Effects of diet on sensitization to cocaine-induced stereotypy in female rats

The progressive increase in cocaine-induced stereotyped behavior that accompanies repeated cocaine injections (sensitization) was examined in rats consuming different diets. Adult female Sprague-Dawley rats were fed one of three diets: low protein (6% casein), adequate protein (25% casein), or a standard chow diet. Following 1 week of adaptation to the diets, the rats were injected every 3-4 days with either cocaine (30 mg/kg, IP) or saline, and the total amount of stereotypy was measured over a 90-min interval following each of four injections. Cocaine-induced stereotypy peaked at 40-50 min following each injection, after which it declined for all diet groups. With repeated injections, the total amount of stereotypy increased in all diet groups. By the fourth injection, the low protein diet group (6% casein) exhibited a slower onset and a possibly prolonged duration of cocaine-induced stereotypy when compared with the two adequate protein diet groups (25% casein and chow). Interestingly, the rats in the two purified diet groups (6% casein and 25% casein) exhibited significantly more stereotypy across injections than those in the chow diet group. Weight differences did not explain the differences in stereotypy present among the diet groups. This study concludes that diet significantly alters the pattern of cocaine-induced stereotypy in female rats, especially after repeated exposure.     

Naltrexone, but not atropine or yohimbine, antagonizes suppression of formalin-induced spinal sensitization by intrathecal nociceptin

We investigated the effects of spinal nociceptin on formalin-induced spinal sensitization and examined the role of the opioidergic, alpha 2-adrenergic and muscarinic cholinergic receptors in the nociceptin-produced suppression of spinal sensitization. The results demonstrated that spinal nociceptin suppressed the formalin-induced spinal sensitization in a dose-dependent manner (1, 5 and 10 nmol). The inhibitory effect of 10 nmol of nociceptin on spinal sensitization, was readily antagonized by naltrexone, but not by atropine or yohimbine. Each of the antagonists, naltrexone, atropine or yohimbine, alone had no effect on the formalin-induced spinal sensitization. Our results show that spinal nociceptin elicits dose-dependent, naltrexone-reversible suppression of spinal sensitization evoked by injection of formalin.     

U-69593, a kappa opioid receptor agonist, decreases cocaine-induced behavioral sensitization in female rats.

This study was designed to investigate if the kappa opioid system regulates the locomotor response to cocaine in the female rat and to determine if the effect is dependent on estradiol treatment. Adult rats were ovariectomized (OVX) and half received an estradiol (OVX-EB) implant. After a week, rats were injected for 5 consecutive days with vehicle or with the kappa opioid receptor (KOPr) agonist U-69593 (0.16, 0.32, and 0.64 mg/kg) 15 min prior to cocaine injection (15 mg/kg). Following a 7-day drug-free period, rats were challenged with cocaine (Day 13). The locomotor response to cocaine was measured on Days 1, 5, and 13. U-69593 (0.32 mg/kg) decreased cocaine-induced locomotor activity in drug-na?ve OVX rats and in those that received the OVX-EB implant. These results indicate that the acute effects of U-69593 are independent of estradiol treatment. Repeated exposure to U-69593 (0.32 mg/kg) prior to cocaine decreased the development of behavioral sensitization in OVX-EB-implanted rats. This decrease in cocaine-induced hyperlocomotion persisted after 1 week of cocaine withdrawal. These data indicate that the KOPr system participates in estradiol modulation of cocaine-induced behavioral sensitization in the female rat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Apnoea and bradycardia during epileptic seizures: relation to sudden death in epilepsy

OBJECTIVE: To record non-invasively ictal cardiorespiratory variables. METHODS: Techniques employed in polysomnography were used in patients with epilepsy undergoing EEG-video recording at a telemetry unit. RESULTS: Apnoea (> 10, range > 10-63, mean 24 s) was seen in 20 of 47 clinical seizures (three secondary generalised, 16 complex partial, and one tonic) and 10 of 17 patients. Apnoea was central in 10 patients, but obstructive apnoea was also recorded in three of 10. Oxyhaemoglobin saturation (SpO2) dropped to less than 85% in 10 seizures (six patients). An increase in heart rate was common (91% of seizures). Bradycardia/sinus arrest was documented in four patients (mean maximum RR interval 5.36, range 2.8-8.6 s) but always in the context of a change in respiratory pattern. CONCLUSION: Ictal apnoea was often seen. The occurrence of bradycardia in association with apnoea suggests the involvement of cardiorespiratory reflexes. Similar mechanisms may operate in cases of sudden death in epilepsy.     

