LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress

Metabotropic glutamate (mGlu) receptors, which include mGlu1-8 receptors, are a heterogeneous family of G-protein coupled receptors (GPCRs) that function to modulate neuronal excitation and plasticity via pre-synaptic, post-synaptic and glial mechanisms. Agonists for group II mGlu receptors (mGlu2 and mGlu3), such as LY354740, have been shown to suppress enhanced glutamatergic excitations in brain synapses known to be involved in the expression of fear/anxiety in animals and humans. Systemic administration of LY354740 increases open-arm time in the elevated plus maze in mice under conditions of moderate to severe stress, blocks the expression but not development of fear-potentiated startle in rats, prevents lactate-induced panic-like responses in panic-prone rats, and attenuates certain physiological, behavioral, and neurochemical consequences of acute stress in rodents. In these preclinical models, LY354740 does not produce the side-effects (e.g. sedation) that are associated with other anxiolytic agents such as benzodiazepines. Early clinical results with LY354740 have demonstrated safety and efficacy in a human anxiety model (panic provocation induced by CO2 challenge). Collectively, these data indicate mGlu2/3 receptor agonists such as LY354740 represent a promising new approach for treatment of anxiety and stress-related disorders in humans.     

Eugenol as an anti-stress agent: modulation of hypothalamic-pituitary-adrenal axis and brain monoaminergic systems in a rat model of stress

Stress is the leading psychopathological cause for several mental disorders. Physiological and psychological responses to stress are mediated by the hypothalamic?pituitary?adrenal (HPA), sympathoadrenal system (SAS), and brain monoaminergic systems (BMS). Eugenol is reported to substantially modulate brain functions by regulating voltage-gated cation channels and release of neurotransmitters. This study was designed to evaluate the anti-stress effect of eugenol in the 4-h restraint model using rats. Ulcer index was measured as a parameter of the stress response. HPA axis and the SAS were monitored by estimating plasma corticosterone and norepinephrine (NE), respectively. Analysis of NE, serotonin (5-HT), dopamine, and their metabolites in discrete brain regions was performed to understand the role of BMS in the anti-stress effect of eugenol. Stress exposure increased the ulcer index as well as plasma corticosterone and NE levels. Eugenol pretreatment for 7 days decreased the stress-induced increase in ulcer index and plasma corticosterone but not NE levels, indicating a preferential effect on the HPA axis. Furthermore, eugenol showed a ?U?-shaped dose?response curve in decreasing ulcer index and plasma corticosterone levels. Eugenol also reversed the stress-induced changes in 5-HT levels in all brain regions, whereas NE levels were reversed in all brain regions except hippocampus. These results suggest that eugenol possesses significant anti-stress activity in the 4-h restraint model and the effect is due to modulation of HPA and BMS.     

Effects of toe length,foot arch length and toe joint axis on walking biomechanics

Toe joint articulation has been shown to affect gait mechanics, as evidenced by walking simulations, biped robots, and foot prostheses. However, it is not known how parameters such as toe length, foot arch length (i.e., heel-to-toe-joint length) or toe joint axis angle affect human walking. We utilized a previously developed adjustable ankle-toe prosthesis to systematically examine these three foot parameters. We tested ten able-bodied persons walking on a force instrumented-treadmill while wearing a pair of adjustable prostheses attached bilaterally below simulator boots (which fixated their biological ankles). We collected motion and ground reaction force data to compute lower-limb kinematics and kinetics as well as COM power and work. We observed that increasing the foot arch length by 60 mm (35%) increased COM Push-off work by ~5 J, due to increased energy storage and return by the ankle spring. Increasing the toe length by 40 mm (80%) and changing the toe joint axis by ±9° from a neutral angle resulted in negligible effects on COM mechanics and lower limb kinetics. This study provides further insights regarding toe joint function; knowledge which may benefit the design/integration of toe joints into prostheses, exoskeletons and legged robots.     

Effects of (+) SKF 10,047, a sigma-1 receptor agonist, on anxiety,tested in two laboratory models in mice

Recently, sigma-1 receptor modulators have been considered drugs with an interesting therapeutic potential for the treatment of anxiety. However, there is no clear information in preclinical studies about the possible effects of sigma-1 ligands on anxiety in experimental animal models. Therefore, the present study examined the effects of (+)SKF 10,047 (2-8 mg/kg, ip), a sigma-1 agonist, on anxiety, tested in two classical laboratory models (social interaction test and elevated plus maze). (+)SKF 10,047 (8 mg/kg) produced a significant decrease of social investigation in the "social interaction test", whereas in the "elevated plus maze", the drug (4 and 8 mg/kg) provoked a significant reduction in the number of entries into open arms, as well as in the time spent in this area, as compared with the control group, without affecting motor activity. Overall, these findings indicate that (+)SKF 10,047 exhibits an anxiogenic-like profile in mice. It is suggested that anxiogenic effects of this sigma-1 ligand could be related to its potent ability to modulate diverse neurotransmitter systems involved in anxiety regulation.     

