Selective Pharmacological Manipulation Research Articles

Complex alterations in inflammatory pain and analgesic sensitivity in young and ageing female rats: involvement of ASIC3 and Nav1.8 in primary sensory neurons.

Our aim was to determine an age-dependent role of Nav1.8 and ASIC3 in dorsal root ganglion (DRG) neurons in a rat pre-clinical model of long-term inflammatory pain. We compared 6 and 24months-old female Wistar rats after cutaneous inflammation. We used behavioral pain assessments over time, qPCR, quantitative immunohistochemistry, selective pharmacological manipulation, ELISA and in vitro treatment with cytokines. Older rats exhibited delayed recovery from mechanical allodynia and earlier onset of spontaneous pain than younger rats after inflammation. Moreover, the expression patterns of Nav1.8 and ASIC3 were time and age-dependent and ASIC3 levels remained elevated only in aged rats. In vivo, selective blockade of Nav1.8 with A803467 or of ASIC3 with APETx2 alleviated mechanical and cold allodynia and also spontaneous pain in both age groups with slightly different potency. Furthermore, in vitro IL-1β up-regulated Nav1.8 expression in DRG neurons cultured from young but not old rats. We also found that while TNF-α up-regulated ASIC3 expression in both age groups, IL-6 and IL-1β had this effect only on young and aged neurons, respectively. Inflammation-associated mechanical allodynia and spontaneous pain in the elderly can be more effectively treated by inhibiting ASIC3 than Nav1.8.

Noradrenaline release from the locus coeruleus shapes stress-induced hippocampal gene expression.

Exposure to an acute stressor triggers a complex cascade of neurochemical events in the brain. However, deciphering their individual impact on stress-induced molecular changes remains a major challenge. Here, we combine RNA sequencing with selective pharmacological, chemogenetic, and optogenetic manipulations to isolate the contribution of the locus coeruleus-noradrenaline (LC-NA) system to the acute stress response in mice. We reveal that NA release during stress exposure regulates a large and reproducible set of genes in the dorsal and ventral hippocampus via β-adrenergic receptors. For a smaller subset of these genes, we show that NA release triggered by LC stimulation is sufficient to mimic the stress-induced transcriptional response. We observe these effects in both sexes, and independent of the pattern and frequency of LC activation. Using a retrograde optogenetic approach, we demonstrate that hippocampus-projecting LC neurons directly regulate hippocampal gene expression. Overall, a highly selective set of astrocyte-enriched genes emerges as key targets of LC-NA activation, most prominently several subunits of protein phosphatase 1 (Ppp1r3c, Ppp1r3d, Ppp1r3g) and type II iodothyronine deiodinase (Dio2). These results highlight the importance of astrocytic energy metabolism and thyroid hormone signaling in LC-mediated hippocampal function and offer new molecular targets for understanding how NA impacts brain function in health and disease.

Activation of a Locus Coeruleus to Dorsal Hippocampus Noradrenergic Circuit Facilitates Associative Learning.

Processing of contextual information during a new episodic event is crucial for learning and memory. Neuromodulation in the hippocampus and prefrontal cortex plays an important role in the formation of associations between environmental cues and an aversive experience. Noradrenergic neurons in the locus coeruleus send dense projections to both regions, but their contribution to contextual associative learning has not been established. Here, we utilize selective optogenetic and pharmacological manipulations to control noradrenergic transmission in the hippocampus during the encoding of a contextual fear memory. We find that boosting noradrenergic terminal release in the dorsal CA1 enhances the acquisition of contextual associative learning and that this effect requires local activation of β-adrenenergic receptors. Moreover, we show that increasing norepinephrine release can ameliorate contextual fear learning impairments caused by dopaminergic dysregulation in the hippocampus. Our data suggest that increasing of hippocampal noradrenergic activity can have important implications in the treatment of cognitive disorders that involve problems in contextual processing.