Clozapine and haloperidol block the induction of behavioral sensitization to amphetamine and associated genomic responses in rats

Behavioral sensitization resulting from repeated, intermittent exposure to psychostimulants such as amphetamine (Amp) is hypothesized to model pathophysiology of psychotic disorders. The present study was designed to characterize the effects of a typical and an atypical antipsychotic drug, haloperidol and clozapine, respectively, on the induction of context-independent sensitization to Amp. Peripheral Amp treatment for five days (2 mg/kg/day, s.c.) produced an augmented stimulant response to an acute Amp challenge (2 mg/kg, s.c.) given seven days after the last pretreatment injection. Interestingly, preexposure to high doses of either clozapine (20 mg/kg) or haloperidol (0.5 mg/kg) alone also led to a sensitized behavioral response to an acute Amp challenge. The cross-sensitization between Amp and high doses of the haloperidol and clozapine may have occluded any blockade of Amp behavioral sensitization by the antipsychotics. Indeed, administration of a lower dose of clozapine (4 mg/kg) or haloperidol (0.1 mg/kg) with Amp during the preexposure phase clearly blocked the induction of behavioral sensitization. In addition to the behavioral sensitization, Amp-pretreated rats showed a reduction in the ability of the acute Amp challenge to induce c-fos mRNA in the medial prefrontal cortex and neurotensin/neuromedin N (NT/N) mRNA in the nucleus accumbens-shell. At doses that blocked the initiation of behavioral sensitization to Amp, clozapine fully and haloperidol partially restored the capacity of acute Amp to induce c-fos and NT/N gene expression. These data lend support to the psychostimulant-sensitization model of psychosis and a role of dopamine D2-like receptors in the phenomenon.     

Naltrexone: disposition, metabolism, and effects after acute and chronic dosing

The disposition of naltrexone during acute and chronic administration of 100-mg oral dose was studied in 4 subjects. Following an acute dose the mean (X) peak naltrexone plasma level was 43.6 +/- 29.9 ng/ml at 1 hr and for the major biotransformation product, beta-naltrexol, was 87.2 +/- 25.0 ng/ml at 2 hr. Twenty-four hours after the dose the X levels of naltrexone and beta-naltrexol declined to 2.1 +/- 0.47 and 17.6 +/- 5.0 ng/ml, respectively. Following chronic administration and X peak plasma levels of naltrexone and beta-naltrexol rose to 46.4 +/- 18.5 and 158.4 +/- 89.9 ng/ml at 1 hr, but by 24 hr both compounds declined to levels of the same order as in the acute state at 24 hr. Plasma levels of naltrexone and beta-naltrexol measured 24 hr after the daily doses of naltrexone throughout the study indicated that steady-state equilibrium was rapidly attained and that there was no accumulation of naltrexone and beta naltrexol in the plasma after chronic treatment on 100 mg oral doses. Biexponential kinetics were observed for naltrexone and beta-naltrexol in the first 24 hr. The half-life of naltrexone and beta-naltrexol decreased slightly from the acute to thechronic study from 10.3 +/- 3.3 to 9.7 +/- 1.1 hr and from 12.7 +/- 2.6 to 11.4 +/- 2.0 hr. The plasma levels of naltrexone declined slowly from 24 through 72 hr from 2.4 to 1.7 ng/ml, with an apparent half-life of 96 hr. The renal clearance data indicate that naltrexone is partially reabsorbed while beta naltrexol is actively secreted by the kidney. During acute and chronic naltrexone administration the mean fecal excretion was 2.1% and 3.6% while urinary excretion was 38% and 70% of the dose in a 24-hr period. Opiate antagonism to 25 mg heroin challenges was nearly complete through 48 hr after naltrexone. At 72 hr the objective responses reappeared to a greater extent than the subjective ones. Correlation coefficient (r) between naltrexone plasma levels and opiate antagonism was 0.91 and between individual half-life of naltrexone and opiate antagonism it was 0.99.     

