Search

Context: Motorized treadmills (MTs) present an altered motor task compared to overground (OG) locomotion in that MT belt surfaces are motor-driven, whereas individuals walking/running OG must propel themselves. A possible solution may lie with novel nonmotorized treadmill (NMT) devices as the belt surface is propelled by the user. Objective: The purpose of this study was to compare gait performance during both MT and NMT locomotion to OG. Design: Crossover study. Setting: A university research laboratory. Patients: A total of 20 healthy adults (10 women) participated in the study. Intervention: Each participant performed self-selected walking and running OG, and on both an MT and NMT. Main Outcome Measure: Shoulder, trunk, and lower-extremity kinematics were analyzed for each treadmill condition and compared to OG. Results: The analyses demonstrated that there were no differences between MT and OG gait kinematics during either walking or running. However, NMT gait showed increased hip, knee, and ankle flexions in late swing and early stance compared to OG during both walking and running. For example, during walking, the NMT elicited hip-, knee-, and ankle-flexion/extension angles of 34.7°, 8.0°, and 3.6° at foot strike compared to 24.8°, −3.1°, and −5.8° in the OG condition (P Conclusions: These differences may have implications for both training and rehabilitation on an NMT. Future studies should consider the influence of NMT familiarization on gait performance and should emphasize the assessment of neuromuscular performance.

There is a growing understanding that aberrant GLIA function is an underlying factor in psychiatric and neurological disorders. As drug discovery efforts begin to focus on glia-related targets, a key gap in knowledge includes the availability of validated biomarkers to help determine which patients suffer from dysfunction of glial cells or who may best respond by targeting glia-related drug mechanisms. Biomarkers are biological variables with a significant relationship to parameters of disease states and can be used as surrogate markers of disease pathology, progression, and/or responses to drug treatment. For example, imaging studies of the CNS enable localization and characterization of anatomical lesions without the need to isolate tissue for biopsy. Many biomarkers of disease pathology in the CNS involve assays of glial cell function and/or response to injury. Each major glia subtype (oligodendroglia, astroglia and microglia) are connected to a number of important and useful biomarkers. Here, we describe current and emerging glial based biomarker approaches for acute CNS injury and the major categories of chronic nervous system dysfunction including neurodegenerative, neuropsychiatric, neoplastic, and autoimmune disorders of the CNS. These descriptions are highlighted in the context of how biomarkers are employed to better understand the role of glia in human CNS disease and in the development of novel therapeutic treatments. GLIA 2016;64:1755-1771.

To date, biomechanical analyses of soccer kicking have focused predominantly on lower-extremity motions, with little emphasis on the trunk and upper body. The purpose of this study was to evaluate differences in trunk axial kinematics between novice (n = 10) and skilled (n = 10) participants, as well as to establish the relationship of trunk axial motion and sagittal plane thigh rotation to poststrike ball velocity. Three-dimensional body segmental motion data were captured using high-resolution motion analysis (120 Hz) while each participant completed 5 maximal instep soccer-style kicks. The results demonstrate that skilled participants use 53% greater axial trunk range of motion compared with novice participants (P < .01), as well as 62% greater peak trunk rotation velocity (P < .01). The results also show a moderate, positive correlation of peak trunk rotation velocity with poststrike ball velocity (r = .57; P < .01), and peak hip flexion velocity with poststrike ball velocity (r = .63; P < .01). The current study highlights the potential for trunk rotation-specific training to improve maximum instep kick velocity in developing soccer athletes.

Kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the kynurenine pathway, was identified as a potential therapeutic target for treating neurodegenerative and psychiatric disorders. In this article, we describe a surface plasmon resonance (SPR) assay that delivers both kinetics and the mechanism of binding (MoB) data, enabling a detailed characterization of KMO inhibitors for the enzyme in real time. SPR assay development included optimization of the protein construct and the buffer conditions. The stability and inhibitor binding activity of the immobilized KMO were significantly improved when the experiments were performed at 10°C using a buffer containing 0.05% n-dodecyl-β-d-maltoside (DDM) as the detergent. The KD values of the known KMO inhibitors (UPF648 and RO61-8048) from the SPR assay were in good accordance with the biochemical LC/MS/MS assay. Also, the SPR assay was able to differentiate the binding kinetics (k(a) and k(d)) of the selected unknown KMO inhibitors. For example, the inhibitors that showed comparable IC50 values in the LC/MS/MS assay displayed differences in their residence time (τ = 1/k(d)) in the SPR assay. To better define the MoB of the inhibitors to KMO, an SPR-based competition assay was developed, which demonstrated that both UPF648 and RO61-8048 bound to the substrate-binding site. These results demonstrate the potential of the SPR assay for characterizing the affinity, the kinetics, and the MoB profiles of the KMO inhibitors.

