Joy Brian, McMahon Robert P, Shepard Paul D
Maryland Psychiatric Research Center, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD 21228, USA.
Psychopharmacology (Berl). 2004 Jul;174(2):274-82. doi: 10.1007/s00213-003-1731-4.
Auditory gating deficits observed in patients with schizophrenia have been modeled in animals administered the indirect-acting monoaminergic agonist, D-amphetamine (AMPH). The atypical antipsychotic drug clozapine (CLOZ) reverses the disruption of auditory gating in schizophrenic patients. However, its effects on psychostimulant-induced deficits in animals have yet to be assessed.
In the present series of experiments, an auditory evoked potential paradigm was used to: (a) confirm the ability of AMPH to alter auditory gating in the anesthetized rat, (b) specify the nature of the accompanying change(s) in evoked potential waveforms and (c) determine the effects of CLOZ administration on AMPH-induced alterations in auditory gating.
We compared the effects of acute (5 mg/kg, i.p.) and chronic (28 days, 0.5 mg/ml in drinking water) CLOZ on AMPH-induced (1.8 mg/kg, i.p.) alterations in evoked potentials recorded in the hippocampus of anesthetized rats during presentation of a pair of identical tones. Gating was assessed by comparing the amplitude of conditioning and test responses in CLOZ and AMPH-treated rats.
The ratio of test to conditioning response amplitude (T/C ratio) was not altered by vehicle or CLOZ alone. However, T/C ratio was significantly increased following AMPH due to suppression of the conditioning response. Acute but not chronic CLOZ attenuated but did not prevent the increase in T/C ratio.
Qualitative differences between the idiopathic gating deficits observed in schizophrenic patients and AMPH-induced increases in T/C ratio in animals limit this models utility as a means of evaluating the ability of atypical antipsychotic drugs to restore normal sensory gating.
在给予间接作用的单胺能激动剂D-苯丙胺（AMPH）的动物中模拟了精神分裂症患者观察到的听觉门控缺陷。非典型抗精神病药物氯氮平（CLOZ）可逆转精神分裂症患者的听觉门控破坏。然而，其对精神兴奋剂诱导的动物缺陷的影响尚未评估。
在本系列实验中，使用听觉诱发电位范式来：（a）确认AMPH改变麻醉大鼠听觉门控的能力，（b）明确诱发电位波形伴随变化的性质，以及（c）确定给予CLOZ对AMPH诱导的听觉门控改变的影响。
我们比较了急性（5mg/kg，腹腔注射）和慢性（28天，饮用水中0.5mg/ml）CLOZ对AMPH诱导（1.8mg/kg，腹腔注射）的麻醉大鼠海马在呈现一对相同音调期间记录的诱发电位变化的影响。通过比较CLOZ和AMPH处理大鼠的条件反应和测试反应的幅度来评估门控。
单独使用溶剂或CLOZ不会改变测试与条件反应幅度的比率（T/C比率）。然而，由于条件反应受到抑制，AMPH后T/C比率显著增加。急性而非慢性CLOZ减弱但未阻止T/C比率的增加。
精神分裂症患者中观察到的特发性门控缺陷与动物中AMPH诱导的T/C比率增加之间存在质的差异，限制了该模型作为评估非典型抗精神病药物恢复正常感觉门控能力的手段的效用。
