Pharmacology [?] Therapeutics

Published by Elsevier
Online ISSN: 0163-7258
Publications
Article
Stroke is a major clinical problem, and acute pharmacological intervention with neuroprotective agents has so far been unsuccessful. Recently, there has been considerable interest in the potential therapeutic benefit of nitrone-derived free radical trapping agents as neuroprotective agents. Nitrone compounds have been shown to be beneficial in animal models of various diseases, and the prototypic compound alpha-phenyl-N-tert-butylnitrone (PBN) has been extensively demonstrated to be neuroprotective in rat models of transient and permanent focal ischemia. The nitrone radical trapping agent disodium 2,4-disulfophenyl-N-tert-butylnitrone (NXY-059) has also been shown to be neuroprotective in these models. Furthermore, it has recently been shown to improve neurological function and reduce infarct volume in a primate model of permanent focal ischemia even when given 4 hr postocclusion. While radical trapping activity is demonstrable with NXY-059 and other nitrone compounds such as PBN, this activity is weak. Arguments for and against ascribing radical trapping as the therapeutic mechanism of action are discussed. This compound is well tolerated in human stroke patients and can be administered to produce plasma concentrations exceeding those effective in animal models; crucially, at the same time, it has also been shown to be effective in animal models. NXY-059 may thus be the first compound to be examined in stroke patients using drug exposure and time to treatment that have been shown to be effective in animal models of stroke.
 
Article
This review assimilates information on the regulation of the metabolism of those inositol phosphates and diacylglycerols that respond to receptor activation. Particular emphasis is placed on the regulation of specific enzymes, the occurrence of isoenzymes, and metabolic compartmentalization; the overall aim is to demonstrate the significance of these activities in relation to the physiological impact of the various cell signalling processes.
 
Article
The generation of the second messenger inositol 1,4,5-trisphosphate (Ins(1,4,5)P(3)) and its associated release of Ca(2+) from internal stores is a highly conserved module in intracellular signaling from Drosophila to mammals. Many cell types, often nonexcitable cells, depend on this pathway to couple external signals to intracellular Ca(2+) release. However, despite the presence of the requisite Ins(1,4,5)P(3) signaling machinery, excitable cells such as cardiac myocytes employ a robust alternate system of intracellular Ca(2+) release, namely, a coupled system of Ca(2+) influx, followed by Ca(2+) release via the IP(3)R-related ryanodine receptors. In these systems, Ins(1,4,5)P(3) signaling pathways appear to be largely dormant. In this review, we consider the general features of inositol phosphate (InsP) responses in cardiac myocytes and the molecules mediating these responses. The spatial localization of Ins(1,4,5)P(3) generation and Ins(1,4,5)P(3) receptor (IP(3)Rs) is likely of key importance, and we examine the state of knowledge in atrial, ventricular, and Purkinje myocytes. Several studies have implicated Ins(1,4,5)P(3) generation in both arrhythmogenic and hypertrophic responses, and possible mechanisms involving Ins(1,4,5)P(3) are discussed. While Ins(1,4,5)P(3) is unlikely to be a key player in cardiac excitation-contraction (EC) coupling, its potential role in an alternate Ca(2+) release system to signal changes in gene transcription warrants further investigation. Such studies will help to determine whether cardiac Ins(1,4,5)P(3) generation represents a vestigial pathway or plays an active role in cardiac signaling.
 
Article
Epilepsy is one of the most common neurological disorders. Although epilepsy can be idiopathic, it is estimated that up to 50% of all epilepsy cases are initiated by neurological insults and are called acquired epilepsy (AE). AE develops in 3 phases: (1) the injury [central nervous system (CNS) insult]. (2) epileptogenesis (latency), and (3) the chronic epileptic (spontaneous recurrent seizure) phases. Status epilepticus (SE), stroke, and traumatic brain injury (TBI) are 3 major examples of common brain injuries that can lead to the development of AE. It is especially important to understand the molecular mechanisms that cause AE because it may lead to innovative strategies to prevent or cure this common condition. Recent studies have offered new insights into the cause of AE and indicate that injury-induced alterations in intracellular calcium concentration levels ([Ca(2+)](i)) and calcium homeostatic mechanisms play a role in the development and maintenance of AE. The injuries that cause AE are different, but the share a common molecular mechanism for producing brain damage--an increase in extracellular glutamate and are exposed to increased [Ca(2+)](i) are the cellular substrates to develop epilepsy because dead cells do not seize. The neurons that survive injury sustain permanent long-term plasticity changes in [Ca(2+)](i) and calcium homeostatic mechanisms that are permanent and are a prominent feature of the epileptic phenotype. In the last several years, evidence has accumulated indicating that the prolonged alteration in neuronal calcium dynamics plays an important role in the induction and maintenance of the prolonged neuroplasticity changes underlying the epileptic phenotype. Understanding the role of calcium as a second messenger in the induction and maintenance of epilepsy may provide novel insights into therapeutic advances that will prevent and even cure AE.
 
Article
Within the last 20 years, rapid nongenomic actions of steroid hormones have been demonstrated to occur via an interaction with ligand-gated ion channels. For example, the pregnane neurosteroid allopregnanolone (ALLOP) is a potent positive modulator of gamma-aminobutyric acid(A) (GABA(A)) receptors. The physiological significance of fluctuations in endogenous ALLOP levels has been investigated with regard to disease states and the effect of therapeutic agents on ALLOP levels. Because the pharmacological profile of ALLOP is similar to that of ethanol (EtOH), the modulatory effect of pregnane neurosteroids on EtOH dependence and withdrawal will be the focus of this review. Data on the effects of chronic EtOH exposure and withdrawal on pregnane neurosteroid levels, biosynthetic enzymes, and changes in neurosteroid sensitivity will be summarized. Results from genetic animal models indicate that seizure-prone animals have a persistent decrease in endogenous ALLOP levels during EtOH withdrawal in conjunction with tolerance to ALLOP's anticonvulsant effect. Manipulation of endogenous ALLOP levels with finasteride also markedly reduced the severity of chronic EtOH withdrawal. Gene mapping studies provide a hint for an interaction between genes for GABA(A) receptor subunits and the biosynthetic enzyme 5alpha-reductase. Overall, the results are suggestive of a relationship between endogenous pregnane neurosteroid levels and behavioral changes in excitability during EtOH withdrawal, consistent with recent findings in humans. While the findings with ALLOP emphasize the therapeutic potential of neurosteroid treatment during EtOH withdrawal, the gene mapping studies suggest that pregnane neurosteroid biosynthesis may represent a target for therapeutic intervention in the treatment of alcohol dependence.
 
