Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antipsychotic drug perospirone: Role of serotonin 5-HT1A receptors

Accumulating evidence suggests that the serotonin 5-HT_1A receptor may play a role in the pathophysiology of schizophrenia. The present study was undertaken to examine the effects of perospirone, an atypical antipsychotic drug with 5-HT_1A receptor agonism, on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). Subsequent subchronic (14 days) administration of perospirone (1.0, 3.0, or 10 mg/kg) significantly attenuated PCP (10 mg/kg)-induced cognitive deficits in mice, in a dose-dependent manner. The effects of perospirone (10 mg/kg) were significantly antagonized by co-administration of the selective 5-HT_1A receptor antagonist WAY100635 (1.0 mg/kg). Furthermore, hypothermia by the 5-HT_1A receptor agonist 8-OH DPAT (0.25 mg/kg) was significantly attenuated in mice treated with PCP. Moreover, a receptor binding assay using [³H]WAY100635 revealed that levels of 5-HT_1A receptors in the hippocampus, but not in the frontal cortex, of PCP-treated mice were significantly lower than those of saline-treated mice. These findings suggest that repeated PCP administration alters 5-HT_1A receptor function in the mouse brain, and that subsequent subchronic administration of perospirone ameliorates PCP-induced cognitive deficits via 5-HT_1A receptors. Therefore, perospirone could be a potential therapy for the cognitive deficits observed in schizophrenic patients.     

Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of clozapine, but not haloperidol

This study was undertaken to examine the effects of subsequent administration of antipsychotic drugs (clozapine and haloperidol) on cognitive deficits in mice after repeated administration of phencyclidine (PCP). In the novel object recognition test, repeated administration of PCP (10 mg/kg) significantly decreased exploratory preference in the retention test session but not in the training test session. PCP-induced deficits were significantly improved by subsequent subchronic (2 weeks) administration of clozapine (5 mg/kg), but not haloperidol (0.1 mg/kg). These findings suggest that PCP-induced cognitive deficits using the novel object recognition test may be a potential animal model of atypical antipsychotic activity.     

Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of fluvoxamine: role of sigma-1 receptors.

This study was undertaken to examine the effects of the selective serotonin reuptake inhibitors fluvoxamine and paroxetine on cognitive deficits in mice after repeated administration of the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). In the novel object recognition test, repeated administration of PCP (10 mg/kg/day, 10 days) significantly decreased the exploratory preference in the retention test session, but not in the training test session. PCP-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of fluvoxamine (20 mg/kg/day), but not paroxetine (10 mg/kg/day). Furthermore, the effect of fluvoxamine on PCP-induced cognitive deficits was antagonized by co-administration of the selective sigma-1 receptor antagonist NE-100 (1 mg/kg/day). Moreover, PCP-induced cognitive deficits were also significantly improved by subsequent subchronic (2-week) administration of the selective sigma-1 receptor agonist SA4503 (1 mg/kg/day) or neurosteroid dehydroepiandrosterone 3-sulfate (DHEA-S; 25 mg/kg/day). The effects of SA4503 or DHEA-S were also antagonized by co-administration of NE-100 (1 mg/kg/day), suggesting the role of sigma-1 receptors in the active mechanisms of these drugs. In contrast, acute single administration of these drugs (fluvoxamine, paroxetine, SA4503) alone or combination with NE-100 did not alter PCP-induced cognitive deficits. The present study suggests that agonistic activity of fluvoxamine at sigma-1 receptors plays a role in the active mechanisms of fluvoxamine on PCP-induced cognitive deficits in mice. Therefore, sigma-1 receptor agonists such as fluvoxamine would be potential therapeutic drugs for the treatment of the cognitive deficits of schizophrenia.     

Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of tropisetron: role of alpha7 nicotinic receptors

We examined the effects of tropisetron, a 5-hydroxytryptamine (5-HT(3)) receptor antagonist and alpha7 nicotinic receptor agonist, on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were significantly improved by subsequent subchronic (2 weeks) administration of tropisetron, but not ondansetron. Effects of tropisetron were significantly antagonized by co-administration of the alpha7 nicotinic receptor antagonist methyllycaconitine, suggesting the role of alpha7 nicotinic receptors in the active mechanisms of tropisetron. These findings suggest that tropisetron could be a potential therapeutic drug for cognitive deficits in schizophrenic patients.     

A 13-week subchronic oral toxicity study of l-serine in rats

A subchronic oral toxicity study was conducted to evaluate the safety of l-serine in Sprague–Dawley rats. The test article was administered once daily by gavage in male and female rats at dose levels of 0, 500, 1500, and 3000 mg/kg body weight/day for 13 weeks. Daily clinical signs, body weight, and food consumption were not affected by ingestion of the test article. There were no treatment-related adverse effects on urinalysis, hematology, serum biochemistry, organ weights, gross and histopathological examination. It was concluded that the no-observed-effect level (NOEL) for l-serine was 3000 mg/kg bw/day for both genders.     

