Swerdlow Neal R, Bongiovanni Michele J, Tochen Laura, Shoemaker Jody M
Department of Psychiatry, UCSD School of Medicine, La Jolla, CA 2093-0804, USA.
Psychopharmacology (Berl). 2006 Jun;186(2):246-54. doi: 10.1007/s00213-006-0374-7. Epub 2006 Apr 1.
Startle inhibition by lead stimuli (prepulse inhibition, "PPI"), and the disruption of this process by dopamine agonists and N-methyl-D: -aspartate (NMDA) antagonists, are used in predictive models for antipsychotic development. PPI is also disrupted by the norepinephrine alpha-1 agonist, cirazoline, and the PPI-disruptive effects of the indirect dopamine agonist amphetamine are opposed by the norepinephrine reuptake inhibitor, desipramine. The hypothesis that PPI may be regulated by norepinephrine, or by interactions between dopamine and norepinephrine substrates, was tested in a series of experiments with the alpha-2 agonist, clonidine, which is used clinically to treat Tourette Syndrome (TS).
PPI was measured in male Sprague-Dawley rats after pretreatment with clonidine or the D2 antagonist haloperidol, and treatment with cirazoline, amphetamine, the D1/D2 agonist apomorphine, or the NMDA antagonist, phencyclidine.
PPI was disrupted by cirazoline; this effect was prevented by clonidine but not haloperidol. PPI was disrupted by apomorphine; this effect was prevented by haloperidol but not clonidine. Clonidine also failed to oppose the PPI-disruptive effects of amphetamine and augmented the PPI-disruptive effects of phencyclidine. Over a range of prepulse intervals, clonidine enhanced PPI at short intervals and opposed the PPI-disruptive effects of cirazoline at long intervals.
PPI is regulated by both norepinephrine and dopamine substrates that are neurochemically separable. The PPI-protective effects of clonidine suggest that the noradrenergic regulation of PPI may have utility for predicting therapeutic benefit in TS for drugs other than antipsychotics. Clonidine's failure to prevent the PPI-disruptive effects of apomorphine or phencyclidine further support the specificity of these PPI models for detecting drugs with antipsychotic properties.
铅刺激引起的惊吓抑制（前脉冲抑制，“PPI”），以及多巴胺激动剂和N-甲基-D-天冬氨酸（NMDA）拮抗剂对这一过程的破坏，被用于抗精神病药物研发的预测模型中。去甲肾上腺素α-1激动剂西拉唑啉也会破坏PPI，而去甲肾上腺素再摄取抑制剂地昔帕明则会对抗间接多巴胺激动剂苯丙胺的PPI破坏作用。在一系列使用α-2激动剂可乐定的实验中，对PPI可能受去甲肾上腺素或多巴胺与去甲肾上腺素底物之间相互作用调节的假说进行了检验，可乐定临床上用于治疗妥瑞氏症（TS）。
在用可乐定或D2拮抗剂氟哌啶醇预处理后，以及用西拉唑啉、苯丙胺、D1/D2激动剂阿扑吗啡或NMDA拮抗剂苯环利定处理后，测量雄性Sprague-Dawley大鼠的PPI。
西拉唑啉破坏了PPI；可乐定可预防此效应，但氟哌啶醇不能。阿扑吗啡破坏了PPI；氟哌啶醇可预防此效应，但可乐定不能。可乐定也未能对抗苯丙胺的PPI破坏作用，反而增强了苯环利定的PPI破坏作用。在一系列前脉冲间隔范围内，可乐定在短间隔时增强PPI，在长间隔时对抗西拉唑啉的PPI破坏作用。
PPI受神经化学上可分离的去甲肾上腺素和多巴胺底物调节。可乐定的PPI保护作用表明，PPI的去甲肾上腺素能调节可能有助于预测除抗精神病药物外其他药物对TS的治疗益处。可乐定未能预防阿扑吗啡或苯环利定的PPI破坏作用，进一步支持了这些PPI模型在检测具有抗精神病特性药物方面的特异性。
