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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. Matthew Galloway Kerry Murphy* Navid Seraji-Bozorgzad

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slide1

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

slide4

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.

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.

Aim

methods
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 (p< 0.05), drug v. control.
results summary of significant changes only
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
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 1H or 31P MRS.
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Cortex

MD Thalamus

GLU

GLN

Gaseous Potentiation

GLN

Gaseous Potentiation

GABA

GLU

GLU

GLN

GLU

GLU

Interneuron

GABA

Ketamine Inhibition

Pyramidal

GLU

GABA-A

NMDA

mpg