Objective: Deficits in working memory and cognitive control in schizophrenia are associated with impairments in prefrontal cortical function, including altered gamma band oscillations. These abnormalities are thought to reflect a deficiency in the synchronization of pyramidal cell activity that is dependent, in part, on gamma-aminobutyric acid (GABA) neurotransmission through GABA type A (GABA A ) receptors containing α 2 subunits. The authors conducted a proof-ofconcept clinical trial designed to test the hypothesis that a novel compound with relatively selective agonist activity at GABA A receptors containing α 2 subunits would improve cognitive function and gamma band oscillations in individuals with schizophrenia.Method: Participants were male subjects (N=15) with chronic schizophrenia who were randomly assigned to receive 4 weeks of treatment with the study drug MK-0777, a benzodiazepine-like agent with selective activity at GABA A receptors containing α 2 or α 3 subunits, or a matched placebo in a double-blind fashion. Outcome measures were the Brief Psychiatric Rating Scale (BPRS), Repeatable Battery for the Assessment of Neuropsychological Status, three tests of working memory and/or cognitive control (N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency), and EEG measures of gamma band oscillations induced during the Preparing to Overcome Prepotency task. Results:Compared with placebo, the MK-0777 compound was associated with improved performance on the N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency tasks. The compound was also associated with increased frontal gamma band power during the Preparing to Overcome Prepotency task. No effects of the MK-0777 compound were detected in BPRS or Repeatable Battery for the Assessment of Neuropsychological Status scores, with the exception of improvement on the Repeatable Battery for the Assessment of Neuropsychological Status delayed memory index. The MK-0777 agent was well-tolerated. Conclusions:These findings provide preliminary support for the hypothesis that enhanced GABA activity at α 2 subunit containing GABA A receptors improves behavioral and electrophysiological measures of prefrontal function in individuals with schizophrenia.In individuals with schizophrenia, a characteristic pattern of cognitive deficits occurs with high frequency, is relatively stable over time, is independent of psychosis, and is the best predictor of long-term functional outcome (1-3). Thus, the development of effective treatments for cognitive deficits remains a major goal of schizophrenia research (4). Substantial research has focused on impairments in working memory and cognitive control that are accompanied by altered activation of the dorsolateral prefrontal cortex (5-7). Studies examining neural activity using functional magnetic resonance imaging (fMRI) have indicated that individuals with schizophrenia exhibit an altered relationship with working memory load, behavioral performance, and dorsolateral prefrontal cor...

Maximal aerobic capacity and the ability to sustain submaximal exercise (Ex) declines with advancing age. Whether altered muscle blood flow (BF) plays a mechanistic role in these effects remains to be resolved. The present investigation determined the effects of aging on the hemodynamic and regional BF response to submaximal Ex in rats. Heart rate (HR), mean arterial pressure (MAP), and BF to different organs (kidneys, splanchnic organs, and 28 hindlimb muscles) were determined at rest and during submaximal treadmill Ex (20 m/min, 5% grade) with radiolabeled microspheres in young (Y; 6-8 mo old, 339 +/- 8 g, n = 9) and old (O; 27-29 mo old, 504 +/- 18 g, n = 7) Fischer 344 x Brown Norway rats. Results demonstrated that HR, MAP, and BF to the pancreas, small and large intestine, and total hindlimb musculature were similar between Y and O rats at rest. BF to the kidneys, spleen, and stomach were 33, 60, and 43% lower, respectively, in O compared with Y rats. BF to the total hindlimb musculature increased (P < 0.05) during Ex and was similar for both Y and O rats (Y: 16 +/- 3 to 124 +/- 7 vs. O: 20 +/- 3 to 137 +/- 12 ml.min-1.100 g-1). However, in O vs. Y rats, BF was reduced in 6 (highly oxidative) and elevated in 8 (highly glycolytic) of the 28 individual hindquarter muscles or muscle parts examined (P < 0.05). During Ex, BF to the spleen and stomach decreased (P < 0.05) from rest in Y rats, whereas BF decreased in the kidneys, pancreas, spleen, stomach, as well as the small and large intestines of O rats. In conclusion, these data demonstrate that, despite similar increases in total hindlimb BF in Y and O rats during submaximal Ex, there is a profound BF redistribution from highly oxidative to highly glycolytic muscles.

