Effects of sigma ligands on the ability of rimcazole to inhibit PCP hsp70 induction

Phencyclidine (PCP) can result in schizophrenia-like behavior. It binds at the PCP site on the NMDA-receptor calcium channel and at the sigma receptor. PCP also induces the heat shock gene hsp70 in retrosplenial cortex neurons. An antipsychotic drug, rimcazole, inhibits PCP hsp70 induction. Rimcazole binds predominately to sigma-2 sites. It is hypothesized that sigma ligands without antipsychotic properties and with some sigma-2 affinity should partially reverse the effects of rimcazole. (+)-3-PPP, (+)-cyclazocine, and (+)-pentazocine bind predominately to sigma-1 sites. (+)-3-PPP is also a modest sigma-2 ligand. Female Sprague-Dawley rats (200–260 g) were injected intraperitoneally (IP) with (+)-3-PPP (50 mg/kg), rimcazole (60 mg/kg) and, after 5 min, with PCP (40 mg/kg). Brains were sectioned (100 μm) and presence of the hsp70 gene protein product, HSP70, was determined immunocytochemically. (+)-3-PPP significantly (p < 0.05) diminished the ability of rimcazole to inhibit PCP hsp70 induction in the retrosplenial cortex. (+)-Cyclazocine (15mg/kg, IP) and (+)-pentazocine (80mg/kg, IP) given in an analogous manner did not diminished the ability of rimcazole to inhibit PCP hsp70 induction.     

Iontophoretic effects of sigma ligands on rubral neurons in the rat

Iontophoretic application of the sigma ligands, 1,3-di-o-tolylguanidine (DTG), dextrallorphan, and (+)-pentazocine reliably inhibited the firing rate of rubral neurons. Dextrallorphan inhibited 87% of the neurons tested, DTG inhibited 76%, and (+)-pentazocine inhibited 50%. These inhibitions were current dependent and occurred without significant changes in spike amplitude or duration, suggesting that local anesthetic effects were not involved. In contrast to the other sigma ligands, iontophoretic application of (+)-3-PPP in the rat red nucleus resulted in very few inhibitions and tended to elicit weak excitations instead. Only 14% of rubral neurons were inhibited by (+)-3PPP, while 36% were excited. Although unusual, (+)-3-PPP has atypical effects when compared to other sigma ligands in numerous functional assays for sigma receptor activity. (+)-3-PPP, therefore, appears to have complex effects and may act through nonsigma mechanisms or through a different type of sigma binding site than the other compounds. The inhibition of firing rate produced by the more typical sigma ligands may contribute to the postural changes produced by microinjection of sigma ligands into the rat red nucleus.     

Motor effects of two sigma ligands mediated by nigrostriatal dopamine neurons

(+)-Pentazocine, a potent sigma ligand that lacks affinity for PCP receptors, produced dose-dependent contralateral circling behavior following microinjections in the substantia nigra of rats. This effect was attenuated by 6-hydroxydopamine (6-OHDA) lesions of ascending dopamine neurons and enhanced by systemic injections of amphetamine, 6-OHDA lesions also attenuated the circling produced by another selective sigma ligand, 1,3-di-o-tolylguanidine (DTG). These findings suggest that sigma receptors are involved in the neural control of movement and the regulation of the ascending dopamine system. Since all typical antipsychotic drugs tested bind to sigma receptors with Ki values less than 1 microM, these findings further suggest that sigma receptors may mediate some of the motor side effects of antipsychotic drug therapy.     

Rett综合征四例临床分析

目的对神经系统变性疾病——Ｒｅｔ综合征４例进行分析，以期引起对该病的广泛认识，并促进对其临床和基础的更深研究。方法基于对４例症状发展完全的典型Ｒｅｔ综合征患者的临床研究，阐述该病的特异性，并综合文献，简述其可能的发病机制和治疗方法。结果４例患者均为女性，发病年龄为６～１８个月，发病前精神运动发育正常。临床表现以孤独行为、刻板运动和失用性共济失调为特征，随病程进展相继出现性质特异的症状体征，如痴呆、呼吸节律异常、癫痫发作、尖叫发作、胆小和惊恐、感觉反应迟钝、磨牙、夜间发笑、发育迟缓、上下运动神经元及锥体外系损害、心脏异常和猝死。各症状出现早晚不同，但综合起来颇具诊断价值。结论该病是一种颇具特征的临床综合征，诊断只靠熟知该病独有的临床表现。临床上不必过分拘泥于曾为特定目的制定的临床阶段分期和诊断标准     

