Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response.
Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response.
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发表时间：
1994-11
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通讯作者：
V. Bakshi;N. Swerdlow;M. Geyer
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作者：
V. Bakshi;N. Swerdlow;M. Geyer
强烈的听觉刺激会引起一种不自觉的惊吓反应，当这种惊吓刺激（脉冲）之前立即出现低强度的刺激（预脉冲）时，这种反应会减弱。这种脉冲前抑制（PPI）的现象被用作感觉运动门控的测量，在精神分裂症患者中显著减少。非竞争性n-甲基-d -天冬氨酸拮抗剂，如苯环利定（PCP）和（(+)- d -天冬氨酸5-甲基-10,11-二氢- 5h -二苯并[a，d]环庚烯-5,10-亚胺）（二唑西平，或MK-801），先前已发现可破坏动物的PPI。本研究评估了几种抗精神病药物逆转pcp诱导的大鼠PPI缺陷的能力。动物分别用非典型抗精神病药物氯氮平（0、1.25、2.5、5.0或10.0 mg/kg）、D2多巴胺拮抗剂雷氯pride（0、0.1或0.5 mg/kg）、D1多巴胺拮抗剂SCH23390（0、0.01或0.05 mg/kg）或5-羟色胺2拮抗剂利坦色林（0或2.0 mg/kg）或酮色林（0或1.0 mg/kg）进行预处理，然后给予PCP （1.0 mg/kg）。在给药后，动物们在惊吓室里接受测试。PCP反复而有力地降低PPI，而不影响基线惊吓反应性。氯氮平（5.0 mg/kg）在不改变PPI的情况下拮抗PCP的这种作用。Raclopride、SCH23390、利坦色林和酮色林对逆转pcp诱导的PPI缺陷无效。与PCP一样，0.1 mg/kg的MK-801破坏了PPI；这种破坏也被5.0 mg/kg氯氮平拮抗。因此，氯氮平逆转非竞争性n -甲基- d -天冬氨酸拮抗剂产生的PPI缺陷的能力似乎不能归因于D1多巴胺、D2多巴胺或5-羟色胺2受体的单一拮抗作用。（摘要删节250字）
Intense auditory stimuli elicit an involuntary startle response that is attenuated when the startling stimulus (the pulse) is preceded immediately by a low intensity stimulus (the prepulse). This phenomenon of prepulse inhibition (PPI) is utilized as a measure of sensorimotor gating and is significantly reduced in schizophrenic patients. Noncompetitive N-methyl-D-aspartate antagonists such as phencyclidine (PCP) and ((+)-D-aspartate 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) (dizocilpine, or MK-801) have been found previously to disrupt PPI in animals. The present investigation assessed the ability of several antipsychotic drugs to reverse PCP-induced deficits in PPI in rats. Animals were pretreated with either the atypical antipsychotic clozapine (0, 1.25, 2.5, 5.0 or 10.0 mg/kg), the D2 dopamine antagonist raclopride (0, 0.1 or 0.5 mg/kg), the D1 dopamine antagonist SCH23390 (0, 0.01 or 0.05 mg/kg) or the 5-hydroxytryptamine2 antagonists ritanserin (0 or 2.0 mg/kg) or ketanserin (0 or 1.0 mg/kg) and then were given PCP (1.0 mg/kg). After drug administration, animals were tested in startle chambers. PCP repeatedly and robustly decreased PPI without affecting base-line startle reactivity. Clozapine (5.0 mg/kg) antagonized this effect of PCP without altering PPI by itself. Raclopride, SCH23390, ritanserin and ketanserin were ineffective at reversing the PCP-induced deficit in PPI. As with PCP, 0.1 mg/kg of MK-801 disrupted PPI; this disruption also was antagonized by 5.0 mg/kg of clozapine. Thus, it appears that the ability of clozapine to reverse deficits in PPI produced by noncompetitive N-methyl-D-aspartate antagonists cannot be attributed to a sole antagonism of either D1 dopamine, D2 dopamine or 5-hydroxytryptamine2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)