Article
PDZ (an acronym representing three proteins--postsynaptic density protein PSD95/SAP90, drosophila tumor suppressor DLGA, and tight junction protein ZO-1) domain containing proteins are adapter proteins that play indispensable roles in regulating cell growth, development, and differentiation, predominantly through their capacity to serve as central organizers of protein complexes at the plasma membrane. A recently identified member of this protein family is melanoma differentiation associated gene-9 (mda-9), also known as syntenin, which was first identified as a gene down-regulated during human melanoma differentiation as mda-9 and subsequently recognized as an interacting partner of the cell-surface heparan sulfate syndecans, syntenin. Interest in mda-9/syntenin is intensifying because of its involvement in organization of protein complexes in the plasma membranes, regulation of B cell development, intracellular trafficking and cell surface targeting, cancer metastasis, synaptic transmission, and axonal outgrowth. In this review, we discuss the identification, structure and function of mda-9/syntenin and delineate future studies to address its role in regulating key physiological and pathological processes.
 
Article
The demonstration that Ras requires prenylation for its cancer-causing activity led several groups of investigators to an intense search for farnesyltransferase and geranylgeranyltransferase inhibitors as potential anticancer drugs. Rational design of small organic molecules that mimic the carboxyl terminal tetrapeptide prenylation site on Ras resulted in pharmacological agents capable of inhibiting Ras processing and selectively antagonizing oncogenic signaling, and suppressing human tumor growth in mouse models without side effects. These agents presently are undergoing advanced preclinical studies. This review describes the efforts of several groups to design, synthesize and evaluate the biological activities of several classes of prenyltransferase inhibitors. Several important issues, such as mechanism of action of prenyltransferase inhibitors and potential mechanisms of resistance to inhibition of K-Ras farnesylation, are also discussed.
 
Article
In the past 4 years, RNA interference (RNAi) has become widely used as an experimental tool to analyse the function of mammalian genes, both in vitro and in vivo. By harnessing an evolutionary conserved endogenous biological pathway, first identified in plants and lower organisms, double-stranded RNA (dsRNA) reagents are used to bind to and promote the degradation of target RNAs, resulting in knockdown of the expression of specific genes. RNAi can be induced in mammalian cells by the introduction of synthetic double-stranded small interfering RNAs (siRNAs) 21-23 base pairs (bp) in length or by plasmid and viral vector systems that express double-stranded short hairpin RNAs (shRNAs) that are subsequently processed to siRNAs by the cellular machinery. RNAi has been widely used in mammalian cells to define the functional roles of individual genes, particularly in disease. In addition, siRNA and shRNA libraries have been developed to allow the systematic analysis of genes required for disease processes such as cancer using high throughput RNAi screens. RNAi has been used for the knockdown of gene expression in experimental animals, with the development of shRNA systems that allow tissue-specific and inducible knockdown of genes promising to provide a quicker and cheaper way to generate transgenic animals than conventional approaches. Finally, because of the ability of RNAi to silence disease-associated genes in tissue culture and animal models, the development of RNAi-based reagents for clinical applications is gathering pace, as technological enhancements that improve siRNA stability and delivery in vivo, while minimising off-target and nonspecific effects, are developed.
 
Article
Since its commercial advent in 1985, transcranial magnetic stimulation (TMS), a technique for stimulating neurons in the cerebral cortex through the scalp, safely and with minimal discomfort, has captured the imaginations of scientists, clinicians and lay observers. Initially a laboratory tool for neurophysiologists studying the human motor system, TMS now has a growing list of applications in clinical and basic neuroscience. Although we understand many of its effects at the system level, detailed knowledge of its actions, particularly as a modulator of neural activity, has lagged, due mainly to the lack of suitable non-human models. Nevertheless, these gaps have not blocked the therapeutic application of TMS in brain disorders. Moderate success has been achieved in treating disorders such as depression, where the U.S. Food and Drug Administration has cleared a TMS system for therapeutic use. In addition, there are small, but promising, bodies of data on the treatment of schizophrenic auditory hallucinations, tinnitus, anxiety disorders, neurodegenerative diseases, hemiparesis, and pain syndromes. Some other nascent areas of study also exist. While the fate of TMS as a therapeutic modality depends on continued innovation and experimentation, economic and other factors may be decisive.
 
Article
Studies carried out in the last 20 years indicated that biological rhythms can be detected in the pharmacokinetics of most classes of drugs. These time-dependent variations could be due to parallel changes in the physiological functions and variables involved in the absorption, distribution, metabolism and excretion of drugs. A review of the data available suggests that the peak and trough values of these functions and variables do not occur at the same hour of the day in every factor involved in drug disposition. This information could be used to predict the time-dependent changes in the pharmacokinetics. The presence of circadian variations in the kinetics of drugs raise the rather old question: "When to administer drug?"
 
The coupling of h 2 -adrenergic receptor signaling to CFTR chloride channel function. CFTR, EBP50/NHERF1, and h 2 AR can exist as a macromolecular complex at the apical surfaces of epithelial cells. G proteins can be associated with h 2 AR and protein kinase A (PKA) anchored to AKAP (ezrin) and is likely to be in the complex. Upon agonist activation of the receptor, adenylate cyclase is stimulated through the Gs pathway, leading to an increase in highly compartmentalized cAMP. This increased local concentration of cAMP leads to the activation of PKA, which is in close proximity to CFTR, resulting in a compartmentalized and specific signaling from h 2 AR to the CFTR channel. Phosphorylation disrupts the complex, leading to the receptor-based activation of CFTR (adapted from Naren et al., 2003).  
Article
The cystic fibrosis transmembrane conductance regulator (CFTR) is the product of the gene mutated in patients with cystic fibrosis (CF). CFTR is a cAMP-regulated chloride channel localized primarily at the apical or luminal surfaces of epithelial cells lining the airway, gut, exocrine glands, etc., where it is responsible for transepithelial salt and water transport. CFTR chloride channel belongs to the superfamily of the ATP-binding cassette (ABC) transporters, which bind ATP and use the energy to drive the transport of a wide variety of substrates across extra- and intracellular membranes. A growing number of proteins have been reported to interact directly or indirectly with CFTR chloride channel, suggesting that CFTR might regulate the activities of other ion channels, receptors, or transporters, in addition to its role as a chloride conductor. The molecular assembly of CFTR with these interacting proteins is of great interest and importance because several human diseases are attributed to altered regulation of CFTR, among which cystic fibrosis is the most serious one. Most interactions primarily occur between the opposing terminal tails (N- or C-) of CFTR and its binding partners, either directly or mediated through various PDZ domain-containing proteins. These dynamic interactions impact the channel function as well as the localization and processing of CFTR protein within cells. This review focuses on the recent developments in defining the assembly of CFTR-containing complexes in the plasma membrane and its interacting proteins.
 
