Levin Edward D, Caldwell D Patrick, Perraut Charles
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
Pharmacol Biochem Behav. 2007 Mar;86(3):597-605. doi: 10.1016/j.pbb.2007.02.005. Epub 2007 Feb 13.
Pre-pulse inhibition (PPI) is a phenomenon of neurobehavioral plasticity in which the motor response to a startling sensory stimulus is inhibited by a preceding sensory stimulus of a lower intensity. The current experiment used tactile startle rather than acoustic startle to determine the generality of PPI across sensory modalities. PPI is easily modeled in experimental animals and serves as a useful method for determining the neural bases for sensorimotor plasticity, which can be disturbed in sensory modulation disorders. In the current study, female Sprague-Dawley rats were tested for tactile startle PPI after an auditory pre-pulse. The glutamate NMDA receptor antagonist dizocilpine (MK-801, 0.05 mg/kg) caused a nearly total blockade of the PPI effect (p<0.0005). The antipsychotic drug clozapine (1.25 mg/kg, p<0.001 and 2.5 mg/kg p<0.05) significantly attenuated the dizocilpine-induced PPI impairment. Interestingly, the lower clozapine dose did not by self enhance PPI and the higher clozapine dose when given alone caused a significant (p<0.05) PPI impairment relative to control. Nicotine (0.2 and 0.4 mg/kg) did not significantly interact with the other treatments, though the higher nicotine dose did show a trend toward attenuating the PPI impairment caused by the high clozapine dose. These effects were replicated in a second experiment of clozapine-dizocilpine interactions without nicotine treatment. This study shows that PPI of tactile startle is dramatically impaired by blocking NMDA activation and that the prototypic atypical antipsychotic drug clozapine can correct this deficit. This may be relevant to the action of clozapine in attenuating sensory gating deficits in schizophrenia and may point to new avenues of treatment for sensory modulation disorders in which there is excessive tactile response.
前脉冲抑制（PPI）是一种神经行为可塑性现象，即对强烈感觉刺激的运动反应会被之前强度较低的感觉刺激所抑制。当前实验使用触觉惊吓而非听觉惊吓来确定PPI在不同感觉模态中的普遍性。PPI在实验动物中很容易建模，并且是确定感觉运动可塑性神经基础的有用方法，而感觉运动可塑性在感觉调制障碍中可能会受到干扰。在当前研究中，对雌性斯普拉格-道利大鼠进行了听觉前脉冲后的触觉惊吓PPI测试。谷氨酸NMDA受体拮抗剂地佐环平（MK-801，0.05mg/kg）几乎完全阻断了PPI效应（p<0.0005）。抗精神病药物氯氮平（1.25mg/kg，p<0.001；2.5mg/kg，p<0.05）显著减轻了地佐环平诱导的PPI损伤。有趣的是，较低剂量的氯氮平本身并不会增强PPI，而单独给予较高剂量的氯氮平时，相对于对照组会导致显著的（p<0.05）PPI损伤。尼古丁（0.2mg/kg和0.4mg/kg）与其他处理之间没有显著相互作用，尽管较高剂量的尼古丁确实显示出减轻高剂量氯氮平引起的PPI损伤的趋势。这些效应在氯氮平-地佐环平相互作用的第二个实验中得到了重复，该实验未进行尼古丁处理。本研究表明，阻断NMDA激活会显著损害触觉惊吓的PPI，而典型的非典型抗精神病药物氯氮平可以纠正这一缺陷。这可能与氯氮平减轻精神分裂症感觉门控缺陷的作用有关，并且可能为触觉反应过度的感觉调制障碍指出新的治疗途径。