Kynurenic acid (KYNA) plays a significant role in maintaining normal brain function, and abnormalities in KYNA levels have been associated with various central nervous system disorders. Confirmation of its causality in human diseases requires safe and effective modulation of central KYNA levels in the clinic. The kynurenine aminotransferases (KAT) II enzyme represents an attractive target for pharmacologic modulation of central KYNA levels; however, KAT II and KYNA turnover kinetics, which could contribute to the duration of pharmacologic effect, have not been reported. In this study, the kinetics of central KYNA-lowering effect in rats and nonhuman primates (NHPs, Cynomolgus macaques) was investigated using multiple KAT II irreversible inhibitors as pharmacologic probes. Mechanistic pharmacokinetic-pharmacodynamic analysis of in vivo responses to irreversible inhibition quantitatively revealed that 1) KAT II turnover is relatively slow [16-76 hours' half-life (t1/2)], whereas KYNA is cleared more rapidly from the brain (

The elevation of kynurenic acid (KYNA) observed in schizophrenic patients may contribute to core symptoms arising from glutamate hypofunction, including cognitive impairments. Although increased KYNA levels reduce excitatory neurotransmission, KYNA has been proposed to act as an endogenous antagonist at the glycine site of the glutamate NMDA receptor (NMDAR) and as a negative allosteric modulator at the α7 nicotinic acetylcholine receptor. Levels of KYNA are elevated in CSF and the postmortem brain of schizophrenia patients, and these elevated levels of KYNA could contribute to NMDAR hypofunction and the cognitive deficits and negative symptoms associated with this disease. However, the impact of endogenously produced KYNA on brain function and behavior is less well understood due to a paucity of pharmacological tools. To address this issue, we identified PF-04859989, a brain-penetrable inhibitor of kynurenine aminotransferase II (KAT II), the enzyme responsible for most brain KYNA synthesis. In rats, systemic administration of PF-04859989 dose-dependently reduced brain KYNA to as little as 28% of basal levels, and prevented amphetamine- and ketamine-induced disruption of auditory gating and improved performance in a sustained attention task. It also prevented ketamine-induced disruption of performance in a working memory task and a spatial memory task in rodents and nonhuman primates, respectively. Together, these findings support the hypotheses that endogenous KYNA impacts cognitive function and that inhibition of KAT II, and consequent lowering of endogenous brain KYNA levels, improves cognitive performance under conditions considered relevant for schizophrenia.

Recently, there has been a growth in the popularity of resistance exercises performed on unstable surfaces. However, the relationship between unstable surface training and load coupling on muscle activation is unclear. The purpose of this study was to evaluate changes in muscle activation during a barbell (BB) (coupled) and dumbbell (DB) (uncoupled) chest press exercise performed on an unstable surface. The 3 specific chest press conditions included 50% 1 repetition maximum (RM) with BB (50% BB), 50% 1RM with DBs (50% DB), and 25% 1RM with DBs (25% DB). Ten male subjects participated in the study (age, 23.9 ± 2.6 years; body weight, 82.8 ± 10.2 kg). During testing, mean electromyographic activity was assessed for pectoralis major (PM), triceps brachii, anterior deltoid (AD), and rectus abdominis (RA) and was presented as a percent change across the lifting conditions. It was observed that muscle activation increased by 15% in both the PM and RA from the 50% BB condition to the 50% DB condition. Also, the greatest percent difference in muscle activation between the 50 and 25% DB conditions occurred for PM and AD (+54% during 50% DB). These results suggest that demands on the core musculature to provide stability are increased with the use of DBs (uncoupled) as opposed to a BB (coupled). Where instability training provides a sufficient hypertrophy stimulus in prime mover muscle groups, there may be the added benefit of core stability training. Specifically, this type of training may benefit both untrained persons and those engaged in active rehabilitation.

Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5) have been actively pursued for over a decade as a potential treatment for anxiety, depression, substance abuse, pain, levodopa-induced dyskinesia in Parkinson’s disease, fragile X Syndrome, autism, gastroesophageal reflux disease and lower-urinary-tract disorders. This article begins with an introduction of preclinical validation of potential therapies for psychiatric and neurological disorders, and of clinical results, followed by a comprehensive overview of the mGlu5-negative allosteric modulator patent applications published between 2009 and July 2013, with a focus on the analysis of structure and in silico CNS drug-like properties of example compounds and disclosed data. Given positive results in proof-of-concept studies in humans for certain indications such as levodopa-induced dyskinesia in Parkinson’s disease, fragile X Syndrome, gastroesophageal reflux disease, migraine and anxiety, and the soaring chemical diversity among the mGlu5-negative allosteric modulators, there is reason to believe that a drug will emerge from this therapeutic class in the near future.