Effects of smoking and nicotine on EEG lateralization as a function of personality

The effects of nicotine/smoking on lateralization of the EEG were evaluated in 40 smokers while they responded to a low-stress, visual vigilance task. Smoking a high-nicotine cigarette was associated with a relatively larger increase in right hemisphere EEG arousal in extraverts and Type-A individuals, but with a relatively larger increase in left hemisphere EEG arousal in introverts and Type Bs. These findings suggest that nicotine/smoking may differentially influence the left and right hemispheres and that this interaction may be a function of personality.     

Effects of hypertension on attention, memory, and executive function in older adults.

Hypertension is associated with impairments in cognitive function in older adults, but the nature and extent of these deficits are unclear. Brief cognitive measures lack sensitivity, whereas comprehensive assessments produce numerous variables that are difficult to interpret. The authors performed a principal-components analysis using a computerized cognitive assessment battery and neuropsychological measures of executive function in 506 hypertensive and normotensive older participants. Composite factor scores were used to reanalyze data from 223 untreated participants without vascular complications. The hypertensive group had deficits in Speed of Cognition, Episodic and Working Memory, and Executive Function but not Continuity of Attention. Using composite scores simplified data interpretation and suggested differential effects of hypertension on cognitive performance not clearly evident in individual test results.     

Effects of ontogeny on performance of rats in a novel object-recognition task

The current experiment investigated ontogenetic forgetting on a novel object-recognition task similar to that of Besheer and Bevins. 18-day-old pups (n = 49) and adult (n = 29) rats were tested at two retention intervals (1 min. or 120 min.). By employing exclusion criteria which demanded minimum amounts of object exploration at training and test, the performance of 18-day-old pups but not that of adults was significantly impaired at 120 min. relative to 1 min. Analysis indicated that the ontogeny of the learning and memory measured in novel object recognition follows a developmental trend similar to that of other forms of learning, with older animals remembering more and thus performing better than younger animals. Unfortunately, given the extreme variability inherent to the task and large N necessary to achieve significance, the use of this task in studies of learning, memory, and development is discouraged.     

The effect of cholinergic, GABAergic, serotonergic, and glutamatergic receptor modulation on posttrial memory processing in the hippocampus

Though the hippocampus is widely recognized as important in learning and memory, most of the evidence for this comes from animal lesion and human pathological studies. Due to the relatively small number of drugs that have been tested in the hippocampus for their ability to alter posttrial memory processing, there is a general impression that memory processing involves only a few neurotransmitters. We have evaluated the effects of cholinergic, GABAergic, serotonergic, and glutamatergic receptor agonists and antagonists for their ability to facilitate or impair retention. CD-1 mice received acute intrahippocampal drug infusion following footshock avoidance training in a T-maze. Retention was tested 1 week after training and drug administration. The results indicate that receptor agonists of acetylcholine and glutamate improved retention, while antagonists impaired retention. However, scopolamine did not impair retention, but M1 and M2 antagonists did. Receptor agonists of serotonin and GABA impaired retention, while antagonists improved retention. Drugs acting on 5-HT-1 and 5-HT-2 as well as GABA(A) and GABA(B) receptor subtypes did not differentially effect retention.     

Effects of a 12-month pedometer walking program on gait, body mass index, and lower extremity function in obese women

This study evaluated the effects of a self-reported pedometer-walking program on gait, lower extremity function, and Body Mass Index for 33 obese women, ages 31-65 years (M = 48.0, SD = 8.0) and whose initial average Body Mass Index was 40.30 +/- 9.60 kg/m2. During the 12-mo. intervention participants wore pedometers and reported the number of daily steps walked. Body Mass Index, three gait parameters, steps/day, and lower extremity function were taken over 3-mo. intervals. All participants increased in gait velocity, % single-leg support, and lower extremity function, and decreased in Body Mass Index over time. Those whose steps/day increased by 2000 over 6 mo. had significantly faster velocities and longer step lengths than those whose steps/day did not increase. The 1-yr. walking program stimulated changes in gait, Body Mass Index, and lower extremity function for these obese women. Ultimately, these changes may reduce the risk of falls for this group of women.     

Effects of reinforcer delays on choice as a function of income level

Three rats earned their daily food ration by responding during individual trials either on a lever that delivered one food pellet immediately or on a second lever that delivered three pellets after a delay that was continuously adjusted to ensure substantial responding to both alternatives. Choice of the delayed reinforcer increased when the number of trials per session was reduced. This result suggests that models seeking closure on choice effects must include a parameter reflecting how preference changes with sessionwide income. Moreover, models positing that reinforcer probability and immediacy (1/delay) function equivalently in choice are called into question by the finding that probability and immediacy produce opposing effects when income level is changed.     

Effects of medetomidine, an alpha-2 adrenoceptor agonist, and atipamezole, an alpha-2 antagonist, on spatial memory performance in adult and aged rats.

