Our goal is to understand the decline of cholinergic neurotransmission associated with age and to determine if intervention with exogenous agents such as cholinergic agonists or anti-inflammatory agents modifies this age-related process. We have described a CBAJJ mouse model that reliably reflects normal age-related decline in the expression of high-affinity nicotine-binding sites containing the nicotinic acetylcholine receptor (nAChR) subunit, nAChRa4. This loss was reduced in adult animals that received long-term (11-month) oral nicotine delivery. These studies have been extended to show that neurons exhibiting diminished nAChRa4 expression also co-express 1) other nAChR subunits; 2) a marker of inhibitory neurons (glutamic acid decarboxylase); and 3) they constitutively express a target of NSAIDS, cyclooxygenase-2 (Cox2). The focus of this project is to determine if the long-term administration of nicotine or inhibitors of COX2, or both agents simultaneously, produce benefits in moderating age-related changes in the brain as measured by the retention of adult mouse nAChR expression and transcriptional responses. To do this, the following questions are proposed. First, do age-related changes in the expression of multiple nAChR subunits occur in a predictable manner, and is this modified by long-term nicotine administration? Second, does inhibition of COX2 by long-term administration of non-steroidal anti-inflammatory drugs (NSAIDs) impact age-related changes in neuronal expression of nAChRs? Third, using custom-designed microarray chips, does transcriptional activity in the hippocampus of aged animals differ from that of young animals, especially in response to challenge with an exogenous inflammatory agent, lipopolysaccharide? Does long-term drug administration produce benefits in the aged animal as measured by retention of transcriptional responses to peripheral assaults, and does this correlate with retention of nAChR neurotransmitter receptor systems?
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