Minocycline, a second generation broad-spectrum antibiotic, has been frequently postulated to be a "microglia inhibitor." A considerable number of publications have used minocycline as a tool and concluded, after achieving a pharmacological effect, that the effect must be due to "inhibition" of microglia. It is, however, unclear how this "inhibition" is achieved at the molecular and cellular levels. Here, we weigh the evidence whether minocycline is indeed a bona fide microglia inhibitor and discuss how data generated with minocycline should be interpreted. GLIA 2016;64:1788-1794.

A series of aryl hydroxamates recently have been disclosed as irreversible inhibitors of kynurenine amino transferase II (KAT II), an enzyme that may play a role in schizophrenia and other psychiatric and neurological disorders. The utilization of structure-activity relationships (SAR) in conjunction with X-ray crystallography led to the discovery of hydroxamate 4, a disubstituted analogue that has a significant potency enhancement due to a novel interaction with KAT II. The use of k inact/K i to assess potency was critical for understanding the SAR in this series and for identifying compounds with improved pharmacodynamic profiles.

Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT II. An X-ray crystal structure and (13)C NMR studies of PF-04859989 bound to KAT II have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure-activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors.

Sponsored by the New York Academy of Sciences and with support from the National Institute of Mental Health, the Life Technologies Foundation, and the Josiah Macy Jr. Foundation, “Advancing Drug Discovery for Schizophrenia” was held March 9–11 at the New York Academy of Sciences in New York City. The meeting, comprising individual talks and panel discussions, highlighted basic, clinical, and translational research approaches, all of which contribute to the overarching goal of enhancing the pharmaceutical armamentarium for treating schizophrenia. This report surveys work by the vanguard of schizophrenia research in such topics as genetic and epigenetic approaches; small molecule therapeutics; and the relationships between target genes, neuronal function, and symptoms of schizophrenia.

The purpose of this study was to determine the concurrent validity of a new bench press power (BPP) test using the medicine ball put (MBP) as the criterion measure. Forty-three college-age students (19 males and 24 females) participated in the study. Participants performed 1 repetition at maximum speed using 61.4 kg (males) and 25 kg (females), at a grip width of 130% of biacromial breadth. Timing was initiated manually at the moment of upward bar movement and stopped automatically as the bar broke an infrared beam 0.3 m above the chest. All tests were conducted within 2 weeks. There was 1 practice session for the BPP test and 2 separate testing sessions, one for BPP and the other for the MBP. Three BPP trials were separated by >or=2 minutes of passive recovery. Individual scores were the average of the second and third tests and were expressed in Watts: Power=Bar mass kg.9.81x0.3 m/s. Medicine ball put scores were the average distance the ball was thrown on the second and third trials from a sitting position on a 45 degrees recumbent weight bench. Concurrent validity was determined by conducting a Pearson Correlation on BPP and MBP scores at an alpha level of 0.05: males, r=0.861; females, r=0.79, (p

Compounds that are both norepinephrine reuptake inhibitors (NRI) and 5-HT1(A) partial agonists may have the potential to treat neuropsychiatric disorders including attention deficit hyperactivity disorder (ADHD) and depression. Targeted screening of NRI-active compounds for binding to the 5-HT(1A) receptor provided a series of thiomorpholinone hits with this dual activity profile. Several iterations of design, synthesis, and testing led to substituted piperidine diphenyl ethers which are potent NRIs with 5-HT1(A) partial agonist properties. In addition, optimization of these molecules provided compounds which exhibit selectivity for NRI over the dopamine (DAT) and serotonin (SERT) reuptake transporters. Monoamine and 5-HT(1A) in vitro functional activities for select compounds from the developed piperidine diphenyl ether series are also presented.

The discovery of the CNS-penetrant and selective α 2C adrenergic receptor antagonist N -{2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-[1,4]diazepan-1-yl]-ethyl}-2-phenoxy-nicotinamide, 13 is described. Structure–activity studies demonstrate the structural requirements for binding affinity, functional activity, and selectivity over other α 2 -AR subtypes.

Strength and conditioning professionals, as well as coaches, have emphasized the importance of training the trunk and the benefits it may have on sport performance and reducing the potential for injury. However, no data on the efficacy of trunk training support such claims. The purpose of this study was to examine the maximum differential trunk rotation and maximum angular velocities of the pelvis and upper torso of participants while they performed 4 trunk exercises (seated band rotations, cross-overs, medicine ball throws, and twisters) and compare these trunk exercise kinematics with the trunk kinematics demonstrated in actual throwing performance. Nine NCAA Division I baseball players participated in this study. Each participant's trunk kinematics was analyzed while he performed 5 repetitions of each exercise in both dominant and nondominant rotational directions. Results indicated maximum differentiated rotation in all 4 trunk exercises was similar to maximum differentiated rotation (approximately 50-60 degrees) demonstrated in throwing performance. Maximum angular velocities of the pelvis and upper torso in the trunk exercises were appreciably slower (approximately 50% or less) than the angular velocities demonstrated during throwing performance. Incorporating trunk training exercises that demonstrate sufficient trunk ranges of motion and velocities into a strength and conditioning program may help to increase ball velocity and/or decrease the risk injury.