Article
Over the past decade, there has been increasing interest in the role of serotonin 6 (5-HT6) receptors in higher cognitive processes such as memory. Polymorphisms of the 5-HT6 receptor have been implicated in syndromes that affect cognition, such as schizophrenia and dementia. Manipulation of 5-HT6 receptor activity alters the transmission of several neurotransmitters important in memory: acetylcholine and glutamate, as well as dopamine, ã-aminobutyric acid (GABA), epinephrine (E), and norepinephrine (NE). Several 5-HT6 antagonists have been developed, advancing the understanding of the relationship between 5-HT6 blockade and memory consolidation in diverse learning paradigms. There is also evidence that 5-HT6 receptor activity affects anxiety behaviors and may be involved in the pathophysiology of schizophrenia. Several clinically useful atypical antipsychotics and antidepressants have 5-HT6 affinity, but recently developed selective 5-HT6 receptor antagonists may present attractive, new therapeutic options for several types of disease states.
 
Article
Cyclic nucleotide phosphodiesterases (PDEs), which are ubiquitously distributed in mammalian tissues, play a major role in cell signaling by hydrolyzing cAMP and cGMP. Due to their diversity, which allows specific distribution at cellular and subcellular levels, PDEs can selectively regulate various cellular functions. Their critical role in intracellular signaling has recently designated them as new therapeutic targets for inflammation. The PDE superfamily represents 11 gene families (PDE1 to PDE11). Each family encompasses 1 to 4 distinct genes, to give more than 20 genes in mammals encoding the more than 50 different PDE proteins probably produced in mammalian cells. Although PDE1 to PDE6 were the first well-characterized isoforms because of their predominance in various tissues and cells, their specific contribution to tissue function and their regulation in pathophysiology remain open research fields. This concerns particularly the newly discovered families, PDE7 to PDE11, for which roles are not yet established. In many pathologies, such as inflammation, neurodegeneration, and cancer, alterations in intracellular signaling related to PDE deregulation may explain the difficulties observed in the prevention and treatment of these pathologies. By inhibiting specifically the up-regulated PDE isozyme(s) with newly synthesized potent and isozyme-selective PDE inhibitors, it may be potentially possible to restore normal intracellular signaling selectively, providing therapy with reduced adverse effects.
 
Article
The main inhibitory neurotransmitter system in the brain, the gamma-aminobutyric acid (GABA) system, is the target for many clinically used drugs to treat, for example, anxiety disorders and epilepsy and to induce sedation and anesthesia. These drugs facilitate the function of pentameric A-type GABA (GABA(A)) receptors that are extremely widespread in the brain and composed from the repertoire of 19 subunit variants. Modern genetic studies have found associations of various subunit gene polymorphisms with neuropsychiatric disorders, including alcoholism, schizophrenia, anxiety, and bipolar affective disorder, but these studies are still at their early phase because they still have failed to lead to validated drug development targets. Recent neurobiological studies on new animal models and receptor subunit mutations have revealed novel aspects of the GABA(A) receptors, which might allow selective targeting of the drug action in receptor subtype-selective fashion, either on the synaptic or extrasynaptic receptor populations. More precisely, the greatest advances have occurred in the clarification of the molecular and behavioral mechanisms of action of the GABA(A) receptor agonists already in the clinical use, such as benzodiazepines and anesthetics, rather than in the introduction of novel compounds to clinical practice. It is likely that these new developments will help to overcome the present problems of the chronic treatment with nonselective GABA(A) agonists, that is, the development of tolerance and dependence, and to focus the drug action on the neurobiologically and neuropathologically relevant substrates.
 
Article
The five selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram, have similar antidepressant efficacy and a similar side effect profile. They differ, however, in their pharmacokinetic properties. Under steady-state concentrations, their half-lives range between 1 and 4 days for fluoxetine (7 and 15 days for norfluoxetine) and between 21 (paroxetine) and 36 (citalopram) hr for the other SSRIs. Sertraline and citalopram show linear and fluoxetine, fluvoxamine, and paroxetine nonlinear pharmacokinetics. SSRIs underlie an extensive metabolism with high interindividual variability, whereby cytochrome P450 (CYP) isoenzymes play a major role. Therefore, resulting blood concentrations are highly variable between individuals. Except for N-demethylated fluoxetine, metabolites of SSRIs do not contribute to clinical actions. Therapeutically effective blood concentrations are unclear so far, although there is evidence for minimal effective and upper-threshold concentrations that should not be exceeded. Paroxetine and, to a lesser degree, fluoxetine and norfluoxetine are potent inhibitors of CYP2D6 and fluvoxamine of CYP1A2 and CYP2C19. This can give rise to drug-drug interactions that may have no effect, lead to intoxication, or improve the therapeutic response. These different pharmacokinetic properties of the five SSRIs, especially their drug-drug interaction potential, should be considered when selecting a distinct SSRI for treatment of depression or other disorders with a suggested dysfunction of the serotonergic system in the brain.
 
Article
Following hints in the early literature about adenosine 5'-triphosphate (ATP) injections producing pain, an ion-channel nucleotide receptor was cloned in 1995, P2X3 subtype, which was shown to be localized predominantly on small nociceptive sensory nerves. Since then, there has been an increasing number of papers exploring the role of P2X3 homomultimer and P2X2/3 heteromultimer receptors on sensory nerves in a wide range of organs, including skin, tongue, tooth pulp, intestine, bladder, and ureter that mediate the initiation of pain. Purinergic mechanosensory transduction has been proposed for visceral pain, where ATP released from epithelial cells lining the bladder, ureter, and intestine during distension acts on P2X3 and P2X2/3, and possibly P2Y, receptors on subepithelial sensory nerve fibers to send messages to the pain centers in the brain as well as initiating local reflexes. P1, P2X, and P2Y receptors also appear to be involved in nociceptive neural pathways in the spinal cord. P2X4 receptors on spinal microglia have been implicated in allodynia. The involvement of purinergic signaling in long-term neuropathic pain and inflammation as well as acute pain is discussed as well as the development of P2 receptor antagonists as novel analgesics.
 
