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Brain glutamine synthetase (GS) is an integral part of the glutamate-glutamine cycle and occurs in the glial compartment. In vivo Magnetic Resonance Spectroscopy (MRS) allows noninvasive measurements of the concentrations and synthesis rates of metabolites. N-15 MRS is an alternative approach to C-13 MRS. Incorporation of labeled N-15 from ammonia in cerebral glutamine allows to measure several metabolic reactions related to nitrogen metabolism, including the glutamate-glutamine cycle. To measure N-15 incorporation into the position 5N of glutamine and position 2N of glutamate and glutamine, we developed a novel N-15 pulse sequence to simultaneously detect, for the first time, [5-N-15] Gln and [2-N-15]Gln + Glu in vivo in the rat brain. In addition, we also measured for the first time in the same experiment localized H-1 spectra for a direct measurement of the net glutamine accumulation. Mathematical modeling of H-1 and N-15 MRS data allowed to reduce the number of assumptions and provided reliable determination of GS (0.30 +/- 0.050 mu mol/g per minute), apparent neurotransmission (0.26 +/- 0.030 mu mol/g per minute), glutamate dehydrogenase (0.029 +/- 0.002 mu mol/g per minute), and net glutamine accumulation (0.033 +/- 0.001 mu mol/g per minute). These results showed an increase of GS and net glutamine accumulation under hyperammonemia, supporting the concept of their implication in cerebral ammonia detoxification. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 696-708; doi:10.1038/jcbfm.2011.173; published online 14 December 2011