In the last ~30 years, scientists have made great strides in understanding the biological function of group I metabotropic glutamate receptors (mGlu) in health and disease, as well as developing a broad array of potent and selective agents able to activate or inhibit these receptors. This article provides a comprehensive review of the most recent group I mGlu modulators published in patent and non-patent literatures from 2014 to May, 2015, including design, structure-activity relationship, in silico, in vitro and in vivo properties of key compounds. The current status of clinical mGlu5 negative allosteric modulators (NAMs) and the development of mGlu1 and mGlu5 PET ligands are also highlighted. While the therapeutic potential for group I mGlu modulating agents appears high, significant challenges remain. Strategies to reduce clinical development risks and mitigate important side effects, including psychotomimetic events observed with several mGlu5 NAMs and cellular toxicity associated with mGlu5 positive allosteric modulators (PAMs), while retaining therapeutic efficacy through approaches such as biased ligand signaling are discussed.

Context:Functional knee braces (FKB) are used prophylactically and in rehabilitation to aide in the functional stability of the knee.Objective:To determine if alterations in select lower extremity moments persist throughout a one hour period in healthy individuals.Design:2X5 repeated measures design.Setting:Biomechanics Laboratory.Subjects:Twenty subjects (14 male and 6 female, mean age 26.5±7 yrs; height 172.4±13 cm; weight 78.6±9 kg), separated into braced (B) and no brace (NB) groups.Intervention:A one-hour exercise program divided into three 20 minute increments.Main Outcome Measures:Synchronized three-dimensional kinematic and kinetic data were collected at 20-minute increments to assess the effect of the FKB on select lower extremity moments and vertical ground reaction forces.Results:Increase in hip moment and a decrease in knee moment were noted immediately after brace application and appeared to persist throughout a one hour bout of exercise.Conclusions:The FKB and the exercise intervention caused decreases in knee joint moments and increases in hip joint moments.

Context:Closed kinetic chain exercises are reported to provide a more functional rehabilitation outcome.Objective:To determine the amount of muscle activity in 4 shoulder muscles during exercise on the Cuff Link.Design:Repeated measures.Setting:Laboratory.Subjects:10 men and 10 women, age 18–50.Intervention:Subjects performed 3 sets of 5 revolutions on the Cuff Link in non-weight-bearing, partial-weight-bearing, and full-weight-bearing positions.Main Outcome Measures:Electromyography data were collected from the upper trapezius, anterior deltoid, serratus anterior, and pectoralis major and were expressed as percentage of maximal isometric contractions.Results:Significant differences were found across the weight-bearing conditions for all 4 muscles. Exercise on the Cuff Link required minimal to significant amounts of muscle recruitment.Conclusions:Muscle recruitment increases as weight bearing increases during use of the Cuff Link, suggesting an increase in dynamic stabilization of the glenohumeral joint.

The developing prefrontal cortex receives a dense serotonergic innervation, yet little is known about the actions of serotonin [5-Hydroxytryptamine (5-HT)] in this region during development. Here, we examined the developmental regulation of 5-HT receptors controlling the excitability of pyramidal neurons of this region. Using whole-cell recordings inin vitrobrain slices, we identified a dramatic shift in the effects of 5-HT on membrane potential during the postnatal developmental period. In slices derived from young animals [postnatal day (P) 6 to P19], administration of 5-HT elicits a robust depolarization of layer V pyramidal neurons, which gradually shifts to a hyperpolarization commencing during the third postnatal week. This progression is the result of coordinated changes in the function of 5-HT7and 5-HT2Areceptors, which mediate different aspects of the depolarization, and of 5-HT1Areceptors, which signal the late developing hyperpolarization. The loss of the 5-HT7receptor-mediated depolarization and the appearance of the 5-HT1Areceptor-mediated hyperpolarization appears to reflect changes in receptor expression. In contrast, the decline in the 5-HT2Areceptor depolarization with increasing age was associated with changes in the effectiveness with which these receptors could elicit a membrane depolarization, rather than loss of the receptors per se. Together, these results outline coordinated changes in the serotonergic regulation of cortical excitability at a time of extensive synaptic development and thus suggest a key role for these receptor subtypes in the postnatal development of the prefrontal cortex.