Article
Steroid hormone biosynthesis is catalyzed by the action of a series of cytochrome P450 enzymes as well as reductases. Defects in steroid hydroxylating P450s are the cause of several severe defects such as the adrenogenital syndrome (AGS), corticosterone methyl oxidase (CMO) I or II deficiencies, or pseudohermaphroditism. In contrast, overproduction of steroid hormones can be involved in breast or prostate cancer, in hypertension, and heart fibrosis. Besides inhibiting the action of the steroid hormones on the level of steroid hormone receptors by using antihormones, which often is connected with severe side effects, more recently the steroid hydroxylases themselves turned out to be promising new targets for drug development. Since the 3-dimensional structures of steroid hydroxylases are not yet available, computer models of the corresponding CYPs may help to develop new inhibitors of these enzymes. During the past years, the necessary test systems have been developed and new compounds have been synthesized, which displayed selective and specific inhibition of CYP17, CYP11B2, and CYP11B1. With some of these potential new drugs, clinical trials are under way. It can be expected that in the near future some of these compounds will contribute to our arsenal of new and selective drugs.
 
Article
Asthma and chronic obstructive pulmonary disease (COPD) are inflammatory lung diseases that are characterized by systemic and chronic localized inflammation and oxidative stress. Sources of oxidative stress arise from the increased burden of inhaled oxidants, as well as elevated amounts of reactive oxygen species (ROS) released from inflammatory cells. Increased levels of ROS, either directly or via the formation of lipid peroxidation products, may play a role in enhancing the inflammatory response in both asthma and COPD. Moreover, in COPD it is now recognized as the main pathogenic factor for driving disease progression and increasing severity. ROS and lipid peroxidation products can influence the inflammatory response at many levels through its impact on signal transduction mechanisms, activation of redox-sensitive transcriptions factors, and chromatin regulation resulting in pro-inflammatory gene expression. It is this impact of ROS on chromatin regulation by reducing the activity of the transcriptional co-repressor, histone deacetylase-2 (HDAC-2), that leads to the poor efficacy of corticosteroids in COPD, severe asthma, and smoking asthmatics. Thus, the presence of oxidative stress has important consequences for the pathogenesis, severity, and treatment of asthma and COPD. However, for ROS to have such an impact, it must first overcome a variety of antioxidant defenses. It is likely, therefore, that a combination of antioxidants may be effective in the treatment of asthma and COPD. Various approaches to enhance the lung antioxidant screen and clinical trials of antioxidant compounds are discussed.
 
Article
The pyrethroids are a widely used class of insecticides to which there is significant human exposure. They are however generally regarded as safe to man, and there have been few reports of human fatalities. Their acute toxicity is dominated by pharmacological actions upon the central nervous system (CNS), predominantly mediated by prolongation of the kinetics of voltage-gated sodium channels, although other mechanisms operate. This review summarizes our present understanding of such actions and the pharmacological options to antagonize them. One significant problem is the very clear heterogeneity of pyrethroid sensitivity that is seen across sodium channel subtypes; however, the distribution and function of these across the central nervous system are poorly characterized. The review also provides an overview of recent studies that suggest additional effects of pyrethroids: developmental neurotoxicity, the production of neuronal death, and action mediated via pyrethroid metabolites. The evidence for these is at present equivocal, but all 3 carry important implications for human health.
 
Article
Embryonic stem (ES) cells are specialised cells derived from the early embryo, which are capable of both sustained propagation in the undifferentiated state as well as subsequent differentiation into the majority of cell lineages. Human ES cells are being developed for clinical tissue repair, but a number of problems must be addressed before this becomes a reality. However, they also have potential for translational benefit through its use as a test system for screening pharmaceutical compounds. In the cardiac field, present model systems are not ideal for either screening or basic pharmacological/physiological studies. Cardiomyocytes produced from human ES differentiation have advantages for these purposes over the primary isolated cells or the small number of cell lines available. This review describes the methodology for obtaining cardiomyocytes from human embryonic stem cell-derived cardiomyocyte (hESCM), for increasing the proportion of cardiomyocytes in the preparation and for isolating single embryonic stem cell-derived cardiomyocyte (ESCM) from clusters. Their morphological, contractile and electrophysiological characteristics are compared to mature and immature primary cardiomyocytes. The advantages and disadvantages of the hESCM preparation for long term culture and genetic manipulation are described. Basic pharmacological studies on adrenoceptors and muscarinic receptors in hESCM have been performed, and have given stable and reproducible responses. Prolongation of repolarisation can be detected using hESCM cultured on multielectrode arrays (MEA). Human ESCM have a clear potential to improve model systems available for both basic scientific studies and pharmaceutical screening of cardiac target compounds.
 
Article
Since the London fog of 1952, in which more than 4000 people were killed in 4 days, the combined efforts of scientists from several disciplines, including those from the environmental health, clinical and biomedical disciplines, have raised serious concerns about the impact of air pollutants on human health. These environmental pollutants are rapidly being recognized as important and independent risk factors for several diseases such as asthma, chronic obstructive pulmonary disease, lung cancer, atherosclerosis, ischemic heart disease and stroke. Although the relative effects of particulate matter air pollution (aerodynamic diameter <10 microm, or PM(10)) are greater for respiratory than for cardiovascular deaths, the number of deaths attributable to PM(10) is much larger for cardiovascular than for respiratory reasons due to the higher prevalence of cardiovascular disease in the general population. This review summarizes current understanding of the mechanisms underlying the associations between PM(10) exposure and cardiovascular morbidity and mortality.
 
Article
Norepinephrine (NE) has widespread projections throughout the brain, and thus, is ideally positioned to orchestrate neural functions based on arousal state. For example, NE can increase "signal/noise" ratio in the processing of sensory stimuli, and can enhance long-term memory consolidation in the amygdala and hippocampus through actions at alpha-1 and beta adrenoceptors. Over the last 20 years, NE has also been shown to play a powerful role in regulating the working memory and attention functions of the prefrontal cortex (PFC). Moderate levels of NE released under control conditions strengthen prefrontal cortical functions via actions at post-synaptic alpha-2A adrenoceptors with high affinity for NE, while high levels of NE release during stress impair PFC cortical functions via alpha-1 and possibly beta-1 receptors with lower affinity for NE. Thus, levels of NE determine whether prefrontal cortical or posterior cortical systems control our behavior and thought. Understanding these receptor mechanisms has led to new intelligent treatments for neuropsychiatric disorders associated with PFC dysfunction.
 
