Ibotenic acid lesions in the amygdaloid central nucleus but not in the lateral subthalamic area prevent the acquisition of differential Pavlovian conditioning of bradycardia in rabbits

The present study examined the effect of ibotenic acid lesions in the amygdaloid central nucleus (ACe) or in the lateral zona incerta of the subthalamus (LZI) on the acquisition of differential Pavlovian conditioning of bradycardia in rabbits. Previous work has shown that bilateral electrolytic lesions in either ACe or LZI abolished the retention of conditioned heart rate (HR) responses. In order to determine whether these findings were due to destruction of cells intrinsic to ACe or LZI, ibotenic acid lesions were placed bilaterally in either structure or in control sites. Following recovery, animals were subjected to differential Pavlovian conditioning in which one tone (CS+) was paired with periorbital shock and a second tone (CS−) was presented alone. It was found that destruction of cell bodies in ACe, but not LZI, prevented the acquisition of the differential bradycardiac conditioned response. In addition, ACe lesions did not interfere with baseline HR, the HR orienting response, the HR unconditioned response to shock, or the concomitantly conditioned corneoretinal potential. The results of this study suggest that destruction of cells intrinsic to ACe selectively prevents the acquisition of differentially conditioned HR, and perhaps other conditioned responses related to conditioned arousal, but does not affect unlearned HR responses or specific somatomotor conditioned responses

Glutamate antagonist MK-801 attenuates incomplete but not complete infarction in thrombotic distal middle cerebral artery occlusion in Wistar rats

The purpose of this study was to investigate the effects of a non-competitive N-methyl- d-aspartate antagonist, MK-801, on incomplete infarction (selective neuronal necrosis), a zone of which had been found previously in a thrombotic distal middle cerebral artery (MCA) occlusion model in Wistar rats. Male Wistar rats were treated with 1 mg/kg of MK-801 or saline 30 min before MCA occlusion. Laser irradiation with intravenous administration of Rose Bengal dye was used to cause thrombotic distal MCA occlusion. The ipsilateral common carotid artery was occluded permanently and the contralateral carotid artery for 60 min. Head temperature was controlled at 36°C. Cerebral blood fow (CBF) was determined with laser-Doppler flowmetry. Three days after the ischemic insult, brains were perfusion-fixed and volumes of cortical (complete and incomplete) infarction were determined. There were no significant differences in physiological variables or CBF between the two groups. Volumes of complete infarction were equivalent between the two groups (94.9 ± 15.6 mm 3and91.6 ± 14.0 mm 3 in the control and MK-801 treated groups, respectively). In MK-801 treated group, the volume of incomplete infarction was reduced by 44% (6.4 ± 1.7 mm 3vs3.6 ± 2.1 mm 3 in control and MK-801 treated groups, respectively, P < 0.05). Although the zone responsive to MK-801 was small in this thrombotic MCA occlusion model, our present study revealed that MK-801 has a beneficial effect on the tissue zone containing selective neuronal alterations (incomplete infarction). Our results support the concept that this drug is effective in the area of less severe ischemia

Hypothalamic, midbrain and bulbar areas involved in the defense reaction in rabbits

The present study mapped neuroanatomical sites in the hypothalamus and periaqueductal gray (PAG) of the rabbit which, when stimulated electrically, evoked the cardiorespiratory components of the defense reaction (CRDR). This included increases in heart rate, blood pressure, hindlimb blood flow and respiration rate. All of the components of the CRDR were elicited by electrical stimulation of the posterior hypothalamus, at sites dorsal and medial to the fornix. Although there were regions throughout the PAG in which electrical stimulation elicited concomitant increases in blood pressure, hindlimb blood flow and respiration rate, only stimulation of the dorsal PAG evoked tachycardia. Injection of horseradish peroxidase into the rostral ventrolateral medulla (RVLM) led to heavy retrograde and anterograde labeling in the region of the hypothalamus that yielded the CRDR when stimulated electrically. Heavy labeling was also observed in the dorsal and ventral PAG. The results of this study provide evidence that the posterior hypothalamus and the dorsal PAG are nodal structures in the mediation of the CRDR and that cells in posterior hypothalamus, dorsal PAG and ventral PAG make monosynaptic connections with the RVLM

Sensorimotor and cognitive consequences of middle cerebral artery occlusion in rats