In recent years, the role of kynurenine and its neuroactive metabolites as they relate to human disease has been intensely studied. Though much work has focused on kynurenine metabolism in neurodegenerative diseases, it is becoming clear that disruption of this pathway can have profound behavioral effects that are also relevant for neuropsychiatric indications. The following chapter will review both preclinical and clinical studies where kynurenine and its most abundant metabolic products were evaluated in relation to a range of highly prevalent neuropsychiatric disorders including schizophrenia, depression, and ADHD. Each section will summarize the kynurenine disruptions thought to be associated with a particular disorder, discuss the functional consequences of these effects, and speculate on means to improve unmet medical needs through manipulation of the kynurenine pathway.

Recently, there has been a growth in the popularity of resistance exercises performed on unstable surfaces. However, the relationship between unstable surface training and load coupling on muscle activation is unclear. The purpose of this study was to evaluate changes in muscle activation during a barbell (BB) (coupled) and dumbbell (DB) (uncoupled) chest press exercise performed on an unstable surface. The 3 specific chest press conditions included 50% 1 repetition maximum (RM) with BB (50% BB), 50% 1RM with DBs (50% DB), and 25% 1RM with DBs (25% DB). Ten male subjects participated in the study (age, 23.9 ± 2.6 years; body weight, 82.8 ± 10.2 kg). During testing, mean electromyographic activity was assessed for pectoralis major (PM), triceps brachii, anterior deltoid (AD), and rectus abdominis (RA) and was presented as a percent change across the lifting conditions. It was observed that muscle activation increased by 15% in both the PM and RA from the 50% BB condition to the 50% DB condition. Also, the greatest percent difference in muscle activation between the 50 and 25% DB conditions occurred for PM and AD (+54% during 50% DB). These results suggest that demands on the core musculature to provide stability are increased with the use of DBs (uncoupled) as opposed to a BB (coupled). Where instability training provides a sufficient hypertrophy stimulus in prime mover muscle groups, there may be the added benefit of core stability training. Specifically, this type of training may benefit both untrained persons and those engaged in active rehabilitation.

We have utilized an organotypic slice culture system to determine factors which directly influence the expression of striatal preprotachykinin (PPT) mRNA. Striatal slices were generated from 3-day-old male rat pups and cultured on Millicell-CM inserts in serum-containing media. Under these conditions, striatal PPT mRNA levels fell significantly (-55.7+/-6.2%) in slices cultured for 2 days in vitro (2DIV) as compared to slices placed in culture for 3 h (0DIV). However, striatal PPT mRNA expression did not decline further in 4DIV cultured slices (-59.6+/-7.1%). When 2DIV slices were exposed to combined high potassium (K(+), 10 mM) and forskolin (10 microM) stimulation for 3 h, PPT mRNA levels were increased within areas of the brain normally associated with tachykinin production. Application of the dopamine (DA) D1 receptor agonist SKF-38393 (10 microM) at 2DIV for 3 h also increased (+162.9+/-28.9%) PPT mRNA expression, but increases were localized within the striatum. SKF-38393-stimulated increases were completely blocked by the D1 antagonist SCH-23390 (10 microM), which alone had no effect on mRNA levels. However, a 3-h incubation with SKF-38393 on 0DIV slice cultures did not affect PPT mRNA expression whereas SCH-23390 decreased PPT message levels (-24.5+/-5.4%). These findings indicate that tachykinin gene expression is inducible within slice culture preparations and that the maintenance of normal striatal PPT mRNA levels depends on DA D1 receptor tone.

Several clinical observations point to a role of chronic inflammation in the progression of major depressive disorder. Attention is therefore shifting away from drugs that regulate monoamines to interventions that normalize an imbalance of inflammatory mediators such as cytokines and metabolites of tryptophan that participate in the central nervous system response to inflammation. Regulation of interleukin-1beta (IL-1β) biosynthesis is of interest since this is the key cytokine for initiating the innate immune response. In this respect, drug discovery efforts are focusing on two important components of the inflammasome: the purinergic receptor P2X 7 and the cysteine protease caspase-1. Downstream of proinflammatory cytokine release, kynurenine metabolism is disturbed during inflammation, resulting in metabolism favoring production of quinolinic acid over kynurenic acid. This imbalance has been reported after both acute and chronic inflammation stimuli to induce mood disturbances in animal models. Inhibition of IDO (indolamine 2,3-dioxygenase) or KMO (kynurenine 3-monooxygenase) normalizes these disturbances providing support for these enzymes as potential drug discovery targets.