Abstract 5833: Senescence is a central response to chemotherapy in ovarian cancer

Abstract High-grade serous ovarian carcinoma (HGSOC) commonly responds to initial therapy, but this response is rarely durable. Understanding the cell fate decisions taken by HGSOC cells in response to treatment could guide new therapeutic opportunities. Here, we find that more than 90% of tissue-derived primary HGSOC cultures, reflecting the original disease, retain the capacity to undergo stress-induced cellular senescence and primarily undergo therapy-induced senescence (TIS) in response to first-line carboplatin/taxol chemotherapy. HGSOC-TIS displays senescence-associated hallmarks, including a stable proliferation arrest, increased p16INK4A expression, persistent DNA damage, an inflammatory secretome, and senolytic sensitivity, suggesting new avenues for selective pharmacological manipulation of these cells. Comparison of pre- and post-chemotherapy patient HGSOC tissue samples revealed changes in physio-pathological senescence biomarkers supporting the occurrence of post-treatment TIS. Whether cell senescence induced by cancer therapy is beneficial or detrimental to treatment outcomes remains unknown. We find that patients with stronger TIS biomarkers in post-chemotherapy tissues have a more favorale 5-year survival, suggesting that the induction of senescence in HGSOC cells accounts, at least in part, for beneficial responses to treatment. Given that HGSOC cells almost universally retain the capacity to undergo senescence and that senescence appears beneficial in this context, senescence-centric therapeutic avenues should be further explored. Citation Format: Michael Skulimowski, Llilians Calvo-Gonzales, Shuofei Cheng, Isabelle Clément, Lise Portelance, Yu Zhan, Euridice Carmona, Manon de Ladurantaye, Julie Lafontaine, Kurosh Rahimi, Diane Provencher, Anne-Marie Mes-Masson, Francis Rodier. Senescence is a central response to chemotherapy in ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5833.

Neuropeptide Y Y2 antagonist treated ovariectomized mice exhibit greater bone mineral density

Osteoporosis, a disease characterized by progressive bone loss and increased risk of fracture, often results from menopausal loss of estrogen in women. Neuropeptide Y has been shown to negatively regulate bone formation, with amygdala specific deletion of the Y2 receptor resulting in increased bone mass in mice. In this study, ovariectomized (OVX) mice were injected once daily with JNJ-31020028, a brain penetrant Y2 receptor small molecule antagonist to determine the effects on bone formation. Antagonist treated mice had reduced weight and showed increased whole-body bone mineral density compared to vehicle-injected mice. Micro computerized tomography (micro-CT) demonstrated increased vertebral trabecular bone volume, connectivity density and trabecular thickness. Femoral micro-CT analysis revealed increased bone volume within trabecular regions and greater trabecular number, without significant difference in other parameters or within cortical regions. A decrease was seen in serum P1NP, a measure used to confirm positive treatment outcomes in bisphosphonate treated patients. C-terminal telopeptide 1 (CTX-1), a blood biomarker of bone resorption, was decreased in treated animals. The higher bone mineral density observed following Y2 antagonist treatment, as determined by whole-body DEXA scanning, is indicative of either enhanced mineralization or reduced bone loss. Additionally, our findings that ex vivo treatment of bone marrow cells with the Y2 antagonist did not affect osteoblast and osteoclast formation suggests the inhibitor is not affecting these cells directly, and suggests a central role for compound action in this system. Our results support the involvement of Y2R signalling in bone metabolism and give credence to the hypothesis that selective pharmacological manipulation of Y2R may provide anabolic benefits for treating osteoporosis.

