Abstract
There is growing recognition that glial proinflammatory activation importantly contributes to the rewarding and reinforcing effects of a variety of drugs of abuse, including cocaine, methamphetamine, opioids, and alcohol. It has recently been proposed that glia are recognizing, and becoming activated by, such drugs as a CNS immunological response to these agents being xenobiotics; that is, substances foreign to the brain. Activation of glia, primarily microglia, by various drugs of abuse occurs via toll like receptor 4 (TLR4). The detection of such xenobiotics by TLR4 results in the release of glial neuroexcitatory and neurotoxic substances. These glial products of TLR4 activation enhance neuronal excitability within brain reward circuitry, thereby enhancing their rewarding and reinforcing effects. Indeed, selective pharmacological blockade of TLR4 activation, such as with the non-opioid TLR4 antagonist (+)-naltrexone, suppresses a number of indices of drug reward/reinforcement. These include: conditioned place preference, self-administration, drugprimed reinstatement, incubation of craving, and elevations of nucleus accumbens shell dopamine. Notably, TLR4 blockade fails to alter self-administration of food, indicative of a selective effect on drugs of abuse. Genetic disruption of TLR4 signaling recapitulates the effects of pharmacological TLR4 blockade, providing converging lines of evidence of a central importance of TLR4. Taken together, multiple lines of evidence converge to raise TLR4 as a promising therapeutic target for drug abuse.
Keywords: (+)-naloxone, (+)-naltrexone, alcohol, cocaine, drug reward, drug reinforcement, morphine, opioid, psychostimulants, reinstatement.
CNS & Neurological Disorders - Drug Targets
Title:Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4
Volume: 14 Issue: 6
Author(s): Ryan Bachtell, Mark R. Hutchinson, Xiaohui Wang, Kenner C. Rice, Steven F. Maier and Linda R. Watkins
Affiliation:
Keywords: (+)-naloxone, (+)-naltrexone, alcohol, cocaine, drug reward, drug reinforcement, morphine, opioid, psychostimulants, reinstatement.
Abstract: There is growing recognition that glial proinflammatory activation importantly contributes to the rewarding and reinforcing effects of a variety of drugs of abuse, including cocaine, methamphetamine, opioids, and alcohol. It has recently been proposed that glia are recognizing, and becoming activated by, such drugs as a CNS immunological response to these agents being xenobiotics; that is, substances foreign to the brain. Activation of glia, primarily microglia, by various drugs of abuse occurs via toll like receptor 4 (TLR4). The detection of such xenobiotics by TLR4 results in the release of glial neuroexcitatory and neurotoxic substances. These glial products of TLR4 activation enhance neuronal excitability within brain reward circuitry, thereby enhancing their rewarding and reinforcing effects. Indeed, selective pharmacological blockade of TLR4 activation, such as with the non-opioid TLR4 antagonist (+)-naltrexone, suppresses a number of indices of drug reward/reinforcement. These include: conditioned place preference, self-administration, drugprimed reinstatement, incubation of craving, and elevations of nucleus accumbens shell dopamine. Notably, TLR4 blockade fails to alter self-administration of food, indicative of a selective effect on drugs of abuse. Genetic disruption of TLR4 signaling recapitulates the effects of pharmacological TLR4 blockade, providing converging lines of evidence of a central importance of TLR4. Taken together, multiple lines of evidence converge to raise TLR4 as a promising therapeutic target for drug abuse.
Export Options
About this article
Cite this article as:
Bachtell Ryan, Hutchinson R. Mark, Wang Xiaohui, Rice C. Kenner, Maier F. Steven and Watkins R. Linda, Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4, CNS & Neurological Disorders - Drug Targets 2015; 14 (6) . https://dx.doi.org/10.2174/1871527314666150529132503
DOI https://dx.doi.org/10.2174/1871527314666150529132503 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
Call for Papers in Thematic Issues
Diagnosis and treatment of central nervous system infectious diseases
Infectious diseases of the central nervous system (CNS) can be divided into bacterial, tuberculous, viral, fungal, parasitic infections, etc. Early etiological treatment is often the most crucial means to reduce the mortality rate of patients with central nervous system infections, reduce complications and sequelae, and improve prognosis. The initial clinical ...read more
Techniques of Drug Repurposing: Delivering a new life to Herbs & Drugs
Of late, with the adaptation of innovative approaches and integration of advancements made towards medical sciences as well as the availability of a wide range of tools; several therapeutic challenges are being translated into viable clinical solutions, with a high degree of efficacy, safety, and selectivity. With a better understanding ...read more
Trends and perspectives in the rational management of CNS disorders
Central nervous system (CNS) diseases enforce a significant global health burden, driving ongoing efforts to improve our understanding and effectiveness of therapy. This issue investigates current advances in the discipline, focusing on the understanding as well as therapeutic handling of various CNS diseases. The issue covers a variety of diseases, ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Dynamic Medicinal Chemistry in the Elaboration of Morphine-6- Glucuronide Analogs
Current Topics in Medicinal Chemistry Cyclic Opioid Peptides
Current Medicinal Chemistry Editorial [Hot Topic: Alzheimer Drug Design Based on the Amyloid Hypothesis (Executive Editors: D. Munoz-Torrero and P. Camps)]
Current Pharmaceutical Design Biological Applications of the Receptor Mimetic Peptide Mastoparan
Current Protein & Peptide Science Peroxisome Proliferator-Activated Receptor Agonists as Potential Therapeutic Agents in Multiple Sclerosis
Mini-Reviews in Medicinal Chemistry Synthesis and Biological Evaluation of Dihydroisoquinoline-2(1H)- Carbothioamide Derivatives as TRPV1 Antagonists
Letters in Drug Design & Discovery Current Anti-Inflammatory Therapies and the Potential of Secretory Phospholipase A2 Inhibitors in the Design of New Anti-Inflammatory Drugs: A Review of 2012 - 2018
Current Medicinal Chemistry Vascular Inflammation During Human Rickettsioses: An Essential Host Response and a Potential Target for Supplemental Therapy
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Recent Advances in Validating MDM2 as a Cancer Target
Anti-Cancer Agents in Medicinal Chemistry The Role of Neurohypophyseal Hormones Vasopressin and Oxytocin in Neuropsychiatric Disorders
Endocrine, Metabolic & Immune Disorders - Drug Targets Cognitive and Cardiovascular Benefits of Docosahexaenoic Acid in Aging and Cognitive Decline
Current Alzheimer Research In Vitro Models of Human T Cell Development: Dishing Out Progenitor T Cells
Current Immunology Reviews (Discontinued) JLK Inhibitors: Isocoumarin Compounds as Putative Probes to Selectively Target the γ-Secretase Pathway
Current Alzheimer Research Stimulating Effects of H1-Antagonists
Current Pharmaceutical Design Drug Discovery and Design for Complex Diseases through QSAR Computational Methods
Current Pharmaceutical Design Encapsulation in Cell Therapy: Methodologies, Materials, and Clinical Applications
Current Pharmaceutical Biotechnology Fuzzy Classification Methods Based Diagnosis of Parkinson’s disease from Speech Test Cases
Current Aging Science Scope of Lipid Nanoparticles in Neuroscience: Impact on the Treatment of Neurodegenerative Diseases
Current Pharmaceutical Design Differential Mechanisms Underlying Antidepressant Responses of Ketamine and Imipramine
CNS & Neurological Disorders - Drug Targets Obstructive Sleep Apnoea Syndrome and Diabetes. Fortuitous Association or Interaction?
Current Diabetes Reviews