Dose-dependent effects of d-N-allylnormetazocine on regional cerebral metabolic rates for glucose

Cerebral metabolic patterns produced by different doses of the benzomorphan opioid drug,d-N-allylnormetazocine (d-NANM), were stud using the 2-deoxy-d-[1-¹⁴C]glucose method in rats. The lowest dose ofd-NANM (0.5 mg/kg) decreased regional cerebral metabolic rates for glucose (rCMRglc) in areas, such as cranial nerve nuclei, that contain high densities of sigma (σ) receptors. However, higher doses of the drug (2.7 and 5 mg/kg) increased rCMRglc in components of the extrapyramidal motor and limbic systems. Some of these latter areas (e.g. molecular layer of the dentate gyrus, accumbens nucleus, globus pallidus, ventral posterior nucleus of the thalamus) are not enriched in σ receptors. Reductions in rCMRglc produced by the lowerst dose ofd-NANM probably reflect direct interactions of the drug with σ receptors, whereas increases in rCMRglc observed with the highest doses more likely result from effects ofd-NANM on PCP receptors.     

Further characterization of the effects of BMY 14802 on dopamine neuronal activity

Further evaluation of the effects of BMY 14802 on dopamine (DA) neuronal activity in the rat substantia nigra pars compacta (A9) was conducted with single-unit recording and microiontophoresis in anesthetized rats. Microiontophoretic administration of BMY 14802 (sigma, serotonin (5-HT)-1A and α-1 adrenoceptor ligand) had no effect on DA neurons. Microiontophoretic administration of (+)-3-PPP (weak D2 agonist with high affinity for sigma receptors) and quinpirole (D2/D3 agonist) inhibited A9 DA neuronal activity. Coiontophoresis or i.v. pretreatment with BMY 14802 had no effect on the current-response curves for the effects of microiontophoretic (+)-3-PPP or quinpirole on A9 DA neurons. Coiontophoretic administration of (?)-sulpiride, a selective D2 antagonist, blocked the inhibitory effects of microiontophoretic (+)-3-PPP. The effects of BMY 14802 (0.25-8 mg/kg, i.v.) on DA neurons (increased firing rate, increased burst-firing, reduced regularity of firing pattern) were not altered by acute brain hemitransection, but were blocked by pretreatment with NAN-190, an antagonist of 5-HT-1A and α-1 receptors. The α-1 receptor antagonist, prazosin, did not block these effects of BMY 14802. In conclusion, the effects of BMY 14802 on DA neuronal firing rate and firing pattern are indirect, perhaps due in part to the occupation of 5-HT-1A receptors. © 1993 Wiley-Liss, Inc.     

Neuroprotective sigma ligands interfere with the glutamate-activated NOS pathway in hippocampal cell culture

We studied neuroprotective properties of 12 structurally different sigma site ligands in primary rat hippocampal cell cultures and analyzed whether they interfere with glutamate-induced activation of the nitric oxide synthase (NOS) pathway. Neurotoxicity was triggered with 1mM glutamate on day 8 of culture. Cells were treated with various concentrations of the compounds for 7 days before glutamate exposure (prolonged pretreatment), or during glutamate exposure (acute treatment). Protection was seen after prolonged pretreatment (long-term protection) with sabeluzole, opipramole, haloperidol, ifenprodil, fenpropimorph, carbetapentane, and tiospirone, with pIC₅₀S of 7.30, 7.15, 6.87, 6.68, 6.66, 6.39, and 6.34, respectively. There was no protection with PD 128298, 1,3-ortho-di-tolylguanidine, BMY-14802, (+)3-(3-hydroxyphenyl)-N-l(propy1) piperidine, or dextromethorphan. Upon acute treatment, only ifenprodil was protective. Interference of the drugs with glutamate activation of the NOS pathway was determined by measuring glutamate-activated cGMP formation and citrulline levels. Glutamate-activated cGMP formation was reduced by all neuroprotective sigma ligands after prolonged pretreatment but not after acute treatment. Sigma ligands added to cell culture iysate did not reduce citrulline formation, evidence that there was no direct effect on the NOS enzyme. We conclude that some but not all sigma ligands exert long-term protective properties against glutamate-induced neurotoxicity in primary hippocampal cultures, and that this protection is accompanied by attenuation of cGMP formation in the NOS pathway. However, inhibition of cGMP formation by itself appeared not sufficient for obtaining neuroprotective effects, as inhibition of glutamate-activated cGMP formation by N-nitro-L-arginine, haemoglobin, or PD128298 did not provide neuroprotection. © 1995 Wiley-Liss, Inc.     