Reduced NPY Y1 receptor hippocampal expression and signs of decreased vagal modulation of heart rate in mice

Central neuropeptide Y (NPY) signaling participates in the regulation of cardiac autonomic outflow, particularly via activation of NPY-Y1 receptors (Y1Rs). However, the specific brain areas and neural pathways involved have not been completely identified yet. Here, we evaluate the role of hippocampal Y1Rs in the modulation of the autonomic control of cardiac function using a conditional knockout mouse model. Radiotelemetric transmitters were implanted in 4-month-old male mice exhibiting reduced forebrain expression (rfb) of the Y1R (Npy1rrfb, n=10) and their corresponding controls (Npy1r2lox, n=8). ECG signals were recorded (i) during resting conditions, (ii) under selective pharmacological manipulation of cardiac vagal activity, and (iii) during acute and chronic psychosocial stress challenges, and analyzed via time- and frequency-domain analysis of heart rate variability. Npy1rrfb mice showed a lower Npy1r mRNA density in the dentate gyrus and in the CA1 region of the hippocampus. Under resting undisturbed conditions, Npy1rrfb mice exhibited (i) a higher heart rate, (ii) a reduced overall heart rate variability, and (iii) lower values of the indices of vagal modulation compared to Npy1r2lox counterparts. Following pharmacological vagal inhibition, heart rate was higher in control but not in Npy1rrfb mice compared to their respective baseline values, suggesting that tonic vagal influences on heart rate were reduced in Npy1rrfb mice. The magnitude of the heart rate response to acute stressors was smaller in Npy1rrfb mice compared to Npy1r2lox counterparts, likely due to a concurrent lower vagal withdrawal. These findings suggest that reduced Y1R expression leads to a decrease in resting vagal modulation and heart rate variability, which, in turn, may determine a reduced cardiac autonomic responsiveness to acute stress challenges.

Modeling autism-relevant behavioral phenotypes in rats and mice: Do 'autistic' rodents exist?

Autism spectrum disorders (ASD) are among the most severe developmental psychiatric disorders known today, characterized by impairments in communication and social interaction and stereotyped behaviors. However, no specific treatments for ASD are as yet available. By enabling selective genetic, neural, and pharmacological manipulations, animal studies are essential in ASD research. They make it possible to dissect the role of genetic and environmental factors in the pathogenesis of the disease, circumventing the many confounding variables present in human studies. Furthermore, they make it possible to unravel the relationships between altered brain function in ASD and behavior, and are essential to test new pharmacological options and their side-effects. Here, we first discuss the concepts of construct, face, and predictive validity in rodent models of ASD. Then, we discuss how ASD-relevant behavioral phenotypes can be mimicked in rodents. Finally, we provide examples of environmental and genetic rodent models widely used and validated in ASD research. We conclude that, although no animal model can capture, at once, all the molecular, cellular, and behavioral features of ASD, a useful approach is to focus on specific autism-relevant behavioral features to study their neural underpinnings. This approach has greatly contributed to our understanding of this disease, and is useful in identifying new therapeutic targets.

Regulation of photoreceptor gap junction phosphorylation by adenosine in zebrafish retina.

Electrical coupling of photoreceptors through gap junctions suppresses voltage noise, routes rod signals into cone pathways, expands the dynamic range of rod photoreceptors in high scotopic and mesopic illumination, and improves detection of contrast and small stimuli. In essentially all vertebrates, connexin 35/36 (gene homologs Cx36 in mammals, Cx35 in other vertebrates) is the major gap junction protein observed in photoreceptors, mediating rod-cone, cone-cone, and possibly rod-rod communication. Photoreceptor coupling is dynamically controlled by the day/night cycle and light/dark adaptation, and is directly correlated with phosphorylation of Cx35/36 at two sites, serine110 and serine 276/293 (homologous sites in teleost fish and mammals, respectively). Activity of protein kinase A (PKA) plays a key role during this process. Previous studies have shown that activation of dopamine D4 receptors on photoreceptors inhibits adenylyl cyclase, down-regulates cAMP and PKA activity, and leads to photoreceptor uncoupling, imposing the daytime/light condition. In this study, we explored the role of adenosine, a nighttime signal with a high extracellular concentration at night and a low concentration in the day, in regulating photoreceptor coupling by examining photoreceptor Cx35 phosphorylation in zebrafish retina. Adenosine enhanced photoreceptor Cx35 phosphorylation in daytime, but with a complex dose-response curve. Selective pharmacological manipulations revealed that adenosine A2a receptors provide a potent positive drive to phosphorylate photoreceptor Cx35 under the influence of endogenous adenosine at night. A2a receptors can be activated in the daytime as well by micromolar exogenous adenosine. However, the higher affinity adenosine A1 receptors are also present and have an antagonistic though less potent effect. Thus, the nighttime/darkness signal adenosine provides a net positive drive on Cx35 phosphorylation at night, working in opposition to dopamine to regulate photoreceptor coupling via a push-pull mechanism. However, the lower concentration of adenosine present in the daytime actually reinforces the dopamine signal through action on the A1 receptor.

