIVD was completely absent and remained absent for several weeks, suggesting that CIVD loss is an important component in development of NFCI. Cold-induced disturbances of cutaneous blood flow in the rat tail consisted of a sequence of distinctive stages analogous to those described in human NFCI. These stages were evidenced initially by several days of reduced blood flow and thermal sensitivity, followed in a week by a hyperemia stage, and later by enhanced vascular and thermal sensitivity. The cutaneous blood flow alterations and sequence of variations following prolonged cold exposure suggest that the rat tail may be a valid model of human NFCI.

Amyloid precursor protein in the cerebral cortex is rapidly and persistently induced by loss of subcortical innervation.

Lesions of the cholinergic nucleus basalis of Meynert elevate the ex vivo synthesis of beta amyloid precursor protein (beta-APP) in the cerebral cortex, a major projection region. We have found that this elevation is reflected by increased levels of beta-APP mRNA. The induction is rapid (occurring 60 min after placement of the lesion) and persistent (remaining for at least 45 days after lesioning). Two other subcortical lesions, which result in reductions of cortical adrenergic and serotonergic innervation, similarly induced cortical beta-APP. The beta-APP induction is reversible and does not require loss of the subcortical neurons. Infusion of lidocaine, a calcium antagonist that disrupts neurotransmitter release, into the nucleus basalis of Meynert leads to the temporary reduction of released acetylcholine in the cortex. In this model, beta-APP mRNA levels are elevated shortly after the infusion of lidocaine (90 min) but return to preinfusion levels 7 days after the lidocaine treatment. However, metabolic stresses of the brain, including chronic physostigmine, glucocorticoid, and diabetogenic treatments, fail to induce the beta-APP response. These results suggest that the induction of beta-APP is a specific response to the loss of functional innervation in the cortex. Importantly, these studies show that cortical beta-APP is induced by lesions that mimic the neurochemical deficits most frequently observed in Alzheimer disease.

Effects of repeated administration of corticotropin-releasing factor on schedule-controlled behavior in rats.

To examine the effects of repeated administration of corticotropin-releasing factor (CRF) on behavior, rats were administered ICV injections of either CRF or saline on alternate days for 10 days prior to performing on a multiple fixed-interval (FI) 60 s/fixed-ratio (FR) 20 schedule for food reinforcement. A daily session consisted of 10 components of each schedule that alternated, starting with the FI component. CRF doses were individually determined for each rat and were either 1.0, 3.0, or 10 micrograms CRF based upon the dose that occasioned more than a 50% reduction in the rate of responding. Acute administration of CRF decreased the rate of responding in both components well below control rates; this decrease in responding was associated with a 20 or 50% decrease in the number of earned reinforcements in the FI and FR components, respectively. With repeated administration, CRF-induced suppression of responding was attenuated, although CRF continued to decrease response rate. Despite the continued reduction in response rate, subsequent CRF injections did not result in a loss of reinforcements in the FI component, whereas rats continued to lose 20% of the reinforcers in the FR component. After an 18-day hiatus in which no CRF was administered, the baseline rate of responding on the multiple schedule increased, in particular in the FI component. When CRF was readministered, response rates were slightly suppressed relative to a reestablished saline control but significantly higher than CRF-induced suppression on the last day of the chronic regimen. These data demonstrate that with repeated administration tolerance develops to CRF-induced suppression of responding in rats.

Tyrosine ameliorates a cold-induced delayed matching-to-sample performance decrement in rats.

Exposure to cold stress has been shown to impair short-term, or working, memory which may be related to a reduction in brain catecholamines. Administration of the catecholamine precursor tyrosine may alleviate a cold-stress-induced memory impairment by preventing a deficit in brain catecholamine levels. To test this hypothesis, eight rats performed a delayed matching-to-sample (DMTS) task at an ambient temperature of either 2 degrees C (cold) or 22 degrees C, following intraperitoneal administration of saline or tyrosine (50, 100 or 200 mg/kg). Rats administered saline prior to 22 degrees C exposure demonstrated a characteristic delay gradient in which accuracy decreased as the delay interval between sample and comparison stimuli increased from 1 to 16 s. Consistent with previous research, and relative to 22 degrees C exposure sessions, matching accuracy during 2 degrees C exposure sessions was reduced, which is attributed to the effect of cold on short-term, or working, memory. In particular, during cold exposure sessions matching accuracy was significantly reduced at the longer delay intervals, relative to matching accuracy at 22 degrees C. Additional analysis of cumulative matching errors within sessions showed that during exposure to cold, errors occurred at a constant rate throughout the session, indicating rats' performance was equally debilitated by the stressor over the entire session. During cold exposure sessions, the higher doses of 100 and 200 mg/kg tyrosine significantly improved overall matching accuracy relative to saline, but did not completely reverse the effect of cold exposure, as overall matching accuracy did not increase entirely to levels obtained at 22 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Tyrosine pretreatment alleviates suppression of schedule-controlled responding produced by corticotropin releasing factor (CRF) in rats.