Cerebral metabolic effects of sigma ligands in the rat

The 2-deoxy-D-[1-14C]glucose method was used to study the effects of sigma-type drugs, BMY 14802, (+)-pentazocine and BW 234U (rimcazole), on cerebral metabolism in 44 male Fischer 344 rats. Drug effects were observed in epithalamic, methathalamic, hypothalamic and mesencephalic regions, as well as in cranial nerve nuclei, the cerebellum, and the medulla oblongata. BMY 14802 and (+)-pentazocine increased local cerebral glucose utilization (LCGU) in areas that generally did not overlap; BW 234U administered 30 min before the radiotracer decreased LCGU. Most of the areas that showed changes in LCGU are known to contain sigma receptor sites. Differences in pharmacological properties, including effects on neuronal electrical excitability, may have resulted in the different distributions and effects of the drugs on LCGU. The present findings did not discriminate the compounds as agonists or antagonists for sigma receptor sites. However, the 2-deoxy-D-[1-14C]glucose method appeared useful in delineating the distribution of CNS responses to sigma drugs in the rat.     

Effects of sigma ligands on mouse cerebellar cyclic guanosine monophosphate (cGMP) levels in vivo: further evidence for a functional modulation ofN-methyl-d-aspartate (NMDA) receptor complex-mediated events by sigma ligands

In the present investigation, the effects of sigma ligands[WY-47384 {;8-fluoro-2,3,4,5-tetrahydro-2[3-(3-pyridinyl)propyl)1H-pyrido(4, 3b)indole}, (+)-pentazocine, (+)-SFK 10,047 (N-allylnormetazocine), mafoprazine, opipramol, dextromethorphan, dextrorphan, (+)-3-PPP [3-(3-hydroxyphenyl)-N-propylpiperidine], (−)-butaclamol, DTG [1,3-di(2-tolyl)guanidine], rimcazole, ifenprodil and BMY-14802 {α-(fluorophenyl)-4-(5-fluoropyrimidinyl)-1-piperazine butanol}] on harmaline-, pentylenetetrazol (PTZ)-, methamphetamine (MA)- andd-serine-induced increases in mouse cerebellar levels of cGMP were determined. Ifenprodil, BMY-14802, dextromethorphan, dextrorphan, (+)-SKF 10,047, opipramol and mafoprazine reversed harmaline-, PTZ-, MA- andd-serine-induced increases in levels of cGMP. Rimcazole reversed only the harmaline-induced response. WY-47384 reversed harmaline-, MA-,d-serine-, but not PTZ- or quisqualate-induced increases in levels of cGMP. (+)-Pentazocine attenuated harmaline- andd-serine-, but not PTZ- and MA-induced cGMP responses. Haloperidol did not affect harmaline- andd-serine-induced cGMP responses. (+)-3-PPP and (−)-butaclamol did not affect any of the responses studied. Furthermore, (+)-3-PPP-induced increases in levels of cGMP were reversed by the competitiveN-methyl-d-aspartate (NMDA) antagonist, CPP} 3-(2-car☐ypiperazin-4-yl)propyl-1-phosphonic acid, the non-competitive NMDA antagonist, (+)-MK-801 (dizocilipine maleate), the NMDA-associated glycine receptor antagonist, HA-966 (3-amino-1-hydroxypyrrolidin-2-one), the partial glycine agonist, DCS (d-cycloserine) as well as by the sigma ligands, ifenprodil, WY-47384, (+)-pentazocine, (+)-SKF 10,047, dextromethorphan and dextrorphan but not by rimcazole. These data further support functional modulation by sigma ligands of events mediated by the NMDA receptor complex established in earlier investigations.     