Bcl-2 and Bcl-XL can differentially block chemotherapy-induced cell death

Bcl-2 and its homologue Bcl-XL are expressed in a variety of tumors and their expression modulates the sensitivity of tumor cells to a wide spectrum of chemotherapeutic agents and gamma-irradiation. In the present report, we generated clones of FL5.12 lymphoid cells with similar levels of Bcl-2 and Bcl-XL using the Flag epitope to determine if these survival proteins could provide equivalent protection when challenged with chemotherapy or gamma-irradiation. Using four M-phase specific chemotherapeutic agents, Bcl-XL and Bcl-2 provided similar protection against vincristine and vinblastine whereas Bcl-XL afforded as much as 50% greater cell viability than Bcl-2 against etoposide and teniposide-induced cell death. In addition, Bcl-XL provided significantly greater cell viability than Bcl-2 against methotrexate, fluorouracil, and hydroxyurea, three S-phase specific agents. In apoptosis induced by gamma-irradiation and cisplatin, two antitumor treatments that are cell-cycle phase-nonspecific agents, both Bcl-XL and Bcl-2 conferred similar protection against gamma-irradiation, but Bcl-XL provided better protection than Bcl-2 against cisplatin. These results indicate that Bcl-XL and Bcl-2 confer a differential ability to protect against chemotherapy-induced cell death, which appears to be dependent on the molecular mechanism targeted by the drug rather than its cell-cycle phase specificity.     

Arrhythmogenic right ventricular cardiomyopathy underlies syndrome of right bundle branch block, ST-segment elevation, and sudden death

In all experimental mammals tested (rats, dogs, primates), intramuscular injections of the oil-soluble antimalarial artemisinin derivatives artemether and arteether have produced an unusual pattern of selective damage to brain stem centers predominantly involved in auditory processing and vestibular reflexes. Artesunate, the most widely used of these compounds, is a water soluble hemisuccinate derivative given parenterally either by intravenous or intramuscular injection. The neurotoxic potential of parenteral artesunate and artemether was compared in a murine model. Adult Swiss albino mice were assigned randomly to 28-day regimens of intramuscular artemether or artesunate in doses ranging from 30 to 100 mg/kg/day. At 30 mg/kg/day, no abnormalities were detected with either drug. At 50 mg/kg/day, abnormalities were observed in six of 12 artemether recipients and two of 12 artesunate recipients. These were reversible in all but one (artemether) mouse. At 100 mg/kg/day, eight of 36 artemether recipients, two of 36 artesunate recipients, and one of 18 control mice died. All but four surviving mice in the artemether group (86%) showed obvious and usually irreversible abnormalities of balance and equilibrium, whereas only four artesunate recipients (11%) exhibited abnormalities, and these were reversible in each case (P < 0.001). At this dose the relative risk (95% confidence interval) for death or disability was 5.3 (2.6-11.2) for artemether recipients. Intramuscular artemether is significantly more neurotoxic than intramuscular artesunate in this murine model.     

Relationship of cocaine-induced c-Fos expression to behaviors and the role of serotonin 5-HT2A receptors in cocaine-induced c-Fos expression.

Serotonin 5-HT2A receptor antagonists have been shown to attenuate the locomotor stimulant effects of cocaine in rats. The present study used the expression of c-Fos protein as a marker to identify brain areas through which 5-HT2A receptors may modulate cocaine-induced behaviors. Significant correlations were observed between cocaine-induced hyperactivity and c-Fos expression in the nucleus accumbens core (NAcC), caudate-putamen (CPu), and subthalamic nucleus. In a separate experiment, a low, behaviorally relevant dose of cocaine was found to increase c-Fos immunoreactivity in the medial CPu, NAcC, and nucleus accumbens shell (NAcSh). The selective 5-HT2A receptor antagonist M100907 significantly attenuated cocaine-induced c-Fos expression in the medial CPu and in the NAcSh. These data suggest that 5-HT2A receptors in the NAcSh and CPu or in afferents to these regions may contribute to genomic responses to cocaine in the brain as well as to cocaine-induced locomotor activity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of naltrexone and its derivatives, nalmefene and naltrindole, on conditioned anticipatory behaviour and saccharin intake in rats

