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NMDA receptor antagonism with ketamine selectively increases GABA measured with proton magnetic resonance spectroscopy: Comparison with gaseous anesthetics.

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Presentation on theme: "NMDA receptor antagonism with ketamine selectively increases GABA measured with proton magnetic resonance spectroscopy: Comparison with gaseous anesthetics."— Presentation transcript:

1 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

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

5 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

6 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.

7 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

8 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.

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


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