Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box #104790, Durham, NC 27710, USA.
Psychopharmacology (Berl). 2012 Jan;219(1):99-108. doi: 10.1007/s00213-011-2377-2. Epub 2011 Jun 28.
Prepulse inhibition (PPI) is the reduction in startle response magnitude when intense stimuli are closely preceded by other weak stimuli. Animal models used to investigate sensorimotor gating deficits include both the stimulation of dopamine receptors (e.g., amphetamine or apomorphine) and the blockade of NMDA-glutamate receptors (e.g., dizocilpine or phencyclidine).
We assessed the effects of idazoxan (an α(2)-adrenergic antagonist) on amphetamine- and dizocilpine-induced PPI disruptions in adult female Sprague-Dawley rats.
In experiment 1, rats were tested for PPI in a bimodal paradigm with an acoustic prepulse and a tactile startle stimulus. Interactions of amphetamine (1 mg/kg) and idazoxan (0.5, 1, and 2 mg/kg) were assessed, with all rats receiving all drug doses in a counterbalanced order. In experiment 2, dizocilpine (0.05 mg/kg) and idazoxan (0.5, 1, and 2 mg/kg) interactions were analyzed.
Amphetamine (1 mg/kg) caused a significant reduction in PPI. Both the 1- and 2-mg/kg doses of idazoxan significantly counteracted this effect. Dizocilpine (.05 mg/kg) effectively inhibited PPI, and the 2-mg/kg idazoxan dose significantly counteracted this impairment.
These results suggest that the effectiveness of atypical antipsychotics such as clozapine in counteracting sensorimotor gating deficits reported in previous studies (e.g., Swerdlow and Geyer, Pharmacol Biochem Behav 44:741-744, 1993; Bakshi et al., J Pharmacol Exp Ther 271:787-794, 1994) may be related to their α(2)-antagonist effects, which may be a critical mechanism of the therapeutic effects of atypical antipsychotics in schizophrenia.
前脉冲抑制（PPI）是指当强烈刺激被其他弱刺激紧密地预先刺激时，起始反应幅度的减小。用于研究感觉运动门控缺陷的动物模型包括多巴胺受体的刺激（例如，安非他命或阿朴吗啡）和 NMDA-谷氨酸受体的阻断（例如，地卓西平或苯环己哌啶）。
我们评估了伊达唑兰（一种 α（2）-肾上腺素能拮抗剂）对成年雌性 Sprague-Dawley 大鼠中安非他命和地卓西平诱导的 PPI 破坏的影响。
在实验 1 中，大鼠在双模态范式中接受 PPI 测试，该范式具有声前脉冲和触觉起始刺激。评估安非他命（1mg/kg）和伊达唑兰（0.5、1 和 2mg/kg）的相互作用，所有大鼠以平衡的顺序接受所有药物剂量。在实验 2 中，分析了地卓西平（0.05mg/kg）和伊达唑兰（0.5、1 和 2mg/kg）的相互作用。
安非他命（1mg/kg）导致 PPI 显著降低。伊达唑兰的 1mg/kg 和 2mg/kg 剂量均显著拮抗这种作用。地卓西平（0.05mg/kg）有效抑制 PPI，而 2mg/kg 伊达唑兰剂量显著拮抗这种损害。
这些结果表明，氯氮平等非典型抗精神病药在以前的研究中报告的对抗感觉运动门控缺陷的有效性（例如，Swerdlow 和 Geyer，Pharmacol Biochem Behav 44：741-744，1993；Bakshi 等人，J Pharmacol Exp Ther 271：787-794，1994）可能与其 α（2）-拮抗剂作用有关，这可能是非典型抗精神病药治疗精神分裂症的疗效的关键机制。