Disruption of performance observed when animals are exposed to physical stressors which deplete brain catecholamines can be alleviated by pretreatment with the catecholamine precursor tyrosine. Central administration of the stress hormone corticotropin releasing factor (CRF) has been shown to affect a variety of behaviors and also to potently increase the release of central catecholamines. Since CRF-induced disruption of behavior may involve CRF-induced depletion of brain catecholamines, the present study examined whether tyrosine would alleviate suppression of schedule-controlled responding in rats resulting from ICV administration of CRF. Administration of CRF (1.0 microgram-10 micrograms) produced dose-dependent suppression of response rate and total number of earned reinforcers in rats responding on a multiple fixed-interval 60 s/fixed-ratio 20 schedule for food reinforcement. Pretreatment with 200 mg/kg tyrosine (IP) administered with ICV saline decreased response rate but did not lower total reinforcers, whereas 400 mg/kg of tyrosine decreased both. Injection of 400 mg/kg tyrosine reduced, but did not completely restore, CRF-induced suppression of behavior. The 200 mg/kg tyrosine dose was less effective in alleviating CRF-induced suppression of performance. These data indicate that pretreatment with the catecholamine precursor tyrosine can partially ameliorate performance decrements resulting from CRF administration.

Antagonism studies with BMY-7378 and NAN-190: effects on 8-hydroxy-2-(di-n-propylamino)tetralin-induced increases in punished responding of pigeons.

The purported serotonin (5-HT)1A antagonists BMY-7378 and NAN-190 were examined in pigeons for their potential to block the effects of the prototypical 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on punished ("conflict") and unpunished behavior and for their binding affinity at the 5-HT1A receptor site labeled by [3H]-8-OH-DPAT. Although BMY-7378 and NAN-190 both displayed high affinity for the 5-HT1A receptor (IC50 values of 0.8 and 7.5 nM, respectively), their effects, when administered alone, as well as in combination with 8-OH-DPAT, were distinct. 8-OH-DPAT (0.3-3.0 mg/kg) produced large increases in punished responding at doses that did not affect or that decreased unpunished responding. Administration of NAN-190 (1.0-3.0 mg/kg) did not increase punished responding, whereas BMY-7378 (1.0-5.6 mg/kg) slightly increased behavior suppressed by punishment. Pretreatment with BMY-7378 attenuated the rate-increasing effects of 8-OH-DPAT on punished responding; however, these effects were accompanied by dose-dependent enhancement of the rate-decreasing effects of 8-OH-DPAT on unpunished responding. In contrast, NAN-190 blocked the rate-increasing effects of 8-OH-DPAT on punished responding and also reversed the rate-decreasing effects of 8-OH-DPAT on responding that was not punished. Pretreatment with NAN-190 failed to block increases in punished responding produced by 0.1 to 1.0 mg/kg of the benzodiazepine midazolam. These data suggest that NAN-190 may be characterized as an antagonist and BMY-7378 a partial agonist with respect to 5-HT1A-induced behavioral changes observed in the conflict procedure with pigeons.

Hippocampal and body temperature changes in rats during delayed matching-to-sample performance in a cold environment.

In order to study the effects of temperature changes induced by cold stress on working memory, telemetry thermistor probes were implanted into the hippocampal region of the brain and into the peritoneal cavity of rats. Temperatures in these regions were monitored while rats performed on a delayed matching-to-sample (DMTS) task at ambient temperatures of 23 degrees C and 2 degrees C. Matching accuracy was significantly decreased during exposure to 2 degrees C, indicating a marked impairment of short-term or working memory. Temperature in the hippocampus increased 2 degrees C during exposure to 23 degrees C, but only 1 degrees C when the environmental temperature was 2 degrees C. Body temperature showed a similar but less pronounced pattern in that cold exposure attenuated the increase in temperature observed when animals performed the DMTS task. These results suggest that cold-induced impairment of working memory may be associated with subtle temperature changes in the brain.