Article
For many years, researchers have suggested that abnormalities in circadian rhythms may underlie the development of mood disorders such as bipolar disorder (BPD), major depression and seasonal affective disorder (SAD). Furthermore, some of the treatments that are currently employed to treat mood disorders are thought to act by shifting or "resetting" the circadian clock, including total sleep deprivation (TSD) and bright light therapy. There is also reason to suspect that many of the mood stabilizers and antidepressants used to treat these disorders may derive at least some of their therapeutic efficacy by affecting the circadian clock. Recent genetic, molecular and behavioral studies implicate individual genes that make up the clock in mood regulation. As well, important functions of these genes in brain regions and neurotransmitter systems associated with mood regulation are becoming apparent. In this review, the evidence linking circadian rhythms and mood disorders, and what is known about the underlying biology of this association, is presented.
 
Article
At the neuromuscular junction, P2-purinoceptors mediate the actions of the co-transmitter ATP and P1-purinoceptors, those of its degradation product adenosine. The classification of the subtypes of P1- and P2-purinoceptors and their signal transduction routes is presented. Purinoceptor-mediated effects on the prejunctional release of acetylcholine and the postjunctional desensitization and expression of nicotinic receptors are discussed in depth. An additional section on the reversal action of the P2-purinoceptor antagonist suramin on neuromuscular block underscores the importance of testing purinoceptor-targeted drugs once they will be marketed, to avoid adverse effects in patients.
 
Article
This review concerns the development of small molecule therapeutics for the inherited neurodegenerative disease Friedreich ataxia (FRDA). FRDA is caused by transcriptional repression of the nuclear FXN gene, encoding the essential mitochondrial protein frataxin and accompanying loss of frataxin protein. Frataxin insufficiency leads to mitochrondrial dysfunction and progressive neurodegeneration, along with scoliosis, diabetes and cardiomyopathy. Individuals with FRDA generally die in early adulthood from the associated heart disease, the most common cause of death in FRDA. While antioxidants and iron chelators have shown promise in ameliorating the symptoms of the disease, there is no effective therapy for FRDA that addresses the cause of the disease, the loss of frataxin protein. Gene therapy and protein replacement strategies for FRDA are promising approaches; however, current technology is not sufficiently advanced to envisage treatments for FRDA coming from these approaches in the near future. Since the FXN mutation in FRDA, expanded GAA.TTC triplets in an intron, does not alter the amino acid sequence of frataxin protein, gene reactivation would be of therapeutic benefit. Thus, a number of laboratories have focused on small molecule activators of FXN gene expression as potential therapeutics, and this review summarizes the current status of these efforts, as well as the molecular basis for gene silencing in FRDA.
 
Article
Macrolide antibiotics administered in sub-antimicrobial doses improve pulmonary function and decrease exacerbation frequency for persons with diffuse panbronchiolitis or cystic fibrosis. Data also suggest a beneficial effect of macrolide antibiotics in the treatment of steroid dependent asthma. Many potential immunomodulatory effects of macrolide antibiotics have been reported including the ability to down-regulate prolonged inflammation, decreasing airway mucus secretion, inhibiting bacterial biofilm, decreasing the production of reactive oxygen species, inhibiting neutrophil activation and mobilization, accelerating neutrophil apoptosis, and blocking the activation of nuclear transcription factors. Macrolides initially decrease, then increase, and have finally a sustained suppression of cytokine secretions from normal human bronchial epithelial cells through inhibition and activation of extracellular signal-regulated kinases (ERK) and then reversibly retard cell proliferation probably through ERK. Consistent with this, macrolide antibiotics possibly reduce mucin production as well as neutrophil migration by interfering with ERK signal transduction.
 
Article
The process of RNA editing involves the modification of mRNA at specific sites by adenosine deaminases that act on RNA (ADAR) enzymes. By catalyzing the conversion of adenosine to inosine, these enzymes alter the way in which the mRNA is translated, and consequently alter the primary structure of the resultant proteins. The serotonin (5HT) 2C receptor (5HT2CR) is currently the only known member of the superfamily of seven transmembrane domain receptors (7TMRs) to undergo this modification, and provides a fascinating case study in the effects of such changes. Here we review the current state of knowledge surrounding the editing of the 5HT2CR, the stark differences in signalling arising due to this process, and the potential for (and difficulties in) exploiting the phenomenon for improved therapeutic intervention in various neurological disorders.
 
Article
Animal models of clinical depression have frequently focused on the contribution of stressors to the induction of behavioral impairments and pharmacological intervention in the amelioration of these disturbances. Stressors provoke various behavioral disturbances and influence the activity of central neurotransmitters implicated in depression. It is our contention that those variables which favor the provocation of amine depletions or prevent the development of a neurochemical adaptation will increase vulnerability to behavioral disturbances. It is essential to consider, however, that marked interindividual and interstrain differences exist in the behavioral and neurochemical response to stressors, and in the effectiveness of antidepressant treatments.
 
Article
Tumor cells have an increased demand for nutrients; this demand is met by increased availability of nutrients through vasculogenesis and by enhanced cellular entry of nutrients through upregulation of specific transporters. This review focuses on three groups of nutrient transporters relevant to cancer: glucose transporters, lactate transporters, and amino acid transporters. Tumor cells enhance glucose uptake via induction of GLUT1 and SGLT1, and coordinate the increased entry of glucose with increased glycolysis. Since enhanced glycolysis in cancer is associated with lactate production, tumor cells must find a way to eliminate lactic acid to prevent cellular acidification. This is achieved by the upregulation of MCT4, a H+-coupled lactate transporter. In addition, the Na+-coupled lactate transporter SMCT1 is silenced in cancer. SMCT1 also transports butyrate and pyruvate, which are inhibitors of histone deacetylases. The silencing of SMCT1 occurs in cancers of a variety of tissues. Re-expression of SMCT1 in cancer cell lines leads to growth arrest and apoptosis in the presence of butyrate or pyruvate, suggesting that the transporter may function as a tumor suppressor. Tumor cells meet their amino acid demands by inducing xCT/4F2hc, LAT1/4F2hc, ASCT2, and ATB0,+. xCT/4F2hc is related primarily to glutathione status, protection against oxidative stress, and cell cycle progression, whereas the other three transporters are related to amino acid nutrition. Pharmacologic blockade of LAT1/4F2hc, xCT/4F2hc, or ATB0,+ leads to inhibition of cancer cell growth. Since tumor cells selectively regulate these nutrient transporters to support their rapid growth, these transporters have potential as drug targets for cancer therapy.
 
