Drug addiction is a costly burden on society and its treatment a seriously unmet medical need. While decades of addiction research have focused on the role of dopamine in mediating most aspects of addiction, pharmacotherapies aimed at this neurotransmitter system have proven largely inefficacious. More recent addiction research has identified a significant role of glutamate in drug reward and addiction-related processes, and it is now widely accepted that many of the drug-induced neuroadaptations that ultimately lead to the 'addicted state' are mediated by changes in glutamate transmission. To date, microdialysis methods have been used to monitor glutamate levels in animal models of drug addiction. While this method offers sensitivity and selectivity, it lacks the temporal resolution needed to measure the fast synaptic transmission of glutamate, and therefore, many important aspects of glutamate neurotransmission may be masked. The project described herein, the use of glutamate biosensors in addiction research, addresses the development of a novel neurochemical method that offers the selectivity and sensitivity of microdialysis methods in conjunction with the superior temporal resolution of voltammetric methods. In this technology, ceramic-based microsensors (100 mu m X 25 mu m) are coated with glutamate oxidase, which allows for the specific detection of glutamate by the microelectrodes. Furthermore, these sensors are capable of measuring extracellular glutamate levels in sub-second time intervals thus permitting improved real-time monitoring of glutamate levels as compared to current dialysis methods. In a first series of studies, these enzyme-based sensors will be used to measure basal and stimulated glutamate release in the prefrontal cortex, nucleus accumbens, and ventral tegmental area of anesthetized rats. In this way, it will be possible to validate the use of these biosensors in vivo as well as to study various temporal patterns of neuronal glutamate release and uptake in these brain regions. Furthermore, the control of glutamate release and uptake by metabotropic glutamate and GABA receptors will be studied using these biosensors. In a second series of studies, the biosensors will be used in animal models of drug addiction. The role of glutamate in conditioned behaviors will be studied using conditioned locomotor activity and conditioned place preference methods. Additionally, intravenous drug self-administration techniques will be used to study the role of glutamate in drug reward and in the ability of drug-related cues to elicit craving and relapse. Through the development and use of these glutamate biosensors for in vivo applications, it will be possible to expand our knowledge of drug-induced alterations in glutamate neurotransmission, and may therefore make it possible to design pharmacotherapies that are effective in combating addiction and the associated cravings that lead to relapse to drug-taking.