Selective pharmacological manipulation of cortical–thalamic co-cultures in a dual-compartment device

In this study, we demonstrate capabilities to selectively manipulate dissociated co-cultures of neurons plated in dual-compartment devices. Synaptic receptor antagonists and tetrodotoxin solutions were used to selectively control and study the network-wide burst propagation and cell firing in cortical–cortical and cortical–thalamic co-culture systems. The results show that in cortical–thalamic dissociated co-cultures, burst events initiate in the cortical region and propagate to the thalamic region and the burst events in thalamic region can be controlled by blocking the synaptic receptors in the cortical region. Whereas, in cortical–cortical co-culture system, one of the region acts as a site of burst initiation and facilitate propagation of bursts in the entire network. Tetrodotoxin, a sodium channel blocker, when applied to either of the regions blocks the firing of neurons in that particular region with significant influence on the firing of neurons in the other region. The results demonstrate selective pharmacological manipulation capabilities of co-cultures in a dual compartment device and helps understand the effects of neuroactive compounds on networks derived from specific CNS tissues and the dynamic interaction between them.

Exploiting the selectivity of protein phosphatase 1 for pharmacological intervention

Selective and reversible phosphorylation is one of the most common post-translational modifications of proteins. Although kinase inhibitors are popular in drug development programmes, selective pharmacological manipulation of phosphatase activity has been challenging to achieve. We review recent advances in the development of selective inhibitors of dephosphorylation events and discuss the potential applications of small-molecule phosphatase inhibitors.

Integrin-Mediated Cell-Matrix Interaction in Physiological and Pathological Blood Vessel Formation

Physiological as well as pathological blood vessel formation are fundamentally dependent on cell-matrix interaction. Integrins, a family of major cell adhesion receptors, play a pivotal role in development, maintenance, and remodeling of the vasculature. Cell migration, invasion, and remodeling of the extracellular matrix (ECM) are integrin-regulated processes, and the expression of certain integrins also correlates with tumor progression. Recent advances in the understanding of how integrins are involved in the regulation of blood vessel formation and remodeling during tumor progression are highlighted. The increasing knowledge of integrin function at the molecular level, together with the growing repertoire of integrin inhibitors which allow their selective pharmacological manipulation, makes integrins suited as potential diagnostic markers and therapeutic targets.

A new approach to the molecular analysis of docking, priming, and regulated membrane fusion

