Access Type

Open Access Dissertation

Date of Award

January 2014

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

Tiffany A. Mathews

Abstract

Dopamine (DA) neurons in the striatum mediate several functions of the brain and have been linked to a host of neurological disorders including Parkinson's disease and addiction, both of which occur as a result of dysfunction in the DA system. In the present study, our first objective was to understand how the striatal DA system adapts to acute and repeated administration of inhalant toluene. The use of toluene as inhalant, like other drugs of abuse, is known to perturb DA neurotransmission in the brain reward pathway. However, the exact mechanism underling toluene's influence on striatal DA neurotransmission is unknown. The current work utilized behavior assays and neurochemical techniques such as slice fast scan cyclic voltammetry (FSCV), in vivo microdialysis, and brain tissue content analysis to examine how toluene inhalation alters the striatal DA system. Overall, both behavior and neurochemical data confirmed that toluene inhalation alters stimulated DA release in striatum. Mechanistically, the neurochemical data indicated that acute toluene inhalation potentiates striatal DA release and catabolism but there is no difference on DA uptake or extracellular DA levels in the caudate putamen (CPu). Furthermore, toluene induced potentiation in DA release is not mediated by DA D3 autoreceptors. Meanwhile, chronic toluene exposure attenuated DA release only in the nucleus accumbens (NAc). Repeated toluene exposure also increased extracellular DA levels in the NAc, which is typical of addictive drugs. However, repeated toluene inhalation had no effect on DA D3 autorecepetors, and DA catabolism. Taken together, the present data suggest that acute or repeated toluene alters the striatal DA system through indirect neuronal action.

The second objective was to understand how brain derived neurotrophic factor (BDNF) modulates striatal DA dynamics. Aside from its conventional role as a neurotrophic factor, BDNF has also been implicated in synaptic transmission and neurological disorders. Since BDNF mediates it neurotrophic functions through tyrosine kinase receptor TrkB, the functional effects of tyrosine kinase receptor TrkB on the striatal DA release and uptake rate were examined. This work utilized FSCV to evaluate the effect of exogenous BDNF, TrkB agonist; 7,8-dihydroxyflavone (7,8-DHF), and TrkB antagonists; genistein, tyrphostin 23, and K252a, on DA dynamics in the CPu of brain slices obtain from BDNF deficient (BDNF+/-) mice and their wildtype littermates. Overall, the results obtained highlighted the utility of FSCV to probe the functional effect of Trk receptors on DA dynamics. The results also showed that activation of TrkB receptors with exogenous BDNF and 7,8-DHF potentiated presynaptic DA release in BDNF+/- and wildtype mice respectively, with no effect on DA uptake. However, concentrations greater than 3 μM 7,8-DHF attenuated DA uptake rates in only BDNF+/− mice. In the presence of K252a, the BDNF or 7,8-DHF induced potentiation of DA release was abolished, suggesting that the effect of BDNF or 7,8-DHF on presynaptic DA release is TrkB mediated.

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