The effects of a novel, highly selective alpha-2 agonist, medetomidine, and its antagonist, atipamezole, were studied on the working memory of rats performing a spatial delayed alternation task. Testing was performed in two stages, at the age of 8.3 months (mean) and again when the rats were 17.6 months (mean). A low dose (3 micrograms/kg) and a high dose (30 micrograms/kg) of medetomidine improved the performance of the old rats in the memory task but had no effect on the young rats. The dose-response curve of medetomidine resembles that of guanfacine, another alpha-2 agonist. At the low dose of medetomidine (3 micrograms/kg) the animals showed no signs of sedation. Since medetomidine even at a low dose has a beneficial effect on the memory performance of old rats, it could be a good candidate for the treatment of age-associated memory dysfunction.     

The communicative functions of touch in humans, nonhuman primates, and rats: a review and synthesis of the empirical research

Although touch is one of the most neglected modalities of communication, several lines of research bear on the important communicative functions served by the modality. The authors highlighted the importance of touch by reviewing and synthesizing the literatures pertaining to the communicative functions served by touch among humans, nonhuman primates, and rats. In humans, the authors focused on the role that touch plays in emotional communication, attachment, bonding, compliance, power, intimacy, hedonics, and liking. In nonhuman primates, the authors examined the relations among touch and status, stress, reconciliation, sexual relations, and attachment. In rats, the authors focused on the role that touch plays in emotion, learning and memory, novelty seeking, stress, and attachment. The authors also highlighted the potential phylogenetic and ontogenetic continuities and discussed suggestions for future research.     

Effects of distance between objects and distance from the vertical axis on shape identity judgments

In three experiments, we independently manipulated the angular disparity between objects to be compared and the angular distance between the central axis of the objects and the vertical axis in a mental rotation paradigm. There was a linear increase in reaction times that was attributable to both factors. This result held whether the objects were rotated (with respect to each other and to the upright) within the frontal-parallel plane (Experiment 1) or in depth (Experiment 2), although the effects of both factors were greater for objects rotated in depth than for objects rotated within the frontal-parallel plane (Experiment 3). In addition, the factors interacted when the subjects had to search for matching ends of the figures (Experiments 1 and 2), but they were additive when the ends that matched were evident (Experiment 3). These data may be interpreted to mean that subjects normalize or reference an object with respect to the vertical upright as well as compute the rotational transformations used to determine shape identity.     

Effects of concurrent monitoring on cognitive load and performance as a function of task complexity

For self‐regulated learning to be effective, students or trainees need to be able to accurately monitor their performance while they are working on a task, use the outcomes as input for self‐assessment of that performance after completing the task and select an appropriate new learning task in response to that assessment. From a cognitive load perspective, monitoring can be seen as a secondary task that may become hard to maintain and hamper performance on the primary task under high load conditions. The experiment presented here investigated the effects of concurrent performance monitoring on cognitive load and performance as a function of task complexity. Results showed that monitoring significantly decreased performance and increased cognitive load on complex, but not on simple tasks. The findings are discussed in terms of theoretical consequences and instructional design for self‐regulated learning. Copyright © 2010 John Wiley & Sons, Ltd.     

Effects of social and intellectual instruction on achievement motivation as a function of role orientation

University women preselected for traditionality of role orientation were administered a task described as a test either of intelligence or social skills. Results generally supported the hypothesis that instructions interact with a women's role orientation in determining both her achievement motivation, as measured projectively, and her performance. Differences in motivation and performance were interpreted in terms of women's definitions of appropriate achievement situations. Nontraditional women displayed achievement motivation on a projective measure under standard intellectual arousal conditions. Traditionally role-oriented women displayed greater achievement motivation under affiliative arousal conditions. The importance of measuring achievement in traditionally feminine areas, in addition to more traditionally masculine intellectual achievement, was stressed.Portions of this research were included in a thesis submitted by the first author in partial fulfillment of the requirements for the M.A. degree at the University of Illinois at Chicago Circle.     

Localization of electrocutaneous stimuli on the fingers and forearm: Effects of electrode configuration and body axis

Four experiments were done on the effects of electrode configuration (concentric vs. unifocal) and body axis (longitudinal vs. transverse) on localization of electrocutaneous pulse stimuli at the fingers and forearm. Subjects pointed to the apparent location of current pulses. For the transverse placement of electrodes, pulses were localized correctly, whatever the configuration and the body site might be. In addition, intrasubject variability at the forearm was smaller for the transverse axis than for the longitudinal axis. For the longitudinal placement of electrodes, pulses were localized as a function of configuration and body site. At the fingers, concentric electrodes provided precise localization but unifocal electrodes provided a great mislocalization; and intrasubject variability of localization was larger for the unifocal electrodes than for the concentric electrodes. At the forearm, whatever the configuration might be, the pulses were localized more proximally than the stimulus site; and intrasubject variability of localization did not differ between the configurations. These results are related to Boring’s anchor theory, apparent distance between two points, and the localization of other somatosensory stimuli.