Some electroanalytical studies of dopamine agonists and antagonists
[Thesis]
M. T. Morocco
J. O. Schenk
Washington State University
1992
132
Ph.D.
Washington State University
1992
This dissertation describes work which will provide further information on the workings of dopaminergic neuronal systems. Chapter 1 is an introduction to dopaminergic neuronal systems and the chemistry of the catecholamine neurotransmitters. Chapter 2 describes the development of a method for the in vitro and in vivo electroanalytical measurement of the antipsychotic drug haloperidol (HAL). Little is known about the mechanism of action of antipsychotic drugs except that their efficacy is a result of their being antagonists of dopamine receptors. The ability to measure the concentration of HAL in brain tissue could provide much information regarding their mechanism of action. It was found that sensitive measurements of HAL (detection limit 0.04 muM) could be made employing carbon paste electrodes since HAL adsorbed strongly to the surface of these electrodes. Chapter 3 describes speciation studies, under physiological conditions, for catechols, catecholamines, as well as several catecholamine agonists. Since the species of dopamine which interacts with the dopamine receptor is unknown, this study was undertaken in order to determine which species of dopamine exists at physiological pH values. The results of this study, which used voltammetric, UV-VIS spectroscopic, and titrimetric procedures, allows for the tentative identification of the chemical form of catecholamine which interacts with biological recognition sites. Chapter 4 involves the study of the nonreceptor mediated antagonism of dopamine by the neuropeptide, neurotensin. The interaction between dopamine and neurotensin was found to have a stoichiometry of 1: 1, with a dissociation constant of 5.9 usd\timesusd 10 mol/L. The association between dopamine and neurotensin was found to be pH dependent when the dissociation constant was measured as a function of pH. The results of studies of the formal potential of dopamine in the presence of Arg and Arg-containing peptides confirmed that the chemical species of dopamine associated with neurotensin is a catecholate form. The kinetics of the complexation is examined, and a hypothetical chemical structure of the complex is suggested.