OBJECTIVE-Brain-derived neurotrophic factor (BDNF) is a key factor known to mediate neuronal proliferation, differentiation, survival and response to stress. Decreases in BDNF levels have been reported in schizophrenia, but studies in treatment naïve patients are few. Herein we report on serum BDNF levels in a series of patients with first-episode treatment naïve psychoses in comparison to age matched healthy controls.METHOD-Fasting serum BDNF levels were measured in 41 patients with treatment naive first episode psychosis (24 with schizophrenia, schizoaffective disorder or schizophreniform disorder, and 17 with non-schizophrenia psychotic disorders) and 41 age-matched healthy controls.RESULTS-A three group analyses of covariance (ANCOVA) showed a diagnosis effect (p = .038) in which patients with schizophrenia had lesser serum BDNF levels than patient with nonschizophrenia psychosis, who in turn had lesser BDNF levels than matched healthy controls. Planned two-group ANCOVAs suggested that patients with schizophrenia had lower serum BDNF level than matched controls (p = .016), whereas patients with non-schizophrenia psychosis did not differ from controls. There were no age effects on BDNF, but there was a trend (p = .08) for a gender by group interaction with greater reductions in female patients with schizophrenia. The BDNF levels did not correlate with magnitude of smoking, body mass index, severity of positive and negative symptoms or overall functioning.CONCLUSIONS-Serum BDNF may be reduced at the onset of psychosis but its role in the pathogenesis of schizophrenia remains unclear. Elucidating the role of BDNF in schizophrenia and related psychotic may provide an important therapeutic target. Further studies are also needed to examine if patients with schizophrenia have more pronounced reductions in BDNF than those with affective psychosis.

Introduction-Though increased risk of sudden death in patients with schizophrenia is welldocumented, the mechanisms remain unclear. Recent studies report two known risk factors for sudden cardiac death and other arrhythmias in schizophrenia, i.e., decreased R-R interval variability (RRV) and increased QT interval variability (QTV). However, these studies did not control for the effects of medication. Herein, we report the results of our study comparing RRV and QTV in first episode neuroleptic-naive psychosis patients with healthy matched controls.

Current literature suggests that chronic nitric oxide synthase (NOS) inhibition has differential effects on endothelium-dependent dilation (EDD) of conduit arteries vs. arterioles. Therefore, we hypothesized that chronic inhibition of NOS would impair EDD of porcine left anterior descending (LAD) coronary arteries but not coronary arterioles. Thirty-nine female Yucatan miniature swine were included in the study. Animals drank either tap water or water with N G -nitro-L-arginine methyl ester (L-NAME; 100 mg/l), resulting in control and chronic NOS inhibition (CNI) groups, respectively. Treatment was continued for 1-3 mo (8.3 ± 0.6 mg · kg −1 · day −1 ). In vitro EDD of coronary LADs and arterioles was assessed via responses to ADP (LADs only) and bradykinin (BK), and endothelium-independent function was assessed via responses to sodium nitroprusside (SNP). Chronic NOS inhibition diminished coronary artery EDD to ADP and BK. Incubating LAD rings with L-NAME decreased relaxation responses of LADs from control pigs but not from CNI pigs such that between-group differences were abolished. Neither indomethacin (Indo) nor sulfaphenazole incubation significantly affected relaxation responses of LAD rings to ADP or BK. Coronary arteries from CNI pigs showed enhanced relaxation responses to SNP. In contrast to coronary arteries, coronary arterioles from CNI pigs demonstrated preserved EDD to BK and no increase in dilation responses to SNP. L-NAME, Indo, and L-NAME + Indo incubation did not result in significant between-group differences in arteriole dilation responses to BK. These results suggest that although chronic NOS inhibition diminishes EDD of LAD rings, most likely via a NOS-dependent mechanism, it does not affect EDD of coronary arterioles. Keywords endothelium-dependent dilation; N G -nitro-L-arginine methyl esterA healthy vascular endothelium promotes arterial homeostasis; in contrast, an injured endothelium portends arterial dysfunction (28). Although the mechanisms by which endothelial dysfunction exacts vascular damage remain to be fully elucidated, it is thought that reduced nitric oxide (NO) production and/or scavenging play a crucial role (27).Chronically decreased NO production by nitric oxide synthase (NOS) inhibition results in significant hemodynamic alterations. Systemically, NOS inhibition via N G -nitro-L-argi-nine methyl ester (L-NAME) or other NOS inhibitor administration increases blood pressure and peripheral resistance while decreasing heart rate and cardiac output (4,11,18,21,24,29). The fact that chronic NOS inhibition causes increased mean arterial pressure in vivo could be Address for reprint requests and other correspondence: M. H. Laughlin, Department of Biomedical Sciences, W102 Veterinary Medicine, 1600 E. Rollins Rd., Univ. of Missouri, Columbia, MO 65211 (e-mail: laughlinm @missouri.edu). * D. G. Ingram and S. C. Newcomer contributed equally to this work. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript evidence that chronic NOS inh...