Nicotine addiction underlies the widespread use oftobacco products. Epidemiological evidence suggests that individuals who begin smoking as adolescents have a higher probability of being life-long smokers than individuals who start smoking in their 20's or later. There is little data on the possible influence ofbrain developmentand aging onthe molecular and metabolic effects ofnicotine whichcould contnbutc to its behavioral and addictive properties. This studywill investigate the effect of acute administration of eithernicotine by patch or placebo to human volunteers (nonsmokers and dependent smokers;age ranges 14-20and 35-45 years) on measures of high-energy phosphate [phosphocreatine (PCr) and adenosine 5'-triphosphate] and membrane phospholipid metabolism [phosphomonoesters (PME) and phosphodiesters (PDE)] by 31P magnetic resonance spectroscopic imaging (MRSI) and on measures of N-acetylaspartate ( a putative measure of neuronal integrity), trimethylamines [glycerophosphocholine, phosphocholine, and choline], and creatine (Cr) (PCr+Cr) by 1HMRSI. Both short correlation time ( S-Tc) and intermediate correlation time (I-Tc) components of the PME and PDE resonances will be quantified. The PME (S-Tc) are precursors of membrane phospholipids and the PME (i-tc) are phosphorylated proteins. The PDE (S-Tc) are breakdown products of membrane phospholipids and PDE (I-Tc) reflect the number of synaptic vesicles in grey matter. The influence of subject age and smoking status on the molecular and metabolic responses to nicotine will be investigated. In addition, quantitative 1H magnetic resonance imaging (MRI) will be performed in order to correlate the metabolic findings with the percent gray matter, white matter, and CSF in the voxels of interest from which the MRSI data is obtained. Our 31 P-1H MRSI pilot data in human nonsmokers in two age groups (young-adult and middle-aged subjects) suggests nicotine-induced transient breakdown of membrane phospholipids to PDE (s-Tc) and then to PME(S-Tc). There also appears to be a nicotine-induced decrease in PDE(i-Tc) levels in grey matter which could be related to transient reduction in synaptic vesicles. The pilot data indicates more robust changes in response to nicotine in the young-adult nonsmokers than in the middle-aged nonsmokers and a nicotine-induced response in different brain regions for young-adult versus middle-aged nonsmokers. We propose to investigate these aspects of brain metabolism in humans using 31P-1H MRSI.
