| Glutamate acting at ionotropic and metabotropic receptors is the principal excitatory neurotransmitter in the brain involved in both physiological and pathophysiological events. Alterations in basal glutamate concentration at the synapse lead to cell death. Therefore, maintaining strict control of glutamate levels is crucial. Understanding the management of this system will hopefully help in the process of developing new therapies for diseases involving glutamate imbalances.; Control theory predicts that administration of agonists and antagonists acting at "autoreceptors" of the glutamate system produce decreases and increases respectively in the extracellular levels of the neurotransmitter. In this study, we used in vivo microdialysis in conscious, unrestrained animals to administer selective compounds with affinity for specific glutamate receptor types and collect samples of brain dialysate for subsequent analysis of extracellular glutamate levels by HPLC.; This thesis clearly implicates the in vivo involvement of NMDA receptors in the control of glutamate in the rat striatum. We used the data obtained from the microdialysis experiments to construct a control curve describing the feedback control of the glutamate system via NMDA receptors. Our results also suggest that striatal group III metabotropic receptors do not fit this control theory model of "autoreceptors". In a separate set of experiments we demonstrated that chronic morphine does not alter basal extracellular glutamate concentrations. We then studied glutamate's control curve in morphine-dependent animals compared to that seen in normal rats finding that it was altered in the chronic morphine condition.; The importance of knowing the control curve for a given ligand lies in its predictive value that can be helpful in designing drug development tests. This control relation provides useful information on various events including release, instability, sensitivity, and oscillations that occur during normal functioning. Alterations in glutamatergic control that may occur in the disease states mentioned throughout this thesis including, drug addiction, schizophrenia, Parkinson's, and epilepsy can be studied in terms of the control relation. Since existing therapies are not effective for everyone suffering from these diseases, this work may provide new insights for potential therapeutic strategies. |