Neuroinflammation (NI) is an important factor of many CNS diseases, and alleviating NI is believed to reduce disease severity and improve patient outcome in a majority of cases. There are a variety of traditionally druggable targets for NI such as enzymes, receptors, and ion channels. In this review, targets are highlighted where advances in medicinal chemistry have been achieved in the recent past and include purinergic receptors P2X4 and P2X7, kynurenine pathway metabolizing enzymes indole 2,3-dioxygenase and kynurenine aminotransferase, toll-like receptors TLR4 and TLR9, and the fractalkine receptor CX3CR1. These targets are also linked to biological mechanisms underlying NI and disease. Even though increased risk of infection is a potential issue for NI targets owing to immunomodulatory effects, there is significant opportunity to discover new molecules for the alleviation of NI in CNS diseases.

Compounds with combined norepinephrine reuptake inhibitor (NRI) and serotonin 1A (5-HT(1A)) partial agonist pharmacology may offer a new therapeutic approach for treating symptoms of neuropsychiatric disorders including ADHD, depression, and anxiety. Herein we describe the design and optimization of novel chemical matter that exhibits favorable dual NRI and 5-HT(1A) partial agonist activity. Lead compounds in this series were found to be devoid of activity at the dopamine transporter and were shown to be brain penetrant with high receptor occupancy.

Evidence suggests that compounds possessing both norepinephrine reuptake inhibition and 5-HT1A partial agonism (NRI/5-HT1A) activities may have a greater efficacy in treating neuropsychiatric disorders than compounds possessing either activity alone. The objectives of the present study were first to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of the plasma concentrations of atomoxetine (NRI) and buspirone (5-HT1A partial agonist), administered alone and in combination, on the prefrontal cortex dopamine levels in rats, and second to use the model developed to characterize the PK/PD relationship of novel NRI/5-HT1A compounds, PF-04269339 and PF-03529936, in a NRI/5-HT1A drug discovery program. Maximal dopamine elevation was twofold higher after administration of atomoxetine and buspirone in combination, PF-04269339, or PF-03529936 than after administration of atomoxetine or buspirone alone. A mechanism-based extended indirect response model characterized the time profiles of the prefrontal cortex dopamine response to atomoxetine and buspirone, administered alone or in combination. After fixing three mechanism-specific pharmacodynamic parameters (Imax and γ2 for NRI and γ1 for 5-HT1A) based on the model for atomoxetine and/or buspirone, the model fitted the exposure–response profiles of PF-04269339 and PF-03529936 well. Good in vitro-to-in vivo correlation was demonstrated with the compound-specific pharmacodynamic parameters (IC50 for NRI and SC50 and Smax for 5-HT1A) across the compounds. In summary, a piecewise modeling approach was used successfully for the characterization of the PK/PD relationship of novel NRI/5-HT1A compounds on prefrontal cortex dopamine levels in rats. The application and value of the mechanism-based modeling in the dual pharmacology drug discovery program are also discussed. Electronic supplementary material The online version of this article (doi:10.1208/s12248-012-9343-8) contains supplementary material, which is available to authorized users.

The purpose of this study was to investigate muscle activation levels of select lower extremity muscles during the pitching motion. Bilateral surface electromyography data on 5 lower extremity muscles (biceps femoris, rectus femoris, gluteus maximus, vastus medialis, and gastrocnemius) were collected on 11 highly skilled baseball pitchers and compared with individual maximal voluntary isometric contraction (MVIC) data. The pitching motion was divided into 4 distinct phases: phase 1, initiation of pitching motion to maximum stride leg knee height; phase 2, maximum stride leg knee height to stride foot contact (SFC); phase 3, SFC to ball release; and phase 4, ball release to 0.5 seconds after ball release (follow-through). Results indicated that trail leg musculature elicited moderate to high activity levels during phases 2 and 3 (38-172% of MVIC). Muscle activity levels of the stride leg were moderate to high during phases 2-4 (23-170% of MVIC). These data indicate a high demand for lower extremity strength and endurance. Specifically, coaches should incorporate unilateral and bilateral lower extremity exercises for strength improvement or maintenance and to facilitate dynamic stabilization of the lower extremities during the pitching motion.

Preclinical studies suggest that compounds with dual norepinephrine reuptake inhibitor (NRI) and 5-HT 1A partial agonist properties may provide an important new therapeutic approach to ADHD, depression, and anxiety. Reported herein is the discovery of a novel chemical series with a favorable NRI and 5-HT 1A partial agonist pharmacological profile as well as excellent selectivity for the norepinephrine transporter over the dopamine transporter.

Diabetes mellitus is commonly associated with erectile dysfunction (ED). Fifty-three diabetic male veterans presenting with ED underwent an extensive medical examination, psychological evaluation, and a detailed assessment of sexual functioning. They then underwent two consecutive nights of inhospital Rigiscan monitoring to assess erectile capacity. Multivariate analyses indicated that patient reports of a.m. erections and erectile quality were highly predictive of Rigiscan measures of penile tip and base rigidity and duration of erectile episodes. These results highlight the importance of attending to patient reports of specific sexual symptomatology in the evaluation of diabetic patients presenting with ED.

