Walker D L, Gold P E
Neuroscience Graduate Program, University of Virginia, Charlottesville 22903.
Behav Neural Biol. 1994 Sep;62(2):151-62. doi: 10.1016/s0163-1047(05)80036-6.
We previously reported that systemically administered N-methyl-D-aspartate (NMDA) antagonists significantly impair spontaneous alternation behavior. Others have reported that the restricted blockade of hippocampal NMDA receptors disrupts performance on different tests of spatial learning and have suggested that the resulting impairments are attributable to a disruption of endogenous NMDA-dependent long-term potentiation (LTP). In the present study, we determined whether spontaneous alternation performance was disrupted by circumscribed blockade of hippocampal NMDA receptors as well as by a second class of compounds which disrupt LTP, protein kinase inhibitors. The effect of hippocampal NMDA blockade on inhibitory avoidance was also examined insofar as this behavior too is disrupted by systemically administered NMDA antagonists. When injected into the hippocampus 15 min prior to spontaneous alternation testing, the NMDA antagonists CPP and D,L-AP5 each decreased alternation rates. The specific protein kinase C (PKC) inhibitor, NPC 15437, also disrupted spontaneous alternation, whereas the more general kinase inhibitor, PMXB, did not. When injected 15 min prior to inhibitory avoidance training, CPP also impaired inhibitory avoidance learning as assessed during a subsequent test session, 48 h later. Interpretation of these data was complicated by the additional findings that intrahippocampal infusion of L-AP5 (which is inactive with respect to NMDA receptors) also disrupted alternation performance, and that both the D- and the L-isomers of AP5 as well as each kinase inhibitor dramatically disrupted evoked responses (i.e., population spike amplitude, spike latency, and EPSP slope), as recorded in the dentate gyrus and evoked by perforant path stimulation. These data indicate that behaviorally effective doses of AP5 may have effects which extend beyond NMDA blockade. Moreover, the effects of these compounds on hippocampal transmission, in general, suggest that attribution of the amnestic consequences of their administration to impaired LTP may be unwarranted.
我们之前报道过，全身给药的N-甲基-D-天冬氨酸（NMDA）拮抗剂会显著损害自发交替行为。其他人报道过，海马NMDA受体的局限性阻断会破坏不同空间学习测试的表现，并提出由此产生的损害归因于内源性NMDA依赖的长时程增强（LTP）的破坏。在本研究中，我们确定了海马NMDA受体的局限性阻断以及另一类破坏LTP的化合物（蛋白激酶抑制剂）是否会破坏自发交替表现。还研究了海马NMDA阻断对抑制性回避的影响，因为全身给药的NMDA拮抗剂也会破坏这种行为。在自发交替测试前15分钟注入海马时，NMDA拮抗剂CPP和D，L-AP5均降低了交替率。特异性蛋白激酶C（PKC）抑制剂NPC 15437也破坏了自发交替，而更通用的激酶抑制剂PMXB则没有。在抑制性回避训练前15分钟注入CPP，在随后48小时的测试中评估时，也损害了抑制性回避学习。这些数据的解释因其他发现而变得复杂，即海马内注入L-AP5（对NMDA受体无活性）也破坏了交替表现，并且AP5的D-和L-异构体以及每种激酶抑制剂都显著破坏了齿状回中记录的、由穿通通路刺激诱发的诱发反应（即群体峰电位幅度、峰潜伏期和兴奋性突触后电位斜率）。这些数据表明，行为有效剂量的AP5可能具有超出NMDA阻断的作用。此外，一般来说，这些化合物对海马传递的影响表明，将其给药导致遗忘的后果归因于LTP受损可能是没有根据的。
