Subanesthetic ketamine treatment promotes abnormal interactions between neural subsystems and alters the properties of functional brain networks

Acute treatment with subanesthetic ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, is widely utilized as a translational model for schizophrenia. However, how acute NMDA receptor blockade impacts on brain functioning at a systems level, to elicit translationally relevant symptomatology and behavioral deficits, has not yet been determined. Here, for the first time, we apply established and recently validated topological measures from network science to brain imaging data gained from ketamine-treated mice to elucidate how acute NMDA receptor blockade impacts on the properties of functional brain networks. We show that the effects of acute ketamine treatment on the global properties of these networks are divergent from those widely reported in schizophrenia. Where acute NMDA receptor blockade promotes hyperconnectivity in functional brain networks, pronounced dysconnectivity is found in schizophrenia. We also show that acute ketamine treatment increases the connectivity and importance of prefrontal and thalamic brain regions in brain networks, a finding also divergent to alterations seen in schizophrenia. In addition, we characterize how ketamine impacts on bipartite functional interactions between neural subsystems. A key feature includes the enhancement of prefrontal cortex (PFC)-neuromodulatory subsystem connectivity in ketamine-treated animals, a finding consistent with the known effects of ketamine on PFC neurotransmitter levels. Overall, our data suggest that, at a systems level, acute ketamine-induced alterations in brain network connectivity do not parallel those seen in chronic schizophrenia. Hence, the mechanisms through which acute ketamine treatment induces translationally relevant symptomatology may differ from those in chronic schizophrenia. Future effort should therefore be dedicated to resolve the conflicting observations between this putative translational model and schizophrenia

Duloxetine compared with fluoxetine and venlafaxine: use of meta-regression analysis for indirect comparisons

BACKGROUND: Data comparing duloxetine with existing antidepressant treatments is limited. A comparison of duloxetine with fluoxetine has been performed but no comparison with venlafaxine, the other antidepressant in the same therapeutic class with a significant market share, has been undertaken. In the absence of relevant data to assess the place that duloxetine should occupy in the therapeutic arsenal, indirect comparisons are the most rigorous way to go. We conducted a systematic review of the efficacy of duloxetine, fluoxetine and venlafaxine versus placebo in the treatment of Major Depressive Disorder (MDD), and performed indirect comparisons through meta-regressions. METHODS: The bibliography of the Agency for Health Care Policy and Research and the CENTRAL, Medline, and Embase databases were interrogated using advanced search strategies based on a combination of text and index terms. The search focused on randomized placebo-controlled clinical trials involving adult patients treated for acute phase Major Depressive Disorder. All outcomes were derived to take account for varying placebo responses throughout studies. Primary outcome was treatment efficacy as measured by Hedge's g effect size. Secondary outcomes were response and dropout rates as measured by log odds ratios. Meta-regressions were run to indirectly compare the drugs. Sensitivity analysis, assessing the influence of individual studies over the results, and the influence of patients' characteristics were run. RESULTS: 22 studies involving fluoxetine, 9 involving duloxetine and 8 involving venlafaxine were selected. Using indirect comparison methodology, estimated effect sizes for efficacy compared with duloxetine were 0.11 [-0.14;0.36] for fluoxetine and 0.22 [0.06;0.38] for venlafaxine. Response log odds ratios were -0.21 [-0.44;0.03], 0.70 [0.26;1.14]. Dropout log odds ratios were -0.02 [-0.33;0.29], 0.21 [-0.13;0.55]. Sensitivity analyses showed that results were consistent. CONCLUSION: Fluoxetine was not statistically different in either tolerability or efficacy when compared with duloxetine. Venlafaxine was significantly superior to duloxetine in all analyses except dropout rate. In the absence of relevant data from head-to-head comparison trials, results suggest that venlafaxine is superior compared with duloxetine and that duloxetine does not differentiate from fluoxetine

NMDA Receptor Hypofunction Leads to Generalized and Persistent Aberrant γ Oscillations Independent of Hyperlocomotion and the State of Consciousness

International audienceNMDAr antagonists acutely produces, in the rodent CNS, generalized aberrant gamma oscillations, which are not dependent on hyperlocomotion-related brain state or conscious sensorimotor processing. These findings suggest that NMDAr hypofunction-related generalized gamma hypersynchronies represent an aberrant diffuse network noise, a potential electrophysiological correlate of a psychotic-like state. Such generalized noise might cause dysfunction of brain operations, including the impairments in cognition and sensorimotor integration seen in schizophrenia

Impact of caloric and dietary restriction regimens on markers of health and longevity in humans and animals: a summary of available findings

