Selective disruption of stimulus-reward learning in glutamate receptor gria 1 knockout mice.

Glutamatergic neurotransmission via AMPA receptors has been an important focus of studies investigating neuronal plasticity. AMPA receptor glutamate receptor 1 (GluR1) subunits play a critical role in long-term potentiation (LTP). Because LTP is thought to be the cellular substrate for learning, we investigated whether mice lacking the GluR1 subunit [gria1 knock-outs (KO)] were capable of learning a simple cue-reward association, and whether such cues were able to influence motivated behavior. Both gria1 KO and wild-type mice learned to associate a light/tone stimulus with food delivery, as evidenced by their approaching the reward after presentation of the cue. During subsequent testing phases, gria1 KO mice also displayed normal approach to the cue in the absence of the reward (Pavlovian approach) and normal enhanced responding for the reward during cue presentations (Pavlovian to instrumental transfer). However, the cue did not act as a reward for learning a new behavior in the KO mice (conditioned reinforcement). This pattern of behavior is similar to that seen with lesions of the basolateral nucleus of the amygdala (BLA), and correspondingly, gria1 KO mice displayed impaired acquisition of responding under a second-order schedule. Thus, mice lacking the GluR1 receptor displayed a specific deficit in conditioned reward, suggesting that GluR1-containing AMPA receptors are important in the synaptic plasticity in the BLA that underlies conditioned reinforcement. Immunostaining for GluR2/3 subunits revealed changes in GluR2/3 expression in the gria1 KOs in the BLA but not the central nucleus of the amygdala (CA), consistent with the behavioral correlates of BLA but not CA function

Food-induced behavioral sensitization, its cross-sensitization to cocaine and morphine, pharmacological blockade, and effect on food intake

Repeated administration of abused drugs sensitizes their stimulant effects and results in a drug-paired environment eliciting conditioned activity. We tested whether food induces similar effects. Food-deprived male mice were given novel food during 30 min tests in a runway (FR group) that measured locomotor activity. Whereas the activity of this group increased with repeated testing, that of a group exposed to the runways but that received the food in the home cage (FH group), or of a group satiated by prefeeding before testing (SAT group), decreased. When exposed to the runways in the absence of food, the paired group was more active than the other groups (conditioned activity); no activity differences were seen in an alternative, non-food-paired, apparatus. Conditioned activity survived a 3-week period without runway exposure. Conditioned activity was selectively reduced by the opiate antagonist naltrexone (10-20 mg/kg) and by the noncompetitive AMPA receptor antagonist GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] (5-10 mg/kg). The D1 antagonist SCH23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] (15-30 microg/kg) and D2 antagonist sulpiride (25-125 mg/kg) reduced activity nonspecifically. A single intraperitoneal dose of cocaine (10 mg/kg) or morphine (20 mg/kg) increased activity compared with saline, the stimulant effect being larger in the FR group, suggesting "cross-sensitization" to these drugs. However, pretreatment with GYKI 52466 or naltrexone at doses that suppressed conditioned activity in FR animals suppressed cross-sensitization to cocaine. When allowed ad libitum access to food in the runway, FR mice consumed more pellets in a time-limited test. Thus, many of the features of behavioral sensitization to drugs can be demonstrated using food reward and may contribute to excessive eating

Mediating a Global Capitalist, Speciesist Moral Vacuum: How Two Escaped Pigs disrupted Dyson Appliances’ State of Nature

In 1998, two Tamworth Ginger pigs escaped on-route to slaughter, remaining fugitive for over a week on Dyson Appliances’ land in Malmesbury, Wiltshire, England, the United Kingdom. Dyson factory workers helped search for them, and media interest was global. National UK newspaper The Daily Mail bought the animals, preventing their slaughter. Whilst two pigs dubbed “Butch” and “Sundance” were publicly “saved,” slaughter continued in private, justified as “natural.” Dyson Appliance’s subsequent decision to sack all 800 Malmesbury vacuum-cleaner production staff was likewise reported as an inevitable, natural consequence of the market. The Press Gazette voted The Daily Mail’s coverage of the Tamworth two the greatest British media scoop of all time. Adopting a Critical Animal Media Studies lens, we explore the contradictions and connections between moral identification in UK media framing of Malmesbury’s animal escape story, moral invisibility of animal-slaughter in general, and reporting of the factory’s closure as a global capitalist state of nature’s “inevitable” and “natural” consequence

