| dc.description.abstract | In this document, the release and uptake of dopamine, a neurotransmitter involved in numerous aspects of brain function, is investigated in two cognitive disorders: post chemotherapy cognitive impairment (PCCI, ‘chemobrain’) and attention deficit hyperactivity disorder (ADHD). RNA sequencing was also used to investigate transcript expression to determine if chemotherapy or a potential rescue mechanism affect gene transcripts. Throughout these projects, the overall goal of this work aimed to correlate neurochemical and behavioral data with symptoms that are reported or are phenotypically present. Doxorubicin (Dox) is a chemotherapy agent commonly used to treat multiple types of cancers, including breast cancer, lymphoma, bladder cancer, Kaposi’s sarcoma, and acute lymphocytic leukemia. Patients treated with Dox often suffer from cognitive dysfunction long after the conclusion of treatment, a condition known as chemobrain. In previous reports, we showed that rats treated with carboplatin and 5- fluorouracil, two other commonly used chemotherapy agents, suffer from diminished executive function and impaired release of dopamine and serotonin. In this document, we found, paradoxically, that calciumdependent dopamine release and reuptake by the dopamine transporter (DAT), measured with fast-scan cyclic voltammetry (FSCV) in brain slices, is increased in rats that had been treated with Dox for two weeks. Pharmacological treatment of brain slices with pramipexole, a D2/D3 agonist, also revealed that Dox treated rats are more sensitive to autoregulation of dopamine release. Additionally, cognitive function, assessed by application of a behavioral paradigm to measure learning acquisition, revealed no difference between Dox-treated and vehicle-treated rats. Collectively, these studies suggest that treatment with Dox for a short time may result in an overactive dopamine system, possibly masking other neural deficiencies that cause chemobrain. Previous research has shown that treatment with 5-fluorouracil (5-FU) impairs cognitive function, but that concurrent treatment with KU-32, a heat shock protein 90 inhibitor, preserves cognitive function. To elucidate mechanisms underlying these phenomena, mRNA from murine brain tissue was sequenced to examine differential expression (DE) of genes and was subjected to a gene ontology analysis. DE analysis iv showed that approximately 1200 genes were differentially expressed between the three groups that were tested. Gene ontology analysis showed that the genes belonged to 57 gene ontology categories that were enriched in mice treated with KU-32+5-FU and depleted in mice treated only with 5-FU. These results suggest that KU-32 may compensate for the genes that are depleted from chemotherapy treatment. Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders in children. There are several defined criteria that must be met to receive a diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders (DSM V). Unfortunately, the mechanism of disorder in ADHD is not fully elucidated. The only treatments for ADHD are pharmaceuticals or behavior therapy. Behavior therapy is becoming the preferred treatment to prevent the substance abuse possibility seen with sustained medication use. Stimulants like amphetamine and methylphenidate are commonly prescribed. This experiment shows how a delay training paradigm is used on an ADHD strain of rat attempting to lower their hyperactive and impulsive behaviors. This behavioral work is complemented by a neurochemical study in which dopamine release and reuptake was measured. The effects of amphetamine on these parameters were also examined. Dopamine is suspected to play a role in ADHD and is highly affected by amphetamine use. The behavior training allowed the rat to overcome a larger delay and appeared to normalized dopamine release so that it was similar to that of the non-ADHD strain. This work supports other studies that suggest behavior therapy can combat the disorder without the use of pharmaceuticals. Collectively, these projects underly the importance of dopamine system function and illustrate how malfunctions in this system may impact behavior. Moreover, we examine the neurochemical effects that a drug-based intervention (KU-32) and a behavior-based intervention (delay training) can have in models of chemobrain and ADHD. The ultimate goal is to gain clearer understanding of how treatments such as these can be leveraged to improve the conditions of those suffering from these disorders. | en_US |