Article
Benzodiazepines produce their pharmacological effects by regulating the interaction of GABA with its recognition site on the GABAA receptor complex. In fact, the anxiolytic effect of benzodiazepines may be considered the consequence of the activation of the GABAA receptors induced by these drugs. On the contrary, beta-carboline derivatives which bind with high affinity to benzodiazepine recognition sites modulate the GABAergic transmission in a manner opposite to that of benzodiazepines. Thus, these compounds reduce the function of the GABA-coupled chloride channel and produce pharmacological effects (anxiogenic, proconvulsant and convulsant) opposite to those of benzodiazepines. Taken together, these data strongly indicate that the GABAA receptor complex plays a major role in the pharmacology, neurochemistry and physiopathology of stress and anxiety. This conclusion is further supported by the finding that the function of the GABAA/benzodiazepine receptor complex may be modified by the emotional state of the animals before sacrifice. Accordingly, using an unstressed animal model, the 'handling-habituated' rats, it has been demonstrated that stress, like anxiogenic drugs, decreases the function of GABAA receptor complex, an effect mimicked by the in vivo administration of different inhibitors of GABAergic transmission and antagonized by anxiolytic benzodiazepines. Moreover, a long-lasting down regulation of GABAergic synapses can be obtained after repeated administration of anxiogenic, proconvulsant and convulsant negative modulators of GABAergic transmission. The latter finding further suggests that GABAergic synapses undergo rapid and persistent plastic changes when the GABAergic transmission is persistently inhibited. Finally, the evidence that the activity of mesocortical dopaminergic pathways is altered in opposite manner by drugs that either inhibit or enhance the GABAergic transmission indicates that GABA has a functional role in regulation of dopaminergic neurons in the rat cerebral cortex. Altogether these results suggest that cortical GABAergic and dopaminergic transmission play a major role in the pharmacology, neurochemistry and pathology of the emotional states and fear.
 
Article
Cannabinoids produce a plethora of biological effects, including the modulation of neuronal activity through the activation of CB(1) receptors and of immune responses through the activation of CB(2) receptors. The selective targeting of either of these two receptor subtypes has clear therapeutic value. Recent evidence indicates that some of the cannabinomimetic effects previously thought to be produced through CB(1) and/or CB(2) receptors, be they on neuronal activity, on the vasculature tone or immune responses, still persist despite the pharmacological blockade or genetic ablation of CB(1) and/or CB(2) receptors. This suggests that additional cannabinoid and cannabinoid-like receptors exist. Here we will review this evidence in the context of their therapeutic value and discuss their true belonging to the endocannabinoid signaling system.
 
Article
Several pharmacotherapies for tobacco dependence and withdrawal have been approved by the Food and Drug Administration to aid smoking cessation. These medicines double to triple the odds of cessation compared to placebo, with the diversity in chemical entity (e.g., nicotine, varenicline, bupropion) and route (e.g., nicotine gum and transdermal patch) providing options for people who find a given medication unacceptable or ineffective. Treatments in development include vaccines, combinations of existing products, and new indications, such as reduced tobacco use and exposure. These therapies have been developed on the foundation of research on the neuropharmacology of tobacco dependence and withdrawal. Ongoing research is expected to contribute to more efficacious use of existing therapies and the development of new approaches. This article addresses these developments as well as the challenges to medication development. Challenges include understanding the population-based and individual differences in the vulnerability to dependence and responsiveness to various treatment options, which could contribute to effective treatment to patient matching. Research on the CNS effects of administration and withdrawal of nicotine and other tobacco product constituents is expanding, providing the basis for more effective therapeutic approaches and new medications development. Additionally, whereas medications are approved on the basis of standardized assessments of efficacy and safety in clinical trials, the public health impact of medications depends also on their appeal to smokers and their effectiveness in actual use settings. Research on more effective medication use along with policies that support improved access and utilization are vital to conquering the tobacco epidemic.
 
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This review is a survey of various approaches to targeting cytotoxic anticancer drugs to tumors primarily through biomolecules expressed by cancer cells or associated vasculature and stroma. These include monoclonal antibody immunoconjugates; enzyme prodrug therapies, such as antibody-directed enzyme prodrug therapy, gene-directed enzyme prodrug therapy, and bacterial-directed enzyme prodrug therapy; and metabolism-based therapies that seek to exploit increased tumor expression of, e.g., proteases, low-density lipoprotein receptors, hormones, and adhesion molecules. Following a discussion of factors that positively and negatively affect drug delivery to solid tumors, we concentrate on a mechanistic understanding of selective drug release or generation at the tumor site.
 
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Immune regulation of cellular activation is a tightly regulated process dictated by a balance of activation and inhibitory signals. Although initially described and characterized on natural killer cells, it has become increasingly apparent that inhibitory receptors are expressed and functional on myeloid cells. These receptors can override signals elicited by activation pathways including cytokine and chemokine receptors, growth factor signaling and more recently innate immune receptor signaling. Inhibitory receptors have key roles in various cellular and pathological processes and are thus potential targets for future therapeutics. In this review, the structure and function of inhibitory receptors will be discussed. Furthermore, utilization of these receptors as pharmacological targets and recent examples of strategies targeting inhibitory receptors will be analyzed.
 
Article
GPR55 has recently attracted much attention as another member of the cannabinoid family, potentially explaining physiological effects that are non-CB1/CB2 mediated. However, the data gathered so far are conflicting with respect to its pharmacology. We review the primary literature to date on GPR55, describing its discovery, structure, pharmacology and potential physiological functions. The CB1 receptor antagonist/inverse agonist AM251 has been shown to be a GPR55 agonist in all reports in which it was evaluated, as has the lysophospholipid, lysophosphatidylinositol (LPI). Whether GPR55 responds to the endocannabinoid ligands anandamide and 2-arachidonylglycerol and the phytocannabinoids, delta-9-tetrahydrocannabidiol and cannabidiol, is cell type and tissue-dependent. GPR55 has been shown to utilize G(q), G(12), or G(13) for signal transduction; RhoA and phospholipase C are activated. Experiments with mice in which GPR55 has been inactivated reveal a role for this receptor in neuropathic and inflammatory pain as well as in bone physiology. Thus delineating the pharmacology of this receptor and the discovery of selective agonists and antagonists merits further study and could lead to new therapeutics.
 