Ontogeny of PCP and sigma receptors in rat brain

Phencyclidine (PCP) binds with high affinity to two receptors in rat brain--the PCP receptor and the Sigma receptor. Although both receptors are present prenatally, and their number increases postnatally, their rate of increase, compared to the increase in brain protein, is quite different, yielding distinct ontogenic profiles. Thus, PCP receptors are present on prenatal day 2 and show a further 15-fold increase by postnatal day 28. In contrast, Sigma receptors are present at their highest density during the perinatal period, and decline thereafter. The Kd of the PCP receptor for TCP remains constant throughout development, whereas the Kd of the Sigma receptor for (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine decreases 40% postnatally. On postnatal day 6, both PCP and Sigma receptors display a pharmacological profile similar to that observed in adult animals.     

The novel N-methyl-D-aspartate (NMDA) antagonist CGS 19755 prevents ischemia-induced reductions of adenosine A1, NMDA, and PCP receptors in gerbil brain

Transient brain ischemia results in a selective destruction of cell bodies within the hippocampus and cortex. This cellular destruction appears to be mediated through a release of endogenous exictatory amino acids following the ischemic episode, since the neurotoxic effects of ischemia can be attenuated by compounds that have antagonist activity at N-methyl-D-aspartate (NMDA) receptors. In the present study, the protective effects of a novel NMDA receptor antagonist, CGS 19755, were further evaluated by using quantitative autoradiography to characterize adenosine A1, NMDA, PCP, and benzodiazepine receptors in ischemic gerbil brain. Bilateral carotid artery occlusion (20 minutes) resulted in marked decreases (30-60%) in adenosine A1, NMDA, and PCP, but not benzodiazepine, receptors in gerbil forebrain. Postischemic treatment with CGS 19755 was found to completely block the ischemia-induced decreases in brain adenosine and NMDA receptors. [3H]TCP binding in ischemic gerbil brain was also elevated by CGS 19755 treatment; significant differences remained, however, between the CGS 19755-treated and control gerbils. These results indicate that transient brain ischemia produces significant and selective alterations in gerbil forebrain receptor systems. The observed decreases in radioligand binding are probably reflective of an ischemia-induced destruction of forebrain structures. However, there is some evidence that transient ischemia can also cause long-term changes in the affinity of some receptor systems. The postischemic efficacy of CGS 19755 appears to be due to its ability to block the neurotoxic effects of transient ischemia.     

Behavioral and biochemical stereoselectivity of sigma opiate/PCP receptors

The relative potencies of the stereoisomers of ketamine, N-allylnormetazocine and cyclazocine were determined at μ opiate and σ opiate/phenycyclidine (PCP) receptors in vitro in rat brain homogenates, as well as in a discriminative stimulus behavioral paradigm in rats trained to discriminate PCP from saline. In all cases the in vivo and in vitro data were in agreement. The (+)-isomers of N-allylnormetazocine and cyclazocine are highly specific sigma opiate/PCP ligands.     

Antipsychotic effects and tolerability of the sigma ligand EMD 57445 (panamesine) and its metabolites in acute schizophrenia: an open clinical trial

Antipsychotic efficacy and side effects of the selective sigma ligand EMD 57445 (panamesine) were investigated in 12 patients (6 males, 6 females) who met DSM-III-R criteria for schizophrenia. A 4-week open clinical study revealed only modest effects of EMD 57445 and its metabolites on positive and negative symptoms of schizophrenia. Extrapyramidal and other side effects were moderate, although a significant increase in mild dyskinetic movements was found. Five patients, four of whom were females, completed the trial. Dropouts were mainly due to treatment failure. Antipsychotic effects were significantly greater in female than male patients.     

Rat cortical sigma receptors differentially regulated by pentazocine and haloperidol

Summary Repeated administrations of 7.5 mg/kg of pentazocine (for 14 days) resulted in a significant decrease in the affinity of³H-haloperidol binding to rat cortical sigma receptors without any changes in the maximal number of binding sites (Bmax). On the other hand, similar treatment with haloperidol (2 or 4 mg/kg) induced a dose dependent decrease in the Bmax values without affecting the affinity of the³H-haloperidol binding. These findings indicate that rat cortical sigma receptors are differentially regulated by pentazocine and haloperidol.     