Rats were subjected to either right proximal middle cerebral artery (MCA) occlusion or sham operation, and examined for an extendend period on a battery of tests designed to measure simple motor function, sensorimotor integration and cognitive function. Rats with MCA occlusion showed extensive neuronal loss in the dorsolateral striatum and variable neuron loss in the parietal, temporal and frontolateral neocortex. MCA occluded animals exhibited significant impairments in tests of postural reflex, visual and tactile forelimb placing, locomotor coordination, and a test of simultaneous bilateral tactile extinction. The reflex and sensorimotor function deficits recovered to pre-operative levels by Day 30 post-ischemia. Five weeks following surgery, rats were tested in 2 versions of the Morris water task. Rats with MCA occlusion demonstrated significant impairments in their ability to navigate to a hidden platform, but were not significantly impaired on the visible (cued) version of the task. This general pattern of transient sensorimotor and reflex deficits, but with more persistent cognitive impairments, is similar to that seen in humans following MCA infarct

The Safety Pharmacology Society salary survey

Introduction Safety pharmacology is a growing discipline with scientists broadly distributed across international geographical regions. This electronic salary survey is the first to be distributed amongst the entire Safety Pharmacology Society (SPS) membership. An electronic survey was sent to all members of the Society. Categorical survey questions assessed membership employment types, annual incomes, and professional certifications, along with other associated career attributes. Methods This survey was distributed to the SPS membership that is comprised of safety pharmacologists, toxicologists and pharmacologists working globally in the pharmaceutical industry, at contract research organizations (CRO), regulatory agencies, and academia or within the technology provider industry. The survey was open for responses from December 2015 to March 2016. Results The survey response rate was 28% (129/453). North America (68%) was the region with the largest number of respondents followed by Europe (28%). A preponderance of respondents (77%) had 12 years of industry experience or more. 52% of responders earned annually between $40,000 and$120,000. As expected, salary was generally positively correlated with the number of years of experience in the industry or the educational background but there was no correlation between salary and the number of employee's directly supervised. The median salary was higher for male vs female respondents, but so was median age, indicative of no gender ‘salary gap’. Discussion Our 2016 SPS salary survey results showcased significant diversity regarding factors that can influence salary compensation within this discipline. These data provided insights into the complex global job market trends. They also revealed the level of scientific specialization embedded within the organization, presently uniquely positioned to support the dynamic career paths of current and future safety pharmacologists

MLi-2, a Potent, Selective, and Centrally Active Compound for Exploring the Therapeutic Potential and Safety of LRRK2 Kinase Inhibition s

ABSTRACT Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of familial and sporadic Parkinson&apos;s disease (PD). That the most prevalent mutation, G2019S, leads to increased kinase activity has led to a concerted effort to identify LRRK2 kinase inhibitors as a potential disease-modifying therapy for PD. An internal medicinal chemistry effort identified several potent and highly selective compounds with favorable drug-like properties. Here, we characterize the pharmacological properties of cis-2,6-dimethyl-4-(6-(5-(1-methylcyclopropoxy)-1H-indazol-3-yl)pyrimidin-4-yl)morpholine (MLi-2), a structurally novel, highly potent, and selective LRRK2 kinase inhibitor with central nervous system activity. MLi-2 exhibits exceptional potency in a purified LRRK2 kinase assay in vitro (IC 50 5 0.76 nM), a cellular assay monitoring dephosphorylation of LRRK2 pSer935 LRRK2 (IC 50 5 1.4 nM), and a radioligand competition binding assay (IC 50 5 3.4 nM). MLi-2 has greater than 295-fold selectivity for over 300 kinases in addition to a diverse panel of receptors and ion channels. Acute oral and subchronic dosing in MLi-2 mice resulted in dosedependent central and peripheral target inhibition over a 24-hour period as measured by dephosphorylation of pSer935 LRRK2. Treatment of MitoPark mice with MLi-2 was well tolerated over a 15-week period at brain and plasma exposures .100Â the in vivo plasma IC 50 for LRRK2 kinase inhibition as measured by pSer935 dephosphorylation. Morphologic changes in the lung, consistent with enlarged type II pneumocytes, were observed in MLi-2-treated MitoPark mice. These data demonstrate the suitability of MLi-2 as a compound to explore LRRK2 biology in cellular and animal models