Article
The mouse skin model of multistage carcinogenesis has for many years provided a conceptual framework for studying carcinogenesis mechanisms and potential means for inhibiting specific stages of carcinogenesis. The process of skin carcinogenesis involves the stepwise accumulation of genetic change ultimately leading to malignancy. Initiation, the first step in multistage skin carcinogenesis involves carcinogen-induced genetic changes. A target gene identified for some skin tumor initiators is c-Ha-ras. The second step, the promotion stage, involves processes whereby initiated cells undergo selective clonal expansion to form visible premalignant lesions termed papillomas. The process of tumor promotion involves the production and maintenance of a specific and chronic hyperplasia characterized by a sustained cellular proliferation of epidermal cells. These changes are believed to result from epigenetic mechanisms such as activation of the cellular receptor, protein kinase C, by some classes of tumor promoters. The progression stage involves the conversion of papillomas to malignant tumors, squamous cell carcinomas. The accumulation of additional genetic changes in cells comprising papillomas has been correlated with tumor progression, including trisomies of chromosomes 6 and 7 and loss of heterozygosity. The current review focuses on the mechanisms involved in multistage skin carcinogenesis, a summary of known inhibitors of specific stages and their proposed mechanisms of action, and the relevance of this model system to human cancer.
 
Article
There are at least two types of cannabinoid receptors, CB1 and CB2, both coupled to G-proteins. CB1 receptors are present in the central nervous system and CB1 and CB2 receptors in certain peripheral tissues. The existence of endogenous cannabinoid receptor agonists has also been demonstrated. These discoveries have led to the development of selective cannabinoid CB1 and CB2 receptor ligands. This review focuses on the classification, binding properties, effector systems and distribution of cannabinoid receptors. It also describes the various cannabinoid receptor agonists and antagonists now available and considers the main in vivo and in vitro bioassay methods that are generally used.
 
Article
Type 2 cytokine responses are typical of immune reactions to parasitic helminth infections, allergies, and asthma, and are characterised by the production of the cytokines interleukin (IL)-4, IL-5, IL-9, and IL-13 by subsets of T helper type 2 (Th2) cells. These cytokines form a complex network of molecular and cellular interactions that mediate protective immunity to worm infection, but also induce inappropriate inflammatory responses to allergic challenge. Although considerable attention has been given to the roles played by IL-4 in Th2 responses, the identification of the related cytokine IL-13 has led to a re-evaluation of how these two molecules combine in the generation of Th2 immunity. Recent reports have highlighted that in certain challenges, IL-4 and IL-13 act in combination to ensure the rapid onset of a Th2-like response. However, these studies have also identified specific responses that are attributable to the individual cytokines. For example, IL-13 appears to play a more dominant role than IL-4 in the expulsion of certain gastrointestinal parasites. In contrast, following schistosome infection, IL-13 induces a detrimental hepatic fibrosis, while IL-4 protects against endotoxemia. These results emphasise the complexity of the cytokine network, and highlight the care that needs to be taken when designing therapeutic intervention.
 
Article
For the first time, allergic diseases have emerged as major public health concerns. Highly effective therapies for allergic disease now exist, but are plagued by serious side effects and the fact that a significant minority of patients remains unresponsive. Studies from many laboratories have established that T helper type 2 (T(H)2) cytokines contribute importantly to diseases such as asthma, and therapeutic strategies that target the key T(H)2 cytokines are of potential benefit in allergic disease. In this article, we will review the biology of the T(H)2 cytokines interleukin (IL)-4, IL-5, and IL-13 and their receptors, and will consider several novel strategies to neutralize these molecules in human and experimental asthma. While promising, newer therapies face a gauntlet of developmental challenges, but offer the hope of reducing allergic diseases once again to minor public health concerns.
 
Communication Pathways from the Periphery to the Brain
Article
There has been an explosion in our knowledge of the pathways and mechanisms by which the immune system can influence the brain and behavior. In the context of inflammation, pro-inflammatory cytokines can access the central nervous system and interact with a cytokine network in the brain to influence virtually every aspect of brain function relevant to behavior including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits that regulate mood, motor activity, motivation, anxiety and alarm. Behavioral consequences of these effects of the immune system on the brain include depression, anxiety, fatigue, psychomotor slowing, anorexia, cognitive dysfunction and sleep impairment; symptoms that overlap with those which characterize neuropsychiatric disorders, especially depression. Pathways that appear to be especially important in immune system effects on the brain include the cytokine signaling molecules, p38 mitogen-activated protein kinase and nuclear factor kappa B; indoleamine 2,3 dioxygenase and its downstream metabolites, kynurenine, quinolinic acid and kynurenic acid; the neurotransmitters, serotonin, dopamine and glutamate; and neurocircuits involving the basal ganglia and anterior cingulate cortex. A series of vulnerability factors including aging and obesity as well as chronic stress also appears to interact with immune to brain signaling to exacerbate immunologic contributions to neuropsychiatric disease. The elucidation of the mechanisms by which the immune system influences behavior yields a host of targets for potential therapeutic development as well as informing strategies for the prevention of neuropsychiatric disease in at risk populations.
 
Article
The last decade has witnessed the approval of monoclonal antibodies (mAbs) and small molecule tyrosine kinase inhibitors (TKIs) for targeting of oncogenic signaling pathways. Generally, the clinical activity of these agents has been less than expected, in part due to unsuspected feed-back loops and cross-talk between different signaling pathways, thereby suggesting the interest of inhibiting multiple pathways. The extensive degree of EGFR-VEGF(R) pathway cross-talk identifies these pathways as particularly promising for joint targeting. Activation of the EGFR pathway increases the production of tumor-derived VEGF that acts on endothelial cells in a paracrine manner to promote angiogenesis. Accordingly, exposure to EGFR inhibitors is accompanied by attenuation of VEGF expression while resistance to EGFR inhibitors is frequently associated with enhanced VEGF levels. Recent data have expanded the biological activities of the two pathways by documenting a role for VEGF signaling in tumor cell survival and demonstrating the expression of EGFR by some tumor-associated endothelial cells. At least part of these signaling events are intracrine (intracellular and autocrine) and thus not readily accessible for the mAbs which target extracellular ligands and membrane receptors. This may explain why two major clinical trials combining EGFR and VEGF-targeted mAbs gave disappointing results and suggest a need for compounds that are able to inhibit intracrine signaling. Clinical application of new combinations should be preceded by preclinical development guided by functional biomarker analysis to identify active drug combinations and to facilitate the identification of patient subgroups likely, or not, to respond to dual pathway inhibition.
 
