强啡肽和苯环利定在高血压大鼠的环腺苷酸生成系统中的作用

采用放射免疫检测方法，观察了强啡肽（Ｄｙｎ）和苯环利定（ＰＣＰ）对高血压大鼠（ＳＨＲ）的环腺苷酸（ｃＡＭＰ）生成系统的影响，结果表明：Ｄｙｎ剂量依赖地降低ＳＨＲ和非高血压大鼠（ＷＫｙ）的外周血管中ｃＡＭＰ的含量，并且对ＳＨＲ的ｃＡＭＰ生成系统的抑制作用大于ＷＫｙ（Ｐ〈０．０５），相反地，ＰＣＰ剂量依赖地升高ＳＨＲ和ＷＫｙ的外周血管中的ｃＡＭＰ的含量，对ＳＨＲ的ｃＡＭＰ生成系统的激活作用小于ＷＫｙ（     

Adaptive changes on sigma- and phencyclidine receptors during long-term halopsridol and raclopride treatment in rats

Laboratory of Psychopharmacology, Tartu University. (Presented by Academician of the Academy of Medical Sciences of the USSR D. A. Eharkevich.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 108, No. 9, pp. 306–309, September, 1989     

NMDA antagonist effects on striatal dopamine release: microdialysis studies in awake monkeys.

Brain imaging studies have suggested that the NMDA antagonist ketamine is as potent a releaser of striatal dopamine as amphetamine. This conclusion contradicts microdialysis findings in the rodent that NMDA antagonists, in contrast to amphetamine, have little or no effect on striatal dopamine release. The present study addressed two mechanisms that could account for this discrepancy: 1) whether there is a species difference, i.e., rodents vs. primates, in the responsivity of striatal dopamine to NMDA antagonists, and 2) whether rapid uptake of dopamine prevents reliable measures of synaptic dopamine release by microdialysis in response to NMDA antagonists. MRI-directed in vivo microdialysis was used to compare the effects of psychotomimetic NMDA antagonists phencyclidine (PCP), ketamine, and amphetamine on extracellular striatal dopamine levels in awake rhesus monkeys. The effect of PCP was also investigated in the presence of intrastriatally applied nomifensine, a dopamine uptake blocker. Amphetamine (0.1 or 0.4 mg/kg) produced robust and dose-dependent increases in dopamine release ranging 2-10-fold above baseline. PCP at 0.1 mg/kg had no effect and at 0.3 mg/kg produced a small 50% increase over baseline. Ketamine, at the relatively high dose of 5 mg/kg, produced only a 30% increase in dopamine release. Intrastriatal application of nomifensine did not influence the effect of PCP, suggesting that rapid uptake of dopamine is not preventing the detection of a PCP-induced increase in dopamine release. These findings suggest that in the primate, ketamine and PCP are not effective dopamine releasers, as has been suggested by previous imaging studies.     

Strain-Specificity in Nicotine Attenuation of Phencyclidine-Induced Disruption of Prepulse Inhibition in Mice: Relevance to Smoking in Schizophrenia Patients

Schizophrenia patients may exhibit high tobacco smoking rates in part to self-medicate sensory gating deficits with nicotine contained in tobacco. To test this hypothesis, we induced sensori-motor gating deficits in four mouse strains with phencyclidine, a noncompetitive antagonist of glutamatergic N -methyl-d-aspartate receptors. Nicotine attenuated the disruption in prepulse inhibition induced by phencyclidine in DBA/2J and C3H/HeJ but not in C57BL/6J or 129T2/SvEmsJ mice. These results highlight genetic variations in the regulation by nicotinic cholinergic systems of the dysfunction in glutamatergic transmission contributing to gating deficits in schizophrenia. Further, these findings support the hypothesis of self-medication of gating deficits in schizophrenia through tobacco smoking, and suggest that treatments targeting genetic dysfunctions in nicotinic-glutamatergic interactions that would treat cognitive deficits will assist schizophrenia patients in minimizing tobacco smoking.     

MK801 induces late regional increases in NMDA and kainate receptor binding in rat brain

Summary We have previously shown that a single dose of PCP produces a dose-related increase in NMDA-sensitive³H-glutamate binding in CA₁ of hippocampus 24 hours later, and some regional changes in kainate binding. Here we report that dizocilpine (MK 801) (O.1 mg/kg and 1 mg/kg), a selective agonist at the PCP receptor and a noncompetitive antagonist of NMDA, produces a similar increase in NMDA-sensitive glutamate and kainate receptor binding in hippocampus 24 hours after a dose. These observations support the conclusion that blockade of glutamate-mediated transmission at the NMDA receptor selectively increases NMDA-sensitive glutamate receptor binding in CA₁ of hippocampus and kainate binding in CA₃ and dentate gyrus at putatively delayed time points. Several additional areas outside of hippocampus also showed receptor changes at 24 hours after MK801.     

Haloperidol prevents induction of the hsp70 heat shock gene in neurons injured by phencyclidine (PCP), MK801, and ketamine.

The non-competitive NMDA receptor antagonists, PCP (phencyclidine), MK801, and ketamine produce psychosis in humans and abnormal vacuoles in posterior cingulate and retrosplenial rat cortical neurons. We show that PCP (> or = 5 mg/kg), MK801 (> or = 0.1 mg/kg), and ketamine (> 20 mg/kg) induce hsp70 mRNA and HSP70 heat shock protein in these vacuolated, injured neurons, and PCP also induces hsp70 in injured neocortical, piriform, and amygdala neurons. The PCP, MK801, and ketamine drug induced injury occurs in 30 day and older rats, but not in 0-20 day old rats, and is prevented by prior administration of the antipsychotic drugs haloperidol and rimcazole. Since haloperidol and rimcazole block dopamine and sigma receptors, and since M1 muscarinic cholinergic receptor antagonists also prevent the injury produced by PCP, MK801, and ketamine, future studies will be needed to determine whether dopamine, sigma, M1, or other receptors mediate the injury.     

高血压大鼠尾动脉上κ,σ和苯环利定受体激动剂的效应(英文)

利用电场刺激引起的大鼠尾动脉收缩模型,研究了κ,(?)和苯环利定(Phe)受体在高血压大鼠(SHR)上的变化,结果,埃托啡和U-50 488H在SHR上的抑制作用显著高于非高血压大鼠(WKY)。( )-3-PPP的结果与上述相反,DTG的作用很小,Phe,TCP和MK-801的增强作用在两者间无显著差别。提示在SHR上κ受体的敏感性增高,(?)受体相反,而Phe受体的敏感性变化较少。     

Neuroleptic-induced catalepsy as a model of Parkinson's disease II. Effect of glutamate antagonists

Summary Subcutaneous administration of fluphenazine elicits catelepsy that can be attenuated by the glutamate antagonists MK801 and phencyclidine (PCP). 3-[-(+)-2-carboxy piperazine-4-yl]-propyl-1-phosphanate (CPP) was found to be ineffective in this model. Intrastriatal injections of sulpiride or fluphenazine were also found to induce catalepsy which could be attenuated by MK801 and PCP. These results illustrate that nondopaminergic compounds might possibly be of value in the treatment of Parkinson's disease. Furthermore it was demonstrated that this paradigm can be utilized to investigate neurotransmitter interactions within the striatum. This was clearly emphasized by the observation that bilateral administration of MK801 into the striatum increased basal locomotor activity.     

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。