Incentive learning underlying cocaine relapse requires mGluR5 receptors located on dopamine D1 receptor-expressing neurons

Understanding the psychobiological basis of relapse remains a challenge in developing therapies for drug addiction. Relapse in cocaine addiction often occurs following exposure to environmental stimuli previously associated with drug taking. The metabotropic glutamate receptor, mGluR5, is potentially important in this respect; it plays a central role in several forms of striatal synaptic plasticity proposed to underpin associative learning and memory processes that enable drug-paired stimuli to acquire incentive motivational properties and trigger relapse. Using cell type-specific RNA interference, we have generated a novel mouse line with a selective knock-down of mGluR5 in dopamine D1 receptor-expressing neurons. Although mutant mice self-administer cocaine, we show that reinstatement of cocaine-seeking induced by a cocaine-paired stimulus is impaired. By examining different aspects of associative learning in the mutant mice, we identify deficits in specific incentive learning processes that enable a reward-paired stimulus to directly reinforce behavior and to become attractive, thus eliciting approach toward it. Our findings show that glutamate signaling through mGluR5 located on dopamine D1 receptor-expressing neurons is necessary for incentive learning processes that contribute to cue-induced reinstatement of cocaine-seeking and which may underpin relapse in drug addiction

An extract of Urtica dioica L. mitigates obesity induced insulin resistance in mice skeletal muscle via protein phosphatase 2A (PP2A)

The leaf extract of Urtica dioica L. (UT) has been reported to improve glucose homeostasis in vivo, but definitive studies on efficacy and mechanism of action are lacking. We investigated the effects of UT on obesity-induced insulin resistance in skeletal muscle. Male C57BL/6J mice were divided into three groups: low-fat diet (LFD), high-fat diet (HFD) and HFD supplemented with UT. Body weight, body composition, plasma glucose and plasma insulin were monitored. Skeletal muscle (gastrocnemius) was analyzed for insulin sensitivity, ceramide accumulation and the post translational modification and activity of protein phosphatase 2A (PP2A). PP2A is activated by ceramides and dephosphorylates Akt. C2C12 myotubes exposed to excess free fatty acids with or without UT were also evaluated for insulin signaling and modulation of PP2A. The HFD induced insulin resistance, increased fasting plasma glucose, enhanced ceramide accumulation and PP2A activity in skeletal muscle. Supplementation with UT improved plasma glucose homeostasis and enhanced skeletal muscle insulin sensitivity without affecting body weight and body composition. In myotubes, UT attenuated the ability of FFAs to induce insulin resistance and PP2A hyperactivity without affecting ceramide accumulation and PP2A expression. UT decreased PP2A activity through posttranslational modification that was accompanied by a reduction in Akt dephosphorylation

Risks and Rewards of Advanced Practice Providers in Cardiothoracic Surgery Training: National Survey

