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:Department of Psychology & Neuroscience, and Center for Neuroscience, University of Colorado - Boulder, Boulder, CO 80309-0345, USA.
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.
