RT Journal Article
SR Electronic
T1 Tiletamine is a potent inhibitor of N-methyl-aspartate-induced depolarizations in rat hippocampus and striatum.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 915
OP 920
VO 243
IS 3
A1 J M ffRench-Mullen
A1 J Lehmann
A1 R Bohacek
A1 R S Fisher
YR 1987
UL http://jpet.aspetjournals.org/content/243/3/915.abstract
AB N-methyl-D,L-aspartate (NMA) antagonists are of potential value in the treatment of epilepsy and ischemia, but commonly utilized compounds are of low potency and poorly penetrate the brain. Tiletamine hydrochloride is a lipophilic and potent veterinary anesthetic. This study shows tiletamine to be similar to ketamine and to phencyclidine, agents known to interact with the NMA receptor. Effects of tiletamine on synaptic transmission and on direct excitatory responses to exogenous amino acids were examined in rat hippocampal and striatal slices. In striatal slices, tiletamine inhibited the NMA-mediated, but not the spontaneous, release of [3H]acetylcholine, with an IC50 of 70 nM. In hippocampal CA1 cells, 3 microM tiletamine in the perfusate reversibly blocked the intracellularly recorded responses to ionophoretically applied NMA, but not to glutamate, quisqualate and kainate. Tiletamine, 3 to 100 microM, had no effect on the orthodromically elicited excitatory postsynaptic potential, action potential amplitude or duration, resting membrane potential, or input resistance. In Mg++-free perfusate, the excitatory postsynaptic potential was greatly augmented to give a paroxysmal depolarization shift and was reversibly blocked by 10 microM tiletamine. Our results show that tiletamine is a potent and reversible antagonist of NMA-mediated responses without itself having major effects in low concentrations on normal membrane and synaptic pyramidal cell properties.