Studies using isolated sea urchin cortical vesicles have proven invaluable in dissecting mechanisms of Ca(2+)-triggered membrane fusion. However, only acute molecular manipulations are possible in vitro. Here, using selective pharmacological manipulations of sea urchin eggs ex vivo, we test the hypothesis that specific lipidic components of the membrane matrix selectively affect defined late stages of exocytosis, particularly the Ca(2+)-triggered steps of fast membrane fusion. Egg treatments with cholesterol-lowering drugs resulted in the inhibition of vesicle fusion. Exogenous cholesterol recovered fusion extent and efficiency in cholesterol-depleted membranes; α-tocopherol, a structurally dissimilar curvature analogue, selectively restored fusion extent. Inhibition of phospholipase C reduced vesicle phosphatidylethanolamine and suppressed both the extent and kinetics of fusion. Although phosphatidylinositol-3-kinase inhibition altered levels of polyphosphoinositide species and reduced all fusion parameters, sequestering polyphosphoinositides selectively inhibited fusion kinetics. Thus, cholesterol and phosphatidylethanolamine play direct roles in the fusion pathway, contributing negative curvature. Cholesterol also organizes the physiological fusion site, defining fusion efficiency. A selective influence of phosphatidylethanolamine on fusion kinetics sheds light on the local microdomain structure at the site of docking/fusion. Polyphosphoinositides have modulatory upstream roles in priming: alterations in specific polyphosphoinositides likely represent the terminal priming steps defining fully docked, release-ready vesicles. Thus, this pharmacological approach has the potential to be a robust high-throughput platform to identify molecular components of the physiological fusion machine critical to docking, priming, and triggered fusion.

Dual-compartment neurofluidic system for electrophysiological measurements in physically segregated and functionally connected neuronal cell culture

We developed a dual-compartment neurofluidic system with inter-connecting microchannels to connect neurons from their respective compartments, placed on a planar microelectrode arrays. The design and development of the compartmented microfluidic device for neuronal cell culture, protocol for sustaining long-term cultures, and neurite growth through microchannels in such a closed compartment device are presented. Using electrophysiological measurements of spontaneous network activity in the compartments and selective pharmacological manipulation of cells in one compartment, the biological origin of network activity and the fluidic isolation between the compartments are demonstrated. The connectivity between neuronal populations via the microchannels and the crossing-over of neurites are verified using transfection experiments and immunofluorescence staining. In addition to the neurite cross-over to the adjacent compartment, functional connectivity between cells in both the compartments is verified using cross-correlation (CC) based techniques. Bidirectional signal propagation between the compartments is demonstrated using functional connectivity maps. CC analysis and connectivity maps demonstrate that the two neuronal populations are not only functionally connected within each compartment but also with each other and a well connected functional network was formed between the compartments despite the physical barrier introduced by the microchannels.

A novel delayed non-match to sample object recognition task that allows simultaneous in vivo microdialysis

We present a modification of the widely used delayed non-match to sample (DNMS) paradigm for assessment of object recognition memory that can be combined with simultaneous in vivo microdialysis. The present study provides evidence that hippocampal ACh release increases from baseline during active exploration of the test environment and an empty test board, but a specific further increase is seen during the recognition memory task performance. This novel experimental model offers a good tool to study the impact of selective lesions or pharmacological manipulation simultaneously on neurotransmitter levels and memory task performance.

Building and manipulating neural pathways with microfluidics.

Communication between different brain regions, and between local circuits in the same brain region, is an important area of study for basic and translational neuroscience research. Selective and chronic manipulation of one of the components in a given neural pathway is frequently required for development and plasticity studies. We designed an in vitro platform that captures some of the complexity of mammalian brain pathways but permits easy experimental manipulation of their constituent parts. Organotypic cultures of brain slices were carried out in compartments interconnected by microchannels. We show that co-cultures from cortex and hippocampus formed functional connections by extending axons through the microchannels. We report synchronization of neural activity in co-cultures, and demonstrate selective pharmacological manipulation of activity in the constituent slices. Our platform enables chronic, spatially-restricted experimental manipulation of pre- and post-synaptic neurons in organotypic cultures, and will be useful to investigators seeking to understand development, plasticity, and pathologies of neural pathways.

