FUNCTIONS OF BIOGENIC AMINE TRANSPORTERS

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DESCRIPTION: (Applicant's Abstract) Biogenic amine transporters are the main targets of cocaine, amphetamines, and antidepressants. My broad, long-term objectives are to understand the functions and mechanisms of these transporters, specifically their roles in the addiction to drugs of abuse and the actions of therapeutic drugs. A Mentored Research Scientist Development Award will allow me to learn new techniques necessary to study the in vivo functions of the biogenic amine transporters and to gain further experience before embarking on a fully independent research program. Biogenic amine transporters have been studied extensively in tissue preparations and cultured cells, and indirectly in whole animals using compounds that block these transporters. The only direct assessment of the roles of the transporters is the recent knockout of dopamine transporter in transgenic mice. Despite the significant new information learned from this study, extensive adaptation changes have set limitations to the study. Therefore, we propose to engineer an inducible antisense suppression system to study the biogenic amine transporters. In this approach, an antisense RNA would be expressed with an improved tetracycline operon based inducible system to suppress a specific transporter in a controllable and reversible manner. We will evaluate the effectiveness of the approach in cultured cells first, and next in transgenic mice. Then we will use this approach to investigate the physiologic and behavioral changes of the animals. We hope to provide new information about the functions of the transporters in whole animals and their roles in the addiction to drugs of abuse and the therapeutic actions of antidepressants. The knowledge gained from these studies may eventually lead to better approach to treat drug addictions, depression and other related diseases.