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
-
Review of Characteristics, Pharmacology, Determination and Pharmacokinetics of Rhaponticin
Mini-Reviews in Organic Chemistry Role of the Cannabinoid System in Pain Control and Therapeutic Implications for the Management of Acute and Chronic Pain Episodes
Current Neuropharmacology Role of Innate Immunity in Triggering and Tuning of Autoimmune Diabetes
Current Molecular Medicine Anti-Oxidative Effect of Curcumin Against Tert-Butylhydroperoxide Induced Oxidative Stress in Human Erythrocytes
The Natural Products Journal Palmitoylethanolamide in Homeostatic and Traumatic Central Nervous System Injuries
CNS & Neurological Disorders - Drug Targets Pediatric Cutaneous Graft Versus Host Disease: A Review
Current Pediatric Reviews Meet Our Editorial Board Member
Current Neuropharmacology Endocannabinoids in the Treatment of Mood Disorders: Evidence from Animal Models
Current Pharmaceutical Design Asymmetric Dimethylarginine: Clinical Significance and Novel Therapeutic Approaches
Current Medicinal Chemistry Synthesis and Characterization of a Nylon/Titanium as Hybrid Biomaterial
Recent Patents on Corrosion Science (Discontinued) Progress and Obstacles in the Application of Precision Medicine in the Management of Hepatocellular Carcinoma
Clinical Cancer Drugs Metabotropic Glutamate Receptor Dependent Cortical Plasticity in Chronic Pain
Current Neuropharmacology The Minority Aging Research Study: Ongoing Efforts to Obtain Brain Donation in African Americans without Dementia
Current Alzheimer Research Meet Our Editorial Board Member
Endocrine, Metabolic & Immune Disorders - Drug Targets The Nature and Implications of Implicit Weight Bias
Current Psychiatry Reviews Generation and Characterization of a Functional Nanobody Against Inflammatory Chemokine CXCL10, as a Novel Strategy for the Treatment of Multiple Sclerosis
CNS & Neurological Disorders - Drug Targets Studies on the Effect of the Apolipoprotein E Genotype on the Lipid Profile in Alzheimers Disease
Current Alzheimer Research Implications of Parkinson’s Disease Pathophysiology for the Development of Cell Replacement Strategies and Drug Discovery in Neurodegenerative Diseases
CNS & Neurological Disorders - Drug Targets Amorphous and Crystalline Particulates: Challenges and Perspectives in Drug Delivery
Current Pharmaceutical Design Upper Airway Resistance Syndrome
Current Respiratory Medicine Reviews