ACTIONS OF KETAMINE, PHENCYCLIDINE AND MK-801 ON NMDA RECEPTOR CURRENTS IN CULTURED MOUSE HIPPOCAMPAL-NEURONS

被引:249
|
作者
MACDONALD, JF
BARTLETT, MC
MODY, I
PAHAPILL, P
REYNOLDS, JN
SALTER, MW
SCHNEIDERMAN, JH
PENNEFATHER, PS
机构
[1] Department of Physiology, University of Toronto, Ontario
来源
JOURNAL OF PHYSIOLOGY-LONDON | 1991年 / 432卷
关键词
D O I
10.1113/jphysiol.1991.sp018396
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
1. Stable N-methyl-D-aspartic acid (NMDA) receptor-mediated currents in cultured mouse hippocampal neurones were evoked by 20 ms pressure pulse applications of L-aspartate, repeatedly applied at 30 or 40 s intervals, to the cell body region of the neurone. We have characterized the voltage- and use-dependent blockade of the currents by three dissociative anaesthetics: ketamine, phencyclidine (PCP) and MK-801 in mouse hippocampal neurones grown in dissociated tissue culture. 2. We have used a simple model of the blockade, based on the 'guarded receptor hypothesis' to interpret our data. The model assumes that receptors are maximally activated at the peak of the response with an open probability (P(o)) approaching 1, that there is no desensitization and that the blocking drug only associates with, or dissociates from, receptor channels which have been activated by agonist (e.g. open channels). 3. The model allows us to estimate forward and reverse rate constants for binding of the blockers to open channels from measurements of the steady-state level of blockade and the rate of change of the current amplitude per pulse during onset and offset of blockade. As predicted by the model, the estimated reverse rate was independent of blocker concentration while the forward rate increased with concentration. Changing the level of positively charged ketamine (pK(a) 7.5) tenfold by changing pH from 6.5 to 8.5 caused a corresponding change in the forward rate while having no effect on the reverse rate. Most of the voltage dependence of the blockade could be accounted for by reduction of the reverse rate by depolarization. 4. Estimated forward rate constants for ketamine, PCP and MK-801 were similar to one another when measured under similar conditions and were 3 x 10(4)-3 x 10(5) M-1 S-1. Most of the differences in potency of the three blockers could be accounted for by differences in the reverse rate constants which were approximately 0.2, 0.03 and 0.003 s-1 for ketamine, PCP and MK-801, respectively. The estimated rate constants actually are the product of the rate constants and 1/P(o). Suggestions that maximum P(o) is much less than 1 for NMDA channels imply that both forward and reverse rate constants of blockade may in fact be larger than we have calculated. However, their magnitudes, relative to one another, are unaffected by this consideration. 5. The reverse rate constant of blockade increased at positive potentials. This increase was prevented when the neurone was loaded with N-methyl-D-glucamine, an impermeant cation which prevented outward currents. This observation suggests that the voltage-dependent blockade by dissociative anaesthetics is in fact current dependent and reflects displacement of anaesthetic molecules, bound to the vicinity of the outer mouth of the channel, by intracellular cations that move out of the cell via the channel at positive potentials. This suggestion is supported by the observation that the voltage dependence of the blockade by the neutral PCP analogue, 1-(1-(2 thienyl)-cyclohexyl)morpholine (TCM) is similar to that of the blockade by PCP. 6. The blockade by dissociative anaesthetics was reduced by 0.5 mM-Mg2+ which itself caused blockade of the NMDA currents. Occupancy of the receptor binding site by the competitive NMDA antagonist DL-2-amino-5-phosphonovaleric acid (APV) had no direct effect on the action of the dissociative anaesthetics other than that expected from preventing activation of the receptor.
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收藏
页码:483 / 508
页数:26
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