Date of Award

Spring 1-1-2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Psychology & Neuroscience

First Advisor

Linda R. Watkins

Second Advisor

Steven F. Maier

Third Advisor

Ryan K. Bachtell

Fourth Advisor

Mark R. Hutchinson

Fifth Advisor

Michael Stallings

Abstract

Drug abuse and addiction is a globally pervasive issue, and has detrimental effects on society in terms of financial burden and undermining the health, well-being, and productivity of the addicted individual as well as their friends and family. Although commonly abused drugs originate from differing classes, such as opioids and psychostimulants, they share a common effect of influencing the mesolimbic dopamine pathway to produce an increase of dopamine within the nucleus accumbens. This increased dopaminergic signaling is thought to underlie the euphoric and reinforcing effects of drugs that prompt repeated drug taking, and can lead to the development of addiction. Understandably, research for the past several decades has focused on neuronal targets for drug actions. Opioids are known to disinhibit ventral tegmental area control over dopaminergic projections to the nucleus accumbens, whereas psychostimulants increase dopamine concentrations through disruption of dopamine transport directly within the nucleus accumbens. Medication development targeting these mechanisms has resulted in very limited success in opioids, and there is no approved pharmacotherapy for psychostimulant abuse.

However, in recent decades the role of glial cells in the brain, including microglia and astrocytes, has garnered much attention, as it has become clear they serve a far more expansive role than simply operating as "supporting cells". It is now known that glial cells express receptors and, when activated, release proinflammatory molecules that can influence neuronal signaling. One such family of receptors is the highly conserved, innate immune Toll-Like Receptors (TLRs), including the prototypical TLR4, responsible for detecting invading pathogens. As a pattern-recognition receptor, TLR4 can also detect and respond to a wide-range of molecules including endogenous danger signals and xenobiotic or "foreign" substances.

Here we demonstrate that opioids, cocaine, and methamphetamine activate TLR4. Further, drug-induced TLR4 signaling is necessary to disrupt mesolimbic functioning and influence reward/reinforcement, leading to our newly proposed xenobiotic hypothesis. We also continue to characterize the (+)-isomers of naloxone/naltrexone, recently identified as selective TLR4 antagonists, ideal for use to study drug-induced TLR4 actions as well as potential candidates for pharmaceutical development to aid in the treatment of addiction.

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