Expanding the Xenobiotic Hypothesis of Drug Reward and Reinforcement: Implications of TLR4 Dependent Cocaine and Methamphetamine Induced Neuroinflammation on Reward, Relapse, Priming, and Neurotoxicity
Type of Thesis
Psychology & Neuroscience
Dr. Linda Watkins
Dr. Jerry Rudy
Dr. Monika Fleshner
Dr. Ryan Bachtell
Conventionally, cocaine is thought to exert its rewarding and reinforcing effects on the mesolimbic dopamine pathway, which is commonly referred to as the reward circuitry of the brain. Cocaine increases dopamine levels within the NAc by blocking dopamine reuptake by antagonizing dopamine transporters (DATs) on the VTA dopaminergic axon terminals. Traditionally, it is believed that with repeated cocaine use, this neuronal action causes neuroadaptations that underlie addiction. However, developments within the last two decades indicate that glial cells within the central nervous system’s immune system act as non-neuronal modulators of drug reward. It was recently found that cocaine interacts with the TLR4/MD-2 complex to produce a proinflammatory response, and that this interaction is necessary for cocaine reward. The present investigation proceeds to demonstrate that cocaine can directly activate microglia cells through TLR4, causing them to upregulate mRNA of the proinflammatory cytokine, IL-1β, within the VTA. Furthermore, cocaine-induced dopamine increases in the NAc depend on cocaine-induced IL-1β signaling within the VTA. TLR4 and IL-1β are also important aspects underlying cocaine-primed reinstatement to drug seeking in a self-administration paradigm. In this self-administration model, repeated exposure to cocaine appeared to induce glial priming, and led to the expression of additional proinflammatory markers throughout the mesolimbic dopamine pathway, providing new targets for further investigation into cocaine reinforcement. The investigation was expanded to include another commonly abused psychostimulant, methamphetamine (meth), which has also been recently shown to interact with the TLR4/MD-2 complex. Here, it is shown that the meth-induced neuroinflammation revealed within the mesolimbic dopamine pathway is TLR4 dependent; however, unlike cocaine, meth reward and reinforcement may be driven by mechanisms other than IL-1β signaling. Comparisons between cocaine-induced and meth-induced neuroinflammation suggest that IL-6 may also be an important molecule in mediating mesolimbic dopamine pathway functionality. The present studies provide evidence that the rewarding and reinforcing effects of psychostimulants arise from synergistic mechanisms involving both direct neuronal actions and neuroimmune interactions.
Fabisiak, Timothy, "Expanding the Xenobiotic Hypothesis of Drug Reward and Reinforcement: Implications of TLR4 Dependent Cocaine and Methamphetamine Induced Neuroinflammation on Reward, Relapse, Priming, and Neurotoxicity" (2015). Undergraduate Honors Theses. 847.