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

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

• Using (HR-MAS) 1H-MRS at 11.7T, determine the
  regional effect of gaseous (Isoflurane or
  Halothane) or injectable (ketamine) anesthetics
  in intact rat brain tissue.

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Methods

• Anesthesia (Male Sprague-Dawley rats)
• Ketamine (100-300 mg/kg i.v. over 30 min)
• Isoflurane (1.1 vol) at 100 O2 for 1 hr.
• Halothane (1.2 vol) at 100 O2 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-1H-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 (plt 0.05), drug v.
  control.

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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

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Discussion

• Acute exposure to either volatile or injectable
  anesthetics produced unique alterations MRS
  visible neurochemicals.
• Gaseous agents (Halothane and Isoflurane)
• Decreased levels of GLUMRS consistent with
  potentiation of endogenous GABA at inhibitory
  GABA-A synapses on glutamatergic pyramidal
  neurons in both the midbrain and cortex.
• Increased LACMRS 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 1H or 31P MRS.

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