Drug craving, the desire to re-experience the effects of a psychoactive substance, may be an important influence on drug-seeking and drug-taking behaviour. In rats, drug-seeking behaviour can be operationalized as conditioned anticipatory behaviour, evidenced by frequent visits to, and an increased time spent and distance travelled in, the drug administration area prior to the availability of the reinforcer. The effects of the opioid antagonist, naltrexone, and its derivatives, nalmefene and naltrindole, on conditioned anticipatory behaviour and drinking-associated behaviour and fluid intake during the access phase were examined. Male Wistar rats were trained to consume 0.1% saccharin and water in a distinct environment in a free-choice limited-access procedure. Naltrexone (0.3, 1 mg/kg) decreased conditioned anticipatory behaviour and drinking-associated behaviour in the saccharin zone without affecting the corresponding behaviour in the water zone. Its derivatives had different effects. Nalmefene (0.1 mg/kg) increased drinking-associated behaviour but not conditioned anticipatory behaviour, whereas naltrindole (1, 2 mg/kg) modestly decreased conditioned anticipatory behaviour but not drinking-associated behaviour. Naltrexone (0.3, 1 mg/kg) and naltrindole (1, 2 mg/kg), but not nalmefene, selectively decreased saccharin intake. These findings suggest that the blockade of selective opioid receptors may differentially alter conditioned anticipatory behaviour, drinking-associated behaviour and consumption levels, and that these behaviours can be modified separately.     

Further characterization of the syndrome of right bundle branch block, ST segment elevation, and sudden cardiac death

There is a lack of defined reference points for reproducible femoral tunnel placement during posterior cruciate ligament (PCL) reconstruction. The PCL, consisting of two major bands, anterolateral (AL) and posteromedial (PM), has a femoral origin that spans 3 cm, which cannot be covered by a substitute graft positioned in one femoral tunnel to reconstruct the PCL. The purpose of this study was to define the location of the anatomic origin of both bands of the PCL in reference to local anatomy to develop landmarks that can be used to reproducibly position two femoral tunnels (one to each band's origin) during PCL reconstruction. The anatomy of the PCL origin was dissected and studied in 20 knees at the time of total knee replacement. The central origin point for each band was marked, and its distance was measured in reference to three axes. The AL band centrally originated 13 +/- 0.5 mm posterior to the medial articular cartilage-intercondylar wall interface and 13 +/- 0.5 mm inferior to the articular cartilage-intercondylar roof interface. The PM band centrally originated 8 +/- 0.5 mm posterior to the medial articular cartilage-intercondylar wall interface and 20 +/- 0.5 mm inferior to the articular cartilage-intercondylar roof interface. These distances were noted to be relatively constant despite varying knee morphologies and size. For this reason, referencing the articular cartilage-intercondylar roof, and wall interfaces may be used as a method to facilitate more reproducible anatomic femoral tunnel placements during PCL reconstruction.     

Motor maps, seizures, and behaviour.

Atypically organised motor maps have been described in some people with epilepsy and we have modelled this in rats. Our goal is to more fully understand the mechanisms responsible for seizure-induced functional brain reorganisation and to reverse their effects. Here we present an overview of the relationship between neocortical motor maps, seizures, and interictal behaviour. To begin we summarise the observations of atypical motor maps with epilepsy and in animal models following experimentally induced seizures. Our novel experiments have established that motor map expansion is linked to a functional alteration of motor behaviour. Evidence for some of the putative brain mechanisms responsible for motor map size is discussed. Our successes reversing seizure-induced map expansion by two different methods are also briefly reviewed. Lastly, unanswered questions for possible future experimentation are posed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Experimental studies of sensitization to beryllium, zirconium, and aluminum compounds in the rabbit