Aminopyrimidine 2 (4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-cyclopropylpyrimidin-2-amine) emerged from a high throughput screen as a novel 5-HT(1A) agonist. This compound showed moderate potency for 5-HT(1A) in binding and functional assays, as well as moderate metabolic stability. Implementation of a strategy for improving metabolic stability by lowering the lipophilicity (cLogD) led to identification of methyl ether 31 (4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-(2-methoxyethyl)pyrimidin-2-amine) as a substantially improved compound within the series.

Context:The Cuff Link is a closed kinetic chain rehabilitation apparatus for the upper extremity. Limited research has established its effectiveness to elicit muscle activation of the scapular muscles.Objective:To determine if scapular muscle activation differs in response to 2 upper extremity closed kinetic chain exercises: Cuff Link and standard push-up.Design:A single-group, repeated-measures design.Setting:Controlled laboratory.Patients or Other Participants:Twenty-eight healthy individuals (13 women: age = 19.69 ± 1.55 years, height = 167.44 ± 9.52 cm, mass = 61.00 ± 8.79 kg; 15 men: age = 22.00 ± 3.91 years, height = 181.44 ± 6.60 cm, mass = 82.36 ± 13.23 kg) with no history of shoulder or low back injury volunteered to participate in this study.Intervention(s):Participants performed 10 trials of complete revolutions on the Cuff Link and 10 full–weight-bearing push-ups. We controlled trial velocity and randomized order. Trunk and shoulder positions were normalized to the participant's height. Using surface electromyography, we recorded muscle activity of the serratus anterior, middle trapezius, and lower trapezius. Rectified and smoothed electromyography data for the serratus anterior, middle trapezius, and lower trapezius were normalized as a percentage of the maximal voluntary isometric contractions (%MVIC).Main Outcome Measure(s):Mean muscle activity of the serratus anterior, middle trapezius, and lower trapezius. We used paired-samples t tests to analyze the mean data for each condition. The α level was adjusted to .016 to avoid a type I error.Results:Middle trapezius %MVIC was greater during push-ups (27.01 ± 20.40%) than during use of the Cuff Link (11.49 ± 9.46%) (P = .001). Lower trapezius %MVIC was greater during push-ups (36.07 ± 18.99%) than during use of the Cuff Link (16.29 ± 8.64%) (P = .001). There was no difference in %MVIC for the serratus anterior between conditions.Conclusions:The push-up demonstrated greater middle trapezius and lower trapezius activation levels compared with the Cuff Link. However, the push-up had a high participant failure rate. Because serratus anterior activation levels were similar, the Cuff Link may be an appropriate alternative for individuals lacking the upper body strength to perform a push-up.

Several studies indicate a role for the serotonin 2 subfamily (5-HT(2A), 5-HT(2B), 5-HT(2C)) in mediation of fear and anxiety responses. The current study began to examine the effects of stimulating 5-HT(2C) receptors within the basolateral (BLA) or central nucleus of the amygdala (CeA) on acute fear-like responses in rats. Bilateral intra-BLA infusions of mCPP (3-3000 pmol), a mixed 5-HT(2) agonist, produced ultrasonic vocalization and reduced exploratory behavior while increasing the latency to investigate a novel object. These responses were attenuated by SB-242084, a 5-HT(2C)-specific antagonist. Furthermore, a selective 5-HT(2C) agonist, IL-639, produced a similar repertoire of behavioral effects with the exception of effects on time spent in the center of an open-field arena. Finally, infusions of mCPP into the CeA produced no anxiogenic behaviors suggesting that 5-HT(2C) receptors primarily within the BLA are responsible for many of the acute fear-like responses reported here. To characterize further the neural circuits associated with 5-HT(2C)-mediated fear responses, we assessed c-fos mRNA expression after intra-BLA infusions of mCPP, IL-639 or their vehicles. Whereas the overall regional pattern of c-fos mRNA induction for the two compounds was distinct, c-fos activation was confined primarily to limbic nuclei with the medial prefrontal cortex as a common regional target of each drug. These results suggest that activation of 5-HT(2C) receptors within the BLA influences the activity of limbic circuits involved in the expression of acute innate fear responses.

