University of North Carolina at Chapel Hill Graduate School
Doi
Abstract
Drugs of abuse, like opioids, cause a diverse array of physiological effects. These effects can become conditioned to occur to any stimulus, for example an environmental context, that becomes associated with drug use. In terms of drug reward conditioning, exposure to drug-paired contexts can elicit craving and re-engagement in drug seeking behaviors, promoting relapse to drug use. Similarly, the immune modulating effects of opioids can be conditioned to occur with exposure to an opioid-paired context. Therefore, exposure to drug-paired contexts can significantly exacerbate both the health consequences and risk of relapse with drugs of abuse. Understanding the neurological mechanisms that allow for the expression of contextually conditioned effects will allow us to better combat the problem of drug abuse. Brain regions governing opioid conditioned reward and immune responses have previously been investigated, but how these regions interact with each other is not fully understood. Previous studies show that the nucleus accumbens, basolateral amygdala, and hippocampus are required for expression of heroin contextually conditioned immune modulation, and this overlaps with what brain regions are required for contextually conditioned reward. The hippocampus is vital for encoding context, and we hypothesize that it instigates the motivational and immunological changes with exposure to a drug-paired context by engaging the other brain regions involved. The present studies are designed to further characterize the hippocampus’ role in contextually conditioned drug behaviors by manipulating this region’s predominant outgoing projections prior to expression of heroin contextually conditioned immune modulation. The hippocampus is not a homogeneous structure, and the dorsal and ventral aspects of the hippocampus connect anatomically to distinct groups of brain regions. Therefore, understanding the relative importance of the dorsal and ventral outputs from the hippocampus will give a clearer understanding of how the hippocampus relays information about context to other brain regions. The chemogenetic technique, designer receptors exclusively activated by designer drugs (DREADDs), lends itself well to inhibiting particular neurons in hippocampal output regions and building toward an understanding of hippocampal circuits. An experiment in Chapter 2 tested whether output from the dorsal hippocampus is required for the expression of heroin contextually conditioned immune modulation. Chapter 3’s experiment tested whether output from the ventral hippocampus is required for the expression of heroin contextually conditioned immune modulation. Chemogenetic inhibition of the dorsal hippocampus output, but not inhibition of the ventral hippocampus output, attenuated the expression of heroin conditioned immune modulation. Thus, Chapter 4’s experiment tested whether a specific anatomical connection between the dorsal hippocampus and retrosplenial cortex is required for expression of conditioned immune modulation. Chemogenetic inhibition of the specific projection from the dorsal hippocampus to the retrosplenial cortex did not attenuate the expression of heroin conditioned immune modulation, leading to the conclusion that this specific projection is not required. The results from these experiments begin to build a picture of how the hippocampus, and its representation of context, can influence immune function and perhaps also the behaviors that lead to cycles of drug abuse.Doctor of Philosoph