White noise analysis of central vestibular neurons with sharp electrodes in whole brain preparations

Event Abstract Back to Event White noise analysis of central vestibular neurons with sharp electrodes in whole brain preparations Christian Rössert1*, Stefan Glasauer1, Lee E. Moore2 and Hans Straka2 1 Ludwig-Maximilian-University, Germany 2 University Paris Descartes, France The signal processing in neuronal networks is determined by intrinsic membrane properties of individual neuronal elements as well as by the synaptic circuitry. The best approach to study the contribution of the synaptic networks to the signal processing is a preparation with an intact circuitry and the use of sharp recording electrodes. In contrast, faithful studies of membrane channel dynamics, especially with regard to modelling, are mostly done in slice preparations using low resistant patch electrodes. The main advantage of this latter approach is the easy control of the membrane potential, which allows detailed analyses of ion channel kinetics with standard electrophysiological methods. However, in slice preparations large parts of the network and dendritic structures are destroyed, making this approach for a complete understanding of the transformation of presynaptic inputs in single cells less suitable. We therefore investigated the possibility to employ sharp electrodes for intracellular recordings with 'white noise' stimulation for a characterization of intrinsic membrane properties of single neurons in a whole brain preparation with functionally intact feed-back and feed-forward circuits. For this purpose second-order vestibular neurons were intracellularly recorded with sharp electrodes in an isolated whole brain preparation of adult frogs in vitro and were synaptically activated by electrical stimulation of individual labyrinthine nerve branches. Sharp electrodes are no simple RC elements and not only rectify but have distributed resistances that are difficult to describe quantitatively, particularly during high-frequency current injection. Therefore, a method was developed that uses subtraction of the electrode properties from the combination of both electrode and cell in the frequency domain, following separate measurements of the electrode alone. In addition, all measurements were performed without capacitance or bridge compensation by the amplifier. This allowed us to obtain details of the membrane properties by a 'white noise' analysis with electrode resistances of ~100 MOhm and to create realistic Hodgkin-Huxley models for the channel kinetics from these data. Thus, sharp electrodes are suitable for both, the characterization of intrinsic properties of neurons, as well as the analysis of network contributions to the synaptic activation. Using selective pharmacological manipulations it will be possible to differentiate between the effects of the intrinsic properties of the membrane and the emerging properties of the network to the processing of synaptic inputs in intact brains. Conference: Bernstein Symposium 2008, Munich, Germany, 8 Oct - 10 Oct, 2008. Presentation Type: Poster Presentation Topic: All Abstracts Citation: Rössert C, Glasauer S, Moore LE and Straka H (2008). White noise analysis of central vestibular neurons with sharp electrodes in whole brain preparations. Front. Comput. Neurosci. Conference Abstract: Bernstein Symposium 2008. doi: 10.3389/conf.neuro.10.2008.01.107 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 17 Nov 2008; Published Online: 17 Nov 2008. * Correspondence: Christian Rössert, Ludwig-Maximilian-University, Munich, Germany, christian.a@roessert.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Christian Rössert Stefan Glasauer Lee E Moore Hans Straka Google Christian Rössert Stefan Glasauer Lee E Moore Hans Straka Google Scholar Christian Rössert Stefan Glasauer Lee E Moore Hans Straka PubMed Christian Rössert Stefan Glasauer Lee E Moore Hans Straka Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

GABA B receptor alterations as indicators of physiological and pharmacological function

Given the widespread distribution of GABA B receptors throughout the central nervous system, and within certain peripheral organs, it is likely their selective pharmacological manipulation could be of benefit in the treatment of a variety of disorders. Studies aimed at defining the clinical potential of GABA B receptor agonists and antagonists have included gene deletion experiments, examination of changes in receptor binding, subunit expression and function in diseased tissue, as well as after the chronic administration of drugs. The results indicate that a functional GABA B receptor requires the combination of GABA B(1) and GABA B(2) subunits, that receptor function does not always correlate with subunit expression and receptor binding, and that GABA B receptor modifications may be associated with the clinical response to antidepressants, mood stabilizers, and GABA B receptor agonists and antagonists. Moreover, changes in GABA B binding or expression suggest this receptor may be involved in mediating symptoms associated with chronic pain, epilepsy and schizophrenia. This, together with results from other types of studies, indicates the potential therapeutic value of developing drugs capable of selectively activating, inhibiting, or modulating GABA B receptor function.

