Date of Award

8-2019

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Developmental and Brain Sciences

First Advisor

S. Tiffany Donaldson

Second Advisor

Richard Hunter

Third Advisor

Vivian Ciaramitaro

Abstract

The chemokine, CXCL12, and its receptor, CXCR4, are neuroinflammatory marks that are localized to neurons and glia and have recently been implicated in activation of midbrain dopamine systems. This overlay of chemokines and reward-motor DA pathways may be relevant for understanding the neuromodulation and neuroplasticity required for lasting dynamic changes following repeated drug use. The research presented in this dissertation sought to determine whether (1) age differentially influences amphetamine sensitization to amphetamine and if CXCR4 antagonism (i.e., with AMD3100) can attenuate sensitization and lower protein levels in limbic areas; (2) biological sex imparts distinct sensitization responses and chemokine protein levels; and (3) context-dependent and -independent learning may result in variations in sensitization levels and RNA for CXCL12 and CXCR4. Results demonstrate the effects of sensitization, protein, and levels of this chemokine ligand-receptor pair that varied by age, sex, and environment. The presented dissertation work highlights greater the increased sensitivity that adolescent rats have towards amphetamine sensitization and demonstrated that posed sensitization was significantly reduced with AMD3100 pre-treatment. Amphetamine caused increased striatal CXCR4 protein levels in all adolescent groups. Findings also revealed elevated CXCL12 protein in mesolimbic areas of amphetamine-sensitized adult males as compared to drug-naïve animals. Furthermore, CXCL12 and CXCR4 mRNA expression showed sex- and treatment-dependent differences in the hippocampus. Using quantitative polymerase chain reaction (qPCR) analyses, previous drug treatment with amphetamine altered CXCL12 mRNA and significantly upregulated CXCR4 mRNA in female rats. In sum, these results extend findings that chemokines are complex regulators of addiction-related learning, that chemokines may serve as a novel therapeutic target, and that key biological factors interact with stimulant-induced behavior and chemokine proinflammation in the brain.

Comments

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