Neurotransmitter basis of the behavioral effects of hallucinogens

Indole and phenethylamine-type hallucinogenic drugs were studied in an FR-40 operant behavioral procedure programmed to quantify “pausing,”·a behavioral disruption somewhat specific to hallucinatory drug effects. LSD, DOM, DMT and mescaline showed a potency ratio to produce pausing that is well correlated with the hallucinatory potencies of these agents in man. Furthermore, combinations of the hallucinogens interact with potentiation to cause FR-40 pausing, whereas a variety of non-hallucinogenic psychoactive drugs failed to shift the dose-response patterns of pausing for DOM or LSD. Depletion of brain catecholamines by pretreatment with intraventricular 6-OHDA reduced baseline FR-40 rates and attenuated the disruptive effects of d-amphetamine, but failed to modify the dose-response patterns of indole and phenethylamine hallucinogens. On the other hand, pretreatment with intraventricular 5,7-DHT to deplete brain 5-HT potentiated the pause-producing effects of the hallucinogens, although the disruptive effects of phenobarbital were not altered by this pretreatment. Injection of 5,7-DHT into the medial forebrain bundle at the hypothalamic level slightly potentiated LSD, attenuated DOM, and did not affect the pausing produced by mescaline. Metergoline pretreatment shifted the LSD and DMT dose-response curves for pausing to the right by a factor of 2–3, but shifted the DOM and mescaline dose-response patterns to a much greater extent. Metergoline alone slightly increased FR-40 response rates and decreased pausing from baseline levels. The patterns of impaired FR-40 performance induced by d-amphetamine and phenobarbital were unaltered by pretreatment with metergoline. The indole and phenethylamine classes of hallucinogens appear to disrupt this behavior by an agonistic effect at central 5-HT receptors. However, the two classes of drugs may interact with brain 5-HT systems by somewhat different mechanisms.     

Neurotransmitter basis of the behavioral effects of hallucinogens

Indole and phenethylamine-type hallucinogenic drugs were studied in an FR-40 operant behavioral procedure programmed to quantify “pausing,”·a behavioral disruption somewhat specific to hallucinatory drug effects. LSD, DOM, DMT and mescaline showed a potency ratio to produce pausing that is well correlated with the hallucinatory potencies of these agents in man. Furthermore, combinations of the hallucinogens interact with potentiation to cause FR-40 pausing, whereas a variety of non-hallucinogenic psychoactive drugs failed to shift the dose-response patterns of pausing for DOM or LSD. Depletion of brain catecholamines by pretreatment with intraventricular 6-OHDA reduced baseline FR-40 rates and attenuated the disruptive effects of d-amphetamine, but failed to modify the dose-response patterns of indole and phenethylamine hallucinogens. On the other hand, pretreatment with intraventricular 5,7-DHT to deplete brain 5-HT potentiated the pause-producing effects of the hallucinogens, although the disruptive effects of phenobarbital were not altered by this pretreatment. Injection of 5,7-DHT into the medial forebrain bundle at the hypothalamic level slightly potentiated LSD, attenuated DOM, and did not affect the pausing produced by mescaline. Metergoline pretreatment shifted the LSD and DMT dose-response curves for pausing to the right by a factor of 2–3, but shifted the DOM and mescaline dose-response patterns to a much greater extent. Metergoline alone slightly increased FR-40 response rates and decreased pausing from baseline levels. The patterns of impaired FR-40 performance induced by d-amphetamine and phenobarbital were unaltered by pretreatment with metergoline. The indole and phenethylamine classes of hallucinogens appear to disrupt this behavior by an agonistic effect at central 5-HT receptors. However, the two classes of drugs may interact with brain 5-HT systems by somewhat different mechanisms.     

SCH 23390-induced behavioral supersensitivity is not related to striatal c-fos levels

Stereotyped behavior and striatal c-fos levels induced by chronic treatment with the D₁ dopamine antagonist SCH 23390 have been investigated in rats which received subsequent subacute dopamine agonist treatment. SCH 23390 treatment (0.5 mg/kg/day) for 21 days increased both apomorphine-induced orofacial stereotypies and striatal c-fos levels. Treatment with the D₁ dopamine agonist SKF 38393 (10 mg/kg/day) and the combination of SKF 38393 with the D₂ dopamine agonist quinpirole (1 mg/kg/day), for 5 consecutive days, attenuated apomorphine-induced stereotypies without changing c-fos levels in rats previously treated with SCH 23390. These findings suggest that SCH 23390-induced behavioral supersensitivity and the increased striatal c-fos levels are concomitant but unrelated phenomena.     

Effect of MS-153 on the development of behavioral sensitization to stereotypy-inducing effect of phencyclidine

The present study examined the effects of a novel compound, MS-153 [(R)-(-)-5-methyl-1-nicotinyl-2-pyrazoline], which has an ability to enhance glutamate uptake and inhibit glutamate release, on the development of behavioral sensitization to phencyclidine (PCP). MS-153 (10 and 100 mg/kg) enhanced stereotypy induced by a single injection of PCP (7.5 mg/kg). Repeated administration of PCP (20 mg/kg, once every day for 5 days) enhanced stereotypy-inducing effects of PCP (7.5 mg/kg) when tested 4 days after the withdrawal from the repeated PCP treatment, indicating the development of behavioral sensitization. MS-153 given 60 and 120 min after the PCP treatments blocked the development of behavioral sensitization to stereotypy-inducing effects of PCP. These results suggest that the attenuation of glutamatergic neural transmission enhances acute effect of PCP, but in contrast, blocks the behavioral sensitization to PCP.     

The Prevalence and Phenomenology of Repetitive Behavior in Genetic Syndromes

We investigated the prevalence and phenomenology of repetitive behavior in genetic syndromes to detail profiles of behavior. The Repetitive Behaviour Questionnaire (RBQ) provides fine-grained identification of repetitive behaviors. The RBQ was employed to examine repetitive behavior in Angelman (N = 104), Cornelia de Lange (N = 101), Cri-du-Chat (N = 58), Fragile X (N = 191), Prader-Willi (N = 189), Lowe (N = 56) and Smith-Magenis (N = 42) syndromes and individuals with intellectual disability of heterogeneous aetiology (N = 56). Repetitive behavior was variable across syndromes. Fragile X syndrome scored highly on all subscales. Angelman syndrome demonstrated a significantly lowered probability for most behaviors. Prader-Willi, Cri-du-Chat and Smith-Magenis syndrome evidenced unique profiles of repetitive behavior. There is extreme heterogeneity of repetitive behavior across genetic syndromes, highlighting syndrome specific profiles.

Lack of effects by sigma ligands on neuropeptide Y-induced G-protein activation in rat hippocampus and cerebellum

It has been suggested that neuropeptide Y (NPY) and sigma (sigma) receptor ligands may share a putative NPY/sigma receptor in rat brain. To study whether NPY and sigma receptor ligands have an inverse agonism at this putative NPY/sigma receptor, we measured their effects on G-protein activity in rat brain. Using [35S]GTPgammaS autoradiography, we found that NPY-induced G-protein activation exhibited a discrete distribution pattern in rat brain. G-protein activation in superficial cortical layers and hippocampal CA1-3 region was mainly attributed to Y1 and Y2 receptors, respectively. In the presence of 10 microM sigma-receptor agonist BD737 or 10 microM sigma-receptor antagonist haloperidol, the distribution and density of [35S]GTPgammaS binding stimulated by 10 nM NPY was not significantly altered. In rat cerebellar membranes, NPY stimulated high-affinity GTPase activity in a dose-related manner, with maximal effects of 29% increase over basal level seen at 500 nM. This NPY-elicited GTPase activity was not significantly affected by micromolar concentrations of the sigma-receptor antagonists Dup734 or haloperidol. Since no significant effects by sigma-receptor ligands on NPY-induced G-protein activation were observed, we did not see an inverse agonism of NPY and sigma-receptor ligands at the putative NPY/sigma receptor measured at the level of G-protein activation, suggesting that sigma receptors and NPY receptors do not represent a common population in rat hippocampus and cerebellum. It is also suggested that G-protein activation is not a convergent point for the signal transduction mechanisms of NPY receptors and sigma receptors.