Background Changes in healthcare have led to increasing utilization of Advanced Practice Providers (APPs), but their role in Cardiothoracic Surgery (CTS) education remains undefined. This study aimed to analyze the extent of APP utilization on the CTS team, their role within the hierarchy of clinical care, and the impact of PEs on CTS training from the resident perspective. Methods CTS residents’ responses to the 2017 Thoracic Surgery Residents Association (TSRA)/Thoracic Surgery Directors Association (TSDA) In-Service Training Examination (ITE) survey regarding the role of APPs in specific clinical scenarios, and perception of APP contribution to residents’ educational environment were analyzed. Statistical analysis of categorical variables was performed in SPSS using a Fisher’s exact test and Pearson Chi-Square with statistical significance set at p<0.05. Results Response rate was 82.1% (280/341). The median number of employed APPs was 16-20 and 50.4% (n=141) reported 11-25 PEs at their institution. The median forAPPs in the operating room, floor, and intensive care unit was 3, 3, and 2 respectively. Overall impression of APPs was positive in 87.5% (n=245) of respondents, with 47.7% (n=133) being “very positive” and 40.1% being “positive” (n=112). In general, residents reported greater resident involvement in post-operative issues and operative consults and greater APP involvement in floor issues. 72.5% of residents had not missed a surgical opportunity due to APPs while, 9.6% missed an opportunity due to a APP despite being at an appropriate level of training. Of those that reported missed opportunities, 44% were I-6 residents. There were no significant differences in APPs’ operative role based on resident seniority. Conclusions The overall impression of APPs among CTS residents is favorable, and they more commonly are involved assisting on the floor or the operating room. Occasionally, residents report missing a surgical opportunity due to APPs. There is further opportunity to optimize and standardize their role within programs, in order to improve clinical outcomes and enhance the CTS educational experience for residents

Early life stress influences acute and sensitised responses of adult mice to cocaine by interacting with GABAA α2 receptor expression

Early life stress (ELS) is known to exert long term effects on brain function, with resulting deleterious consequences for several aspects of mental health, including the development of addiction to drugs of abuse. One potential mechanism in humans is suggested by findings that ELS interacts with polymorphisms of the GABRA2 gene, encoding alpha2 subunits of GABAA receptors, to increase risk for both posttraumatic stress disorder, and vulnerability to cocaine addiction. We used a mouse model, in which the amount of material for nest building was reduced during early postnatal life, to study interactions between ELS and expression of alpha2-containing GABAA receptors in influencing cocaine-related behaviour. Breeding of parents heterozygous for deletion of alpha2 resulted in litters containing homozygous knockout (alpha2-/-), heterozygous knockout (alpha2+/-), and wildtype (alpha2+/+) offspring. Following the ELS procedure, the mice were allowed to develop to adulthood before being tested for the acute effect of cocaine on locomotor stimulation, behavioural sensitisation to repeated cocaine, and to cocaine-conditioned activity. Exposure to ELS resulted in increased acute locomotor stimulant effects of cocaine across all genotypes, with the most marked effects in alpha2-/- mice (which also showed increased activity following vehicle). Repeated cocaine administration to non-stressed mice resulted in sensitisation in alpha2+/+ and alpha2+/- mice, but, in keeping with previous findings, not in alpha2-/- mice. Prior exposure to ELS reduced sensitisation in alpha2+/+ mice, albeit not significantly, and abolished sensitisation in alpha2+/- mice. Conditioned activity was elevated following ELS in all animals, independently of genotype. Thus, while the enhanced acute effects of cocaine following ELS being most marked in alpha2-/- mice suggests a function of alpha2-containing GABAA receptors in protecting against stress, the interaction between ELS and genotype in influencing sensitisation may be more in keeping with ELS reducing expression of alpha2-containing GABAA receptors. The ability of ELS to increase cocaine-conditioned locomotor activity appears to be independent of alpha2-containing GABAA receptors

The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.

RATIONALE Using the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice. OBJECTIVE We test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy. METHODS Thirty-six C57BL/6J mice were tested in a DID procedure. In 2-day cycles, animals experienced one baseline, injection-free session, and one test session when they received two injections, one of test drug and one placebo. All animals received GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min pre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c. 10 min pre-treatment) in a cross-over design. Receptor occupancies following the same doses were determined ex vivo in separate groups by autoradiography, using [3H]DAMGO. Binding in the region of interest was measured integrally by computer-assisted microdensitometry and corrected for non-specific binding. RESULTS Both GSK1521498 and naltrexone dose-dependently decreased ethanol consumption. When drug doses were matched for 70-75 % receptor occupancy, GSK1521498 3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol consumption than naltrexone 0.1 mg/kg, s.c. Both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test of conditioned taste aversion, GSK1521498 (3 mg/kg) reduced sucrose consumption 24 h following exposure to a conditioning injection. CONCLUSIONS Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone