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Title: The effect of anaesthetic and analgesic agents on glutamate uptake and release from rat neuronal preparations
Author: Nicol, Beverley
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 1997
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In rat cerebrocortical and cerebellar synaptosomes the uptake of [3H]L-glutamate was time-, concentration-(Km=-8.6 and ~2.2M respectively), Na+-dependent and L-trans-PDC sensitive. In general the uptake mechanism was insensitive to clinically relevant concentrations of anaesthetics.;Perfused rat cerebrocortical slices depolarised with 2x2min pulses of 46mM K+ (S1 and S2) evoked monophasic releases of endogenous glutamate with an S2/S1 ratio of ~1.07. 0.1mM EGTA pre-treatment significantly inhibited evoked release, confirming a Ca2+ regulated exocytotic process.;A range of and , but not ligands inhibited evoked release of glutamate (e.g. morphine IC50 71nM). A novel heptadecapeptide, nociceptin produced a dose-dependent naloxone insensitive inhibition of evoked glutamate release (IC50 of 51nM). The anaesthetic agents propofol, thiopentone, ketamine and halothane, dose-dependently inhibited the evoked release of glutamate with IC50s of ~20, 10, 18 and 132M respectively. At single doses 1M MK-801, 100M pentobarbital 435M isoflurane significantly inhibited release. A non-anaesthetic barbiturate, barbituric acid was ineffective. These data suggest that glutamate release may be a target for anaesthetic agents.;[3H]MK-801 bound to NMDA receptors in a time- and concentration-dependent manner (KD=~3nM, Bmax=~900fmoles/mg protein). The racemic mixture, R- and S+ isomers of ketamine significantly displaced the binding with estimated Ki values of ~638, 2703 and 568nM respectively. Etomidate significantly displaced the binding of [3H]MK-801 with an estimated Ki of 4M. Propofol, thiopentone and pentobarbital, barbituric acid, halothane and morphine were ineffective. Block of pre-synaptic NMDA receptors alone cannot explain the observed anaesthetic/analgesic inhibition of evoked glutamate release.;Collectively these data support a role for glutamatergic neurotransmission in the mechanism of anaesthesia/analgesia and may implicate anaesthetic/analgesic agents as neuroprotectants.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available