Potentiation of GABA-A receptor function with propofol selectively decreases glutamate measured with proton magnetic resonance spectroscopy KL Murphy^1,2, GM McKelevey², SK O’Leary-Moore¹, N Seraji-Bozorgzad¹, DC Freeman³, A Pustavoitau², KM Haubenreich², GJ Moore, HM Marsh², and MP Galloway¹, Psychiatry¹, Anesthesiology², and Biology³ Wayne State Univ Sch Med, Detroit MI

Propofol is a widely used anesthetic agent that potentiates the inhibitory effect of GABA at GABA-A receptors. Therefore, using magic angle ¹H magnetic resonance spectroscopy (MAS ¹H MRS), we determined the effect of propofol on the metabolomic profile in rat brain in order to gain insight into 1) the mechanism of injectable anesthetics and 2) the role of enhanced GABAergic inhibition on MR-visible neurochemicals. Male rats were treated with propofol (15 mg/kg iv, q 15 min, x5), sacrificed 5 min later, and brain punches (~4 mg) of select regions of interest obtained from 2 mm coronal slices. Chemical shift ¹H-MRS spectra were determined with a Bruker 11.7T magnet with intact tissue in a 10 mL rotor maintained at 4C and spun at 4.2kHz at 54º7’ relative to B₀ using a CPMG rotor-synchronized pulse sequence. Absolute quantities of each neurochemical were determined with a customized LCModel and corrected for tissue weight (nmol/mg). Monoamines were determined by HPLC-EC. Propofol treatment was associated with loss of consciousness as well as significant (p<0.001, multivariate) changes in the neurochemical profile. When data are collapsed on ROIs, propofol increased (p<0.001) glutamine, glutathione, and lactate whereas glutamate was decreased after propofol. The effects were selective for ROIs in that glutamate was decreased (t-test p<0.05) in MD thalamus, posterior striatum, VTA, cingulate, and medial prefrontal cortex but not changed in the accumbens nuclei, s.nigra, or hippocampus CA1. However, GLU/glutamine ratios, a putative marker of GLU turnover, were significantly decreased in all ROIs. Striatal and accumbal dopamine levels were significantly increased by propofol, consistent with GABA-A mediated inhibition of DA cell firing. Overall we conclude that acute potentiation of GABA-A receptor function decreases levels of MR-visible glutamate. Supported by DA-16736