Considerable interest has been shown in the ability of caloric restriction (CR) to improve multiple parameters of health and to extend lifespan. CR is the reduction of caloric intake - typically by 20 - 40% of ad libitum consumption - while maintaining adequate nutrient intake. Several alternatives to CR exist. CR combined with exercise (CE) consists of both decreased caloric intake and increased caloric expenditure. Alternate-day fasting (ADF) consists of two interchanging days; one day, subjects may consume food ad libitum (sometimes equaling twice the normal intake); on the other day, food is reduced or withheld altogether. Dietary restriction (DR) - restriction of one or more components of intake (typically macronutrients) with minimal to no reduction in total caloric intake - is another alternative to CR. Many religions incorporate one or more forms of food restriction. The following religious fasting periods are featured in this review: 1) Islamic Ramadan; 2) the three principal fasting periods of Greek Orthodox Christianity (Nativity, Lent, and the Assumption); and 3) the Biblical-based Daniel Fast. This review provides a summary of the current state of knowledge related to CR and DR. A specific section is provided that illustrates related work pertaining to religious forms of food restriction. Where available, studies involving both humans and animals are presented. The review includes suggestions for future research pertaining to the topics of discussion

The metabotropic glutamate receptors: Potential drug targets for the treatment of anxiety disorders?

Anxiety-related disorders are a common public health issue. Several lines of evidence suggest that altered glutamatergic neurotransmission underlies anxiety. Thus, novel molecules targeting glutamatergic neurotransmission, such as ligands of the metabotropic glutamate receptors (mGlurs) might be promising candidates for the treatment of anxiety disorders. To date, several ligands selective for each mGlu receptor (mGlur) have been synthesized, and pharmacological significances of these compounds have been demonstrated mainly in animal models. Here we critically review advances in research of these emerging molecular targets for the treatment of anxiety, discuss their advantages over currently used anxiolytics as well as remaining challenges. (C) 2013 Elsevier B.V. All rights reserved

Effects of scopolamine and L-NAME on rats' performance in the object location test

The object location task is a new procedure evaluating spatial memory abilities in the rat. The aim of the present study was to characterize this behavioural paradigm by pharmacologic means. For this purpose, the effects of the muscarinic receptor antagonist scopolamine and the inhibitor of the nitric oxide synthase L-NAME on object location were assessed in the rat. In a first study, object location was impaired when the delay condition of 60-min was utilized. Subsequently, pre-training administration of scopolamine (0.2 mg/kg but not 0.07 mg/kg) induced delay-dependent performance deficits in this test. These impairments seem to be centrally mediated since the peripheral muscarinic receptor antagonist methylscopolamine (0.2 mg/kg) did not affect object location under the same conditions. Finally, pre-training treatment With L-NAME (30 mg/kg but not 10 mg/kg) also induced delay-dependent performance deficits in the object location task. These results indicate that the object location test is sensitive to pharmacological treatment and could be used for assessing the therapeutic potential of promnesic compounds. (c) 2007 Elsevier B.V. All rights reserved

The role of nitric oxide (NO) donors in anxiety. Lights and shadows

Anxiety-related disorders are a common public health issues. Current medication for this affective disorder involves the GABA-ergic or the serotonergic transmission. Different forms of anxiety, however, are resistant to treatment with GABA-ergic or serotonergic agents and the use of these compounds can be associated with severe side effects. Thus, almost 60 years after the discovery of the benzodiazepines there is need not only for fresh medications but also alternative targets. The nitrergic system has emerged as a promising target since several lines of evidence suggest that nitric oxide (NO), an intra- and inter-cellular messenger in the brain, is implicated in anxiety. Therefore, NO modulators might be beneficial. Here I critically review advances in research of agents acting on the nitrergic system, such as the NO donors, for the treatment of anxiety. Present analysis suggests that although NO donors are involved in anxiety their potential anxiolytic effect remains to be established. © 2018 Elsevier Inc

The Effect of Crocus sativus L. and Its Constituents on Memory: Basic Studies and Clinical Applications

Memory-related disorders are a common public health issue. Memory impairment is frequent in degenerative diseases (such as Alzheimer's disease and Parkinson disease), cerebral injuries, and schizophrenia. The dried stigma of the plant Crocus sativus L. (C. sativus), commonly known as saffron, is used in folk medicine for various purposes. Several lines of evidence suggest that C. sativus and its constituents are implicated in cognition. Here we critically review advances in research of these emerging molecular targets for the treatment of memory disorders, and discuss their advantages over currently used cognitive enhancers as well remaining challenges. Current analysis has shown that C. sativus and its components might be a promising target for cognition impairments