Acute phencyclidine poisoning in the unanesthetized dog: Pathophysiologic profile of acute lethality

Phencyclidine HCl was infused intravenously (1.0 mg/kg/min) to unanesthetized mongrel dogs until death. All animals experienced tonic-clonic convulsions (mean convulsive dose: 4.7± 0.3 mg/kg) which lasted until shortly before death (mean lethal dose: 49.8 ± 2.5 mg/kg). Significant increases in heart rate, arterial blood pressures, cardiac output, body temperature, and arterial pCO₂ were observed in all animals. Significant reductions from pre-drug control values were observed in total peripheral resistance, arterial pH, arterial pO₂, and respiratory minute volume. Blood lactate, oxygen uptake, and plasma glucose levels rose to values significantly higher than pre-drug control values then declined during the latter phase of the experiment, glucose levels decreased to final values lower than control. Animals appeared to die of primary respiratory failure, which was exacerbated by hyperthermia, and which resulted in final cardiovascular collapse.     

富马酸奎的平在动物模型中的非典型抗精神病作用(英文)

目的:评价富马酸奎的平在精神分裂症阴性和阳性症状模型中的作用及导致锥体外系副反应(EPSE)的可能性。方法:以苯环利啶(10mg·kg~(-1)·d~(-1),sc,14d)引起小鼠在强制性游泳实验中保持不动的时间(immobility time,IT)延长为阴性症状模型,d-苯丙胺游泳正常化实验为阳性症状模型,paw test评价药物导致EPSE的可能性。结果:富马酸奎的平(20,40,80mg·kg~(-1),ig)可逆转苯环利啶引起的小鼠在强制性游泳实验中IT延长;5-80mg·kg~(-1),ig可对抗d-苯丙胺导致的小鼠游泳行为异常;在paw test中更易使后肢回缩时间延长,MED_(FRT)/MED_(HRT)比值为5。结论:富马酸奎的平是对精神分裂症阴性和阳性症状均有效的非典型抗精神病药物。     

Neuregulin 1 Prevents Phencyclidine-Induced Behavioral Impairments and Disruptions to GABAergic Signaling in Mice

Background:

Substantial evidence from human post-mortem and genetic studies has linked the neurotrophic factor neuregulin 1 (NRG1) to the pathophysiology of schizophrenia. Genetic animal models and in vitro experiments have suggested that altered NRG1 signaling, rather than protein changes, contributes to the symptomatology of schizophrenia. However, little is known about the effect of NRG1 on schizophrenia-relevant behavior and neurotransmission (particularly GABAergic and glutamatergic) in adult animals.

Method:

To address this question, we treated adult mice with the extracellular signaling domain of NRG1 and assessed spontaneous locomotor activity and acoustic startle response, as well as extracellular GABA, glutamate, and glycine levels in the prefrontal cortex and hippocampus via microdialysis. Furthermore, we asked whether the effect of NRG1 would differ under schizophrenia-relevant impairments in mice and therefore co-treated mice with NRG1 and phencyclidine (PCP) (3mg/kg).

Results:

Acute intraventricularly- or systemically-injected NRG1 did not affect spontaneous behavior, but prevented PCP induced hyperlocomotion and deficits of prepulse inhibition. NRG1 retrodialysis (10nM) reduced extracellular glutamate and glycine levels in the prefrontal cortex and hippocampus, and prevented PCP-induced increase in extracellular GABA levels in the hippocampus.

Conclusion:

With these results, we provide the first compelling in vivo evidence for the involvement of NRG1 signaling in schizophrenia-relevant behavior and neurotransmission in the adult nervous system, which highlight its treatment potential. Furthermore, the ability of NRG1 treatment to alter GABA, glutamate, and glycine levels in the presence of PCP also suggests that NRG1 signaling has the potential to alter disrupted neurotransmission in patients with schizophrenia.