In a study designed to assess the potential sensitizing and granulomagenic capacities of selected metallic salts, rabbits were inoculated intradermally with zirconium aluminum glycinate (ZAG), sodium zirconium lactate (NZL), aluminum chlorhydrate (ACH), BeSO 4, and ovalbumin (OVA) by single and multiple injections. Animals immunized with BeSO4 and with OVA developed delayed skin reactivity as well as antigen-specific alveolar macrophage migration inhibition. Neither single nor multiple injections of ZAG or ACH resulted in clear-cut positive skin reactivity, macrophage migration inhibitory factor (MIF) production, or lymphocyte stimulation. Rabbits inoculated with multiple injections of NZL (500 microng) showed some marginally positive macrophage migration inhibition and skin reactivity. Histologically, ZAG and ACH were found to induce well-organized foreign-body granulomas after intradermal injection in both normal and inoculated rabbits. NZL and BeSO4 also induced skin granulomas, but these were less organized and distinct. Cell viability and ultrastructural studies indicated that BeSO4 was highly toxic for isolated alveolar macrophages in vitro at concentrations above 10 microng/ml, but NZL and ZAG did not exert such an effect at these dose levels. BeSO4 also depressed lymphocyte stimulation in sensitized animals which demonstrated delayed skin reactivity and macrophage migration inhibition.     

Endoplasmic reticulum stress proteins block oxidant-induced Ca2+ increases and cell death

Oxidants are important human toxicants. Increased intracellular free Ca2+ may be critical for oxidant toxicity, but this mechanism remains controversial. Furthermore, oxidants damage the endoplasmic reticulum (ER) and release ER Ca2+, but the role of the ER in oxidant toxicity and Ca2+ regulation during toxicity is also unclear. tert-Butylhydroperoxide (TBHP), a prototypical organic oxidant, causes oxidative stress and an increase in intracellular free Ca2+. Therefore, we addressed the mechanism of oxidant-induced cell death and investigated the role of ER stress proteins in Ca2+ regulation and cytoprotection after treating renal epithelial cells with TBHP. Prior ER stress induces expression of the ER stress proteins Grp78, Grp94, and calreticulin and rendered cells resistant to cell death caused by a subsequent TBHP challenge. Expressing antisense RNA targeted to grp78 prevents grp78 induction sensitized cells to TBHP and disrupted their ability to develop cellular tolerance. In addition, overexpressing calreticulin, another ER chaperone and Ca2+-binding protein, also protected cells against TBHP. Interestingly, neither prior ER stress nor calreticulin expression prevented lipid peroxidation, but both blocked the rise in intracellular free Ca2+ after TBHP treatment. Loading cells with EGTA, even after peroxidation had already occurred, also prevented TBHP-induced cell death, indicating that buffering intracellular Ca2+ prevents cell killing. Thus, Ca2+ plays an important role in TBHP-induced cell death in these cells, and the ER is an important regulator of cellular Ca2+ homeostasis during oxidative stress. Given the importance of oxidants in human disease, it would appear that the role of ER stress proteins in protection from oxidant damage warrants further consideration.     

Specific IgE-dependent sensitization, atopy, and bronchial hyperresponsiveness in apprentices starting exposure to protein-derived agents

Atopy, specific IgE sensitization, and bronchial hyperresponsiveness (BHR) were examined in a cohort of 769 apprentices starting career programs in animal health or veterinary medicine (Group 1), pastry making (Group 2), and dental hygiene (Group 3). The hypothesis were that: (1) a proportion of subjects can be "sensitized" although no significant specific occupational exposure has occurred; and (2) there is a relationship between baseline specific sensitization to work-related antigens and host characteristics. Skin tests were administered using 11 common inhalants and specific allergens, including six laboratory animal extracts, three cereal antigens, alpha-amylase, and latex. Methacholine challenge tests were performed. The prevalence of atopy was 54.4% in Group 1, 58.1% in Group 2, and 52.5% in Group 3. Skin reactivity to work-specific proteins was as follows: laboratory animal proteins, 13.8% in Group 1, 14.0% in Group 2, and 15.6% in Group 3. No subject was sensitized to alpha-amylase, whereas 1.2% in Group 1, 5% in Group 2, and 4.1% in Group 3 were sensitized to flour. Five subjects reacted to latex. BHR (PC20 < or = 8 mg/ml) was present in 17.6%, 21.2%, and 14.8% of subjects in Groups 1, 2, and 3, respectively. Specific sensitization was associated with positive skin reactions to common allergens, work-related symptoms, and BHR. These results suggest that students starting career programs with exposure to high-molecular-weight allergens have a low but substantial frequency of specific sensitization to work-related allergens that is related to atopy and BHR.