Article
Stress, in its different forms, represents a major environmental component for increased susceptibility to mental illness and, indeed, stressful life events serve as significant predictors of depression. With this respect, since antidepressant drugs may be effective in a variety of conditions that are triggered by, or associated with, exposure to stress, it is important to establish to what extent drug treatment can interfere with behavioral, functional and molecular alterations induced by stress exposure. The aim of this article is to examine the evidence supporting the ability of antidepressant treatment to reverse or modulate stress-induced alterations in humans and animals. Biologically, there is accumulating evidence that antidepressants can modify not only the neuroendocrine response to stress, but also mechanisms that regulate neuronal plasticity and that may play a key role in structural and functional changes associated with major depression. We believe that a detailed analysis of pharmacotherapy effects on stress-induced alterations may be important to define the ability and potency of different antidepressants to 'normalize' alterations that are central to the disease, in order to differentiate them with respect to the pathologic phenotype. This may lead to the identification of new pharmacological targets and contribute to the development of novel and more effective agents, which may eventually achieve higher rates of remission.
 
Article
MicroRNAs (miRNAs) are abundant, endogenous, short, noncoding RNAs that act as important post-transcriptional regulators of gene expression by base-pairing with their target mRNA. During the last decade, substantial knowledge has accumulated regarding the biogenesis of miRNAs, their molecular mechanisms and functional roles in a variety of cellular contexts. Altered expression of certain miRNA molecules in the brains of patients with neurodegenerative diseases such as Alzheimer and Parkinson suggests that miRNAs could have a crucial regulatory role in these disorders. Polymorphisms in miRNA target sites may also constitute an important determinant of disease risk. Additionally, emerging evidence points to specific miRNAs targeting and regulating the expression of particular proteins that are key to disease pathogenesis. Considering that the amount of these proteins in susceptible neuronal populations appears to be critical to neurodegeneration, miRNA-mediated regulation represents a new target of significant therapeutic prospects. In this review, the implications of miRNAs in several neurodegenerative disorders and their potential as therapeutic interventions are discussed.
 
Article
This review focuses on the neurobiology of integrins, pathophysiological roles of integrins in neuroplasticity and nervous system disorders, and therapeutic implications of integrins as potential drug targets and possible delivery pathways. Neuroplasticity is a central phenomenon in many neurological conditions such as seizures, trauma, and traumatic brain injury. During the course of many brain diseases, in addition to intracellular compartment changes, alterations in non-cell compartments such as extracellular matrix (ECM) are recognized as an essential process in forming and reorganizing neural connections. Integrins are heterodimeric transmembrane receptors that mediate cell-ECM and cell-cell adhesion events. Although the mechanisms of neuroplasticity remain unclear, it has been suggested that integrins undergo plasticity including clustering through interactions with ECM proteins, modulating ion channels, intracellular Ca(2+) and protein kinase signaling, and reorganization of cytoskeletal filaments. As cell surface receptors, integrins are central to the pathophysiology of many brain diseases, such as epilepsy, and are potential targets for the development of new drugs for neurological disorders.
 
Article
Increasing evidence suggests that cyclin-dependent kinases (CDKs), enzymes that normally regulate cell cycle progression, may also participate in the death of neurons. This has led to the proposal that CDKs may serve as a therapeutic target for neuropathological conditions such as stroke. This brief review will serve to examine the evidence supporting the role of CDKs in neuronal death, and will evaluate the potential of CDK inhibitors as a neuroprotective strategy for ischemic injury.
 
Article
Pulmonary toxicity caused by an antineoplastic drug, cyclophosphamide is becoming a more frequently recognized entity. Metabolism of cyclophosphamide in lung to alkylating metabolites and acrolein, a reactive aldehyde are in part responsible for pulmonary toxicity. Alterations in pulmonary mixed-function oxidase activity, glutathione content, and microsomal lipid peroxidation may be caused by the reactive metabolite acrolein. Potentiation of cyclophosphamide-induced pulmonary injury under hyperoxic conditions is caused by depression of pulmonary antioxidant defense mechanisms by cyclophosphamide and its other metabolites but not acrolein. Cyclophosphamide- and acrolein-induced alterations in the physical state of membrane lipid bilayer may be the major cause of inactivation of membrane-bound enzymes. These data suggest that cyclophosphamide and its reactive metabolites initiate peroxidative injury resulting in alterations in the physical state of membrane lipids which may be functionally linked to manifestations of cyclophosphamide-induced pulmonary toxicity.
 
Article
Relapse to alcohol use after prolonged withdrawal periods is the major problem in the treatment of alcohol dependence in humans. However, until recently, relatively few preclinical studies concentrated on the elucidation of the neurochemical events underlying relapse to alcohol. In this article we will review recent data from studies in which alcohol-deprivation and reinstatement models were used to determine the mechanisms underlying relapse to alcohol in rats. In the alcohol-deprivation model, the intake of alcohol is determined after prolonged periods of forced abstinence in drug-experienced rats. In the reinstatement model, the ability of acute non-contingent exposure to drug or non-drug stimuli to reinstate drug seeking is determined following training for drug self-administration and subsequent extinction of the drug-reinforced behavior. We will review studies, which used these preclinical models, on the effect of specific pharmacological agents on relapse to alcohol seeking induced by re-exposure to alcohol and to alcohol-associated cues and by exposure to stress. Subsequently, we will describe potential neuronal circuits that may underlie relapse to alcohol. Finally, future directions and clinical implications of the study of relapse to alcohol in laboratory animals will be discussed briefly.
 
Top-cited authors
Roger G Pertwee
  • University of Aberdeen
Geoffrey Burnstock
  • University College London
Eric H Sasso
  • University of Washington Seattle
Paul P Tak
  • Academisch Medisch Centrum Universiteit van Amsterdam
Daniel Tracey
  • Avaxia Biologics, Inc.