NEUROTRANSMITTER AND NEUROMODULATORY MECHANISMS INVOLVED IN ALCOHOL ABUSE AND ALCOHOLISM.

Acute or chronic consumption of alcohol interferes differentially with transmission processes in the CNS, affecting many--if not all--of the known neurotransmitter systems. Conversely, selective pharmacological manipulations of some of these neurotransmitter systems have been shown to reduce ethanol intake and preference as well as the severity of the ethanol withdrawal syndrome in animal models, certain compounds having even been employed successfully in the clinic. This review examines the studies which have attempted to elucidate the roles of these neurotransmitter systems in the mechanisms involved in the various aspects of alcohol abuse and alcoholism, with an emphasis on recent developments. The brain's major amino acid transmitter systems--inhibitory gamma-aminobutyric acid (GABA) and excitatory glutamate--have been widely studied over the past decade, with the general consensus that acute ethanol facilitates GABAergic transmission (by enhancing chloride conductance through the GABAA receptor) and inhibits glutamatergic function (by decreasing cationic conductance through the NMDA receptor). Conversely, the development of tolerance associated with chronic ethanol consumption leads to a reduced GABAergic and increased glutamatergic function. Interactions between ethanol and the monoaminergic transmitter systems are complex. Dopaminergic and noradrenergic mechanisms, along with the endogenous opioid systems of the brain, seem to be implicated in the rewarding effects of ethanol via activation of positive reinforcement pathways, while the serotonergic system mediates negative reinforcement. A number of ligands of the dopaminergic, serotonergic and opioidergic receptors involved in ethanol consumption-related behaviors have been recognized for their effects in reducing ethanol preference and/or alleviating symptoms of the ethanol withdrawal syndrome in various animal models. Several of these substances are being used with success clinically. Studies of the central cholinergic system in alcoholics have provided clues to the mechanisms underlying the deleterious effects of ethanol on learning and memory, and evidence of a reduced central cholinergic activity has been reported in alcohol-dependent patients. Interestingly, acetylcholine-rich grafts and cholinomimetic drugs have been found to ameliorate ethanol-induced behavioral deficits in alcoholized rats. More generally, basic studies on alcohol's effects on central neurotransmission certainly hold the key to the development of new strategies for the treatment of alcoholism.

Elementary cognitive subprocesses in a double-blind study of haloperidol and risperidone in subchronic schizophrenic patients

Recent studies have shown advantages of the atypical neuroleptic agent risperidone against conventional neuroleptic agents in order to enhance or maintain cognitive abilities. It is not yet clear whether unspecific or selective pharmacological manipulation of cognitive subprocesses is responsible for differences in psychometric tests. To answer this question we used the reaction-time decomposition task by Donders (1868) in a double-blind trial of haloperidol and risperidone.

Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia.

Several lines of evidence implicate NMDA receptor dysfunction in the cognitive deficits of schizophrenia, suggesting that pharmacological manipulation of the NMDA receptor may be a feasible therapeutic strategy for treatment of these symptoms. Although direct manipulation of regulatory sites on the NMDA receptor is the most obvious approach for pharmacological intervention, targeting the G-protein coupled metabotropic glutamate (mGlu) receptors may be a more practical strategy for long-term regulation of abnormal glutamate neurotransmission. Heterogeneous distribution, both at structural and synaptic levels, of at least eight subtypes of mGlu receptors suggests that selective pharmacological manipulation of these receptors may modulate glutamatergic neurotransmission in a regionally and functionally distinct manner. Two promising targets for improving cognitive functions are mGlu5 or mGluR2/3 receptors, which can modulate the NMDA receptor-mediated signal transduction by pre- or postsynaptic mechanisms. Preclinical studies indicate that activation of these subtypes of mGlu receptors may be an effective strategy for reversing cognitive deficits resulting form reduced NMDA receptor mediated neurotransmission.