NMDA receptor antagonism with ketamine selectively increases GABA measured with proton magnetic resonance spectroscopy: Comparison with gaseous anesthetics. George M. McKelvey, PhD Postdoctoral Fellow, Anesthesiology

Matthew Galloway Kerry Murphy* Navid Seraji-Bozorgzad Shonagh O'Leary-Moore Kristen Prevost Michael Marsh Aliaksei Pustavoitau George McKelvey

U sing (HR-MAS) 1 H-MRS at 11.7T, determine the regional effect of gaseous (Isoflurane or Halothane) or injectable (ketamine) anesthetics in intact rat brain tissue. Hypothesis Clinically-used anesthetics will alter the acute metabolomic profile of MR-visible neurochemicals in rat brain. Moreover, the profile will differentiate injectable from gaseous agents. Aim

Methods Anesthesia (Male Sprague-Dawley rats) –Ketamine ( mg/kg i.v. over 30 min) –Isoflurane (1.1% vol) at 100% O 2 for 1 hr. –Halothane (1.2% vol) at 100% O 2 for 1 hr. 2x2 mm punches from regions of interest –Cortical (medial prefrontal, cingulate) –Thalamic (medial dorsal, ventrolateral, hypothalamus) –Striatal (anterior, posterior, accumbens) HR-MAS- 1 H-MRS: Data acquisition with rotor-synchronized CPMG pulse sequence on a Bruker 11.7T magnet. Absolute quantification of each neurochemical (nmol/mg tissue) determined with a custom-designed LCModel. Univariate statistics 2 tail t-test (p< 0.05), drug v. control.

Results (Summary of significant changes only) Gaseous Anesthetics (Isoflurane and Halothane) –  Glutamate in cortical, striatal and thalamic regions –  GABA in cortical and striatal regions –  Lactate in cortical, striatal and thalamic regions Ketamine –  GABA in hypothalamus and accumbens –  Glutamine in hypothalamus, decreased in the striatum –  Glycine accumbens –Striatal dopamine levels unchanged Distinct drug-induced neurochemical profiles but no common trends between the two classes of anesthetics

Discussion Acute exposure to either volatile or injectable anesthetics produced unique alterations MRS visible neurochemicals. Gaseous agents (Halothane and Isoflurane) –Decreased levels of [GLU] MRS consistent with potentiation of endogenous GABA at inhibitory GABA-A synapses on glutamatergic pyramidal neurons in both the midbrain and cortex. –Increased [LAC] MRS after gaseous agents may indicate compromised metabolic energy status. Ketamine –Ketamine-induced GABA increases may reflect decreased GABAergic transmission in the absence of NMDA mediated excitatory drive, as predicted by the hyperglutamatergic theory of ketamine-induced psychosis. –Increased MR-visible GABA is common between ketamine and SSRIs, both of which have antidepressant properties. The results provide insight for hypothesis-based experiments with clinical 1 H or 31 P MRS.

GABA GLU GLN GLU GLN GLU GLN Interneuron Pyramidal GABA GABA-A NMDA CortexMD Thalamus Gaseous Potentiation Ketamine Inhibition mpg