We have examined the effects of serotonin2 (5-HT2) stimulation and NMDA antagonism on preprotachykinin (PPT) and preproenkephalin (PPE) gene regulation in the dopamine (DA) depleted striatum. Following DA lesions, PPT mRNA expression was reduced (dorsomedial (DM) 44 +/- 9%, dorsolateral (DL) 40 +/- 4%), whereas PPE message levels were elevated (DM 207+/-28%, DL 198+/-25%). Within this state of dysregulated gene activity, DOI (5-HT2 agonist) increased PPT message levels (174 +/- 5%, DM; 153 +/- 13%, DL) without affecting PPE gene expression. In addition, MK-801 (NMDA antagonist) decreased PPE message levels (DM 59 +/- 10%, DL 52 +/- 7%) without significantly altering PPT mRNA expression. Combined application of DOI and MK-801 resulted in normalization of both PPTand PPE message. Statistical analysis revealed no drug interactions in this paradigm suggesting independent mechanisms for 5-HT2 and NMDA receptors in controlling neuropeptide production following DA depletion.

We examined dopamine (DA) and serotonin (5-HT) receptor-mediated influences on striatal preprotachykinin (PPT, tachykinin precursor) mRNA regulation in organotypic slice cultures. A 3 h exposure to SKF-38393 (10 microM, DA D1 agonist) or DOI (10 microM, 5-HT2 agonist) increased PPT mRNA levels to 196.4% and 154.0%, respectively. Responses to SKF-38393 were prevented by SCH-23390 (10 microM, D1 antagonist) whereas DOI-stimulated increases were prevented by ketanserin (10 microM, 5-HT2A antagonist). Since striatal tachykinin neurons also possess NMDA receptors that regulate gene expression, stimulation of PPT message levels was examined in the presence of MK-801, a non-competitive NMDA antagonist. Alone, MK-801 (10 nM) did not significantly alter basal PPT message levels. However, MK-801 prevented SKF-38393-stimulated increases in PPT mRNA expression while DOI-induced expression was not affected. These results provide evidence that D1 regulation of striatal tachykinin expression is dependent on NMDA-type glutamate neurotransmission while 5-HT2A regulation appears independent.

Peripheral administration of the endotoxin lipopolysaccharide (LPS) is a commonly used immunological challenge in animal models of inflammation-associated depressive-like behavior. LPS stimulates the production of pro-inflammatory cytokines, leading to an induction of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Elevated IDO activity, as measured by the dysregulation of kynurenine pathway metabolites, is proposed to mediate inflammation-induced depressive-like behavior in mice. LPS is subject to considerable variability in potency, which can often lead to variability in results. Control standard endotoxin (CSE) is a highly purified LPS preparation and may reduce the variability in results observed with LPS. CD-1 mice were treated with 0, 0.15, 1.5, 15 or 150 μ g/kg CSE i.p. and sacrificed 24 h later. Brain and plasma were collected for analysis of cytokines and kynurenine pathway metabolites. The highest dose of CSE (150 μ g/kg) increased kynurenine, which was metabolized towards the quinolinic branch of the kynurenine pathway in the brain and plasma. The magnitude of change in kynurenine metabolites was similar to those found in previous studies with 1 mg/kg LPS. Mice treated with CSE had higher levels of interleukin (IL)-1 beta and tumor necrosis factor alpha in the brain, and IL-10 and interferon gamma in the plasma. These results suggest that CSE may be used as an improvement over LPS in an in vivo neuroinflammation model.

The relationship between both the quantity and perceived quality of social support and suicidal risk was examined in a sample of 50 adolescents whose ages ranged from 16 to 20 years. A multiple regression analysis was performed, using scores from Cull and Gill's 1983 Suicide Probability Scale as the criterion measure along with the predictor variables of quantity and quality of experienced social support as measured by the 1983 Social Support Questionnaire of Sarason, Levine, Basham, and Sarason. Analysis showed the social support variables accounted for over 52% of the variance in suicide potential. The greatest proportion of the variance in suicide risk was attributable to the quality of the perceived social support. Adolescents at greater risk for suicide were significantly less satisfied with the quality of their social support.

The purpose of this study was to determine the effect of a 4-week balance training program on specified functional tasks. Thirty-six subjects (age = 22.7 +/- 2.10 years; height = 168.30 +/- 9.55 cm; weight = 71.15 +/- 16.40 kg) were randomly placed into control (C; n = 19) and experimental groups (Tx; n = 17). The Tx group trained using a commercially available balance training device (BOSU). Postural limits (displacement and sway) and functional task (time on ball, shuttle run, and vertical jump) were assessed during a pretest (T1), a posttest (T2), and 2 weeks posttraining (T3). Multivariate repeated measures analysis (alpha = 0.05) revealed significant differences in time on ball, shuttle run, total sway, and fore/aft displacement after the exercise intervention (T2). T3 assessment revealed that total sway and time on ball remained controlled; however, no other measures were retained. Balance training improved performance of selected sport-related activities and postural control measures, although it is unclear whether the effect of training would transfer to general functional enhancement.