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.     

Neonatal handling prevents the effects of phencyclidine in an animal model of negative symptoms of schizophrenia.

BACKGROUND: Environmental factors during the neonatal period have long-lasting effects on the brain. Neonatal handling, an early mild stress, enhances the ability to cope with stress in adult rats. In humans, inappropriate stress responses increase the risk of schizophrenia in genetically predisposed individuals. We studied the effect of neonatal handling on the phencyclidine (PCP)-induced immobility time of rats in the forced swimming test (FST, an animal model of negative symptoms of schizophrenia) and on plasma adrenocorticotropic hormone (ACTH) as a measure of hypothalamic-pituitary-adrenal axis (HPA) reactivity. METHODS: Pups were removed from their mothers 15 min/21 days after birth. Postnatal day 65: animals were submitted to restraint stress. Postnatal day 75: after PCP treatment (5 mg/kg/5 days) animals were submitted to the FST. RESULTS: Neonatal handling reduced HPA reactivity to passive stress (restraint) but not to active coping stress (forced swimming). Immobilization time was significantly lower in saline- and PCP-treated, handled animals than in non-handled ones. Handling prevented the ACTH increase induced by PCP that was observed in the non-handled rats after FST. CONCLUSIONS: First, neonatal handling protects animals from acquiring the schizophrenic-like behavior provoked by sub-chronic PCP treatment, which was associated with a reduced HPA activity. Second, the beneficial properties of handling in stress responses seem to depend on the type of stress.     

Interactions between phencyclidine and cholinergic excitation of hippocampal pyramidal neurons

The interaction between phencyclidine and acetylcholine-evoked responses of hippocampal pyramidal neurons was investigated in normal and catecholamine-depleted rats. Phencyclidine antagonized the acetylcholine-induced excitations in both preparations. However, in the majority of cases, this effect was observed only at doses of phencyclidine which also manifested nonspecific membrane stabilization. In contrast, phencyclidine-induced decreases in firing rate, which have been shown to be mediated by catecholamines, occurred at doses of phencyclidine which do not cause local anesthesia. Taken together, these data suggest that the catecholaminergically-mediated effects of phencyclidine may be more important in the hippocampus.     

Phencyclidine blockade of sodium and potassium channels in neuroblastoma cells

Voltage-clamp experiments with N1E 115 neuroblastoma cells showed that the phenyclidine (PCP) is an efficient blocker of both the K⁺ channel (EC₅₀ = 2.6 μM) and the Na⁺ channel (EC₅₀ = 9.2 μM). Results are also presented for two derivatives of PCP.     

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（     

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。     

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.