SRIF is a neurotransmitter in the CNS involved in the control of locomotor activity and cognitive functions. The role of SRIF in mediating cognitive functions has important clinical implications with regards to Alzheimer's disease (AD), a neuropsychiatric disorder associated with diminished SRIF levels in limbic structures and severe cognitive impairments. Since SRIF receptor levels are normal in AD brain, SRIF replacement therapy could be useful in treating this disorder. SRIF induces its biological actions by interacting with cell surface associated receptors. Recent cloning studies have identified five SRIF receptor subtypes referred to as SSTR1-5. The objective of this proposal is to identify the specific functions of these individual SRIF receptor subtypes in the brain. During the previous period of support, the applicants developed selective agonists at SSTR2,3 and 4. These agonists will be used in the present project to identify specific functions of the receptor subtypes. The peptides will be iodinated and the radioligands will be employed to localize sites in the brain where these receptors subtypes are expressed and may mediate selective actions of SRIF. The investigators have generated antisera that specifically interacts with SSTR2, and they are developing antisera against the other receptor subtypes which will be used to further localize sites in the CNS expressing these receptors by immunoblotting and immunocytochemistry. To investigate selective cellular functions of these receptor subtypes, they have stably expressed each receptor in PC12 cells to determine whether the receptors couple to calcium (Ca2+) and potassium (K+) ion channels using whole-cell patch clamp electrophysiological techniques. Furthermore, the subtype selective agonists, which the applicants have developed, will be used to determine whether SSTR2-4 expressed in brain neurons couple to these ionic conductance channels. The subtype selective agonists will be tested in behavioral studies to determine which receptors mediate the stimulatory effects of SRIF on locomotor activity and cognitive functions. The cognitive effects of SRIF peptides will be assessed using passive avoidance behaviors and the eight-arm radial maze. The project will also test non-peptidic SRIF analogs that can gain entrance to the brain following peripheral administration for their ability to reverse cognitive impairments in rodents induced by depleting central SRIF with the drug cysteamine. The broader relevance of this project is to identify the specific functions of SRIF receptor subtypes in brain to provide a potential foundation for developing SRIF drugs to be used in the treatment of CNS disorders involving imbalances in SRIF transmission, such as AD.
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