MK-801 produces a deficit in sucrose preference that is reversed by clozapine, d-serine, and the metabotropic glutamate 5 receptor positive allosteric modulator CDPPB: Relevance to negative symptoms associated with schizophrenia?

Currently prescribed antipsychotics attenuate the positive symptoms of schizophrenia but fail or only mildly improve negative symptoms. The present study aimed to establish an animal model of negative symptoms by examining the effects of the NMDA receptor antagonist MK-801 on sucrose preference. We sought to validate the model by examining the effects of clozapine and d-serine, for which there are positive clinical data regarding their effects on negative symptoms, and haloperidol which is clinically ineffective. We extended our analysis by examining CDPPB, an mGlu5 receptor positive allosteric modulator. Acute MK-801 produced effects indicative of a shift in the hedonic experience of sucrose not confounded by disruptions in motor abilities or taste as revealed by: 1) a decrease in sucrose intake at low concentrations (0.8% or 1.2%), but no effect on water, 2) an increase in consumption for higher (7%) sucrose concentrations, reflecting a shift to the right in the concentration-consumption curve, and 3) no effect on quinine intake. Sub-chronic clozapine and acute d-serine attenuated the MK-801-induced deficit in 1.2% sucrose consumption, whereas sub-chronic haloperidol (0.02 mg/kg) did not. Finally, acute treatment with CDPPB also attenuated this deficit. These data suggest that this model may be useful for identifying novel agents that improve negative symptoms, and that compounds which enhance NMDA receptor function, such as mGlu5 receptor PAMs, may have clinical utility in this regard.     

Opiate physical dependence and N-methyl-d-aspartate receptors

The present review focused the involvement of N-methyl-d-aspartate (NMDA) receptors in morphine physical dependence. The increased levels of extracellular glutamate, NMDA receptor ζ subunit (NR1) mRNA, NMDA receptor 1 subunit (NR2A) protein, phosphorylated Ca²⁺/calmodulin kinase II (p-CaMKII) protein, c-fos mRNA, c-Fos protein, are observed in the specific brain areas of mice and/or rats showing signs of naloxone-precipitated withdrawal. In preclinical and clinical studies, a variety of NMDA receptor antagonists and pretreatment with an antisense oligonucleotide of the NR1 have been reported to inhibit the development, expression and/or maintenance of opiate physical dependence. In contrast to data obtained in adult animals, NMDA receptor antagonists are neither effective in blocking the development of opiate dependence nor the expression of opiate withdrawal in neonatal rats. In the NMDA receptor-deficient mice, the NR2A knockout mice show the marked loss of typical withdrawal abstinence behaviors precipitated by naloxone. The rescue of NR2A protein by electroporation into the nucleus accumbens of NR2A knockout mice reverses the loss of abstinence behaviors. The activation of CaMKII and increased expression of c-Fos protein in the brain of animals with naloxone-precipitated withdrawal syndrome are prevented by NMDA receptor antagonists, whereas the increased levels of extracellular glutamate are not prevented by them. These findings indicate that glutamatergic neurotransmission at the NMDA receptor site contributes to the development, expression and maintenance of opiate dependence, and suggest that NMDA receptor antagonists may be a useful adjunct in the treatment of opiate dependence.     

Modulation of sensorimotor gating in prepulse inhibition by conditional brain glycine transporter 1 deletion in mice

Inhibition of glycine transporter 1 (GlyT1) augments N-methyl-D-aspartate receptor (NMDAR)-mediated transmission and represents a potential antipsychotic drug target according to the NMDAR hypofunction hypothesis of schizophrenia. Preclinical evaluation of GlyT1 inhibiting drugs using the prepulse inhibition (PPI) test, however, has yielded mixed outcomes. Here, we tested for the first time the impact of two conditional knockouts of GlyT1 on PPI expression. Complete deletion of GlyT1 in the cerebral cortices confers resistance to PPI disruption induced by the NMDAR blocker MK-801 (0.2 mg/kg, i.p.) without affecting PPI expression in unchallenged conditions. In contrast, restricting GlyT1 deletion to neurons in forebrain including the striatum significantly attenuated PPI, and the animals remained sensitive to the PPI-disruptive effect of MK-801 at the same dose. These results demonstrate in mice that depending on the regional and/or cell-type specificity, deletion of the GlyT1 gene could yield divergent effects on PPI.     

d-galactose administration induces memory loss and energy metabolism disturbance in mice: Protective effects of catalpol

The neuroprotective effects of catalpol, an iridoid glycoside isolated from the fresh rehmannia roots, on the behavior and brain energy metabolism in senescent mice induced by d-galactose were assessed. Except control group, mice were subcutaneously injected with d-galactose (150 mg/kg body weight) for 6 weeks. From the fifth week, drug group mice were treated with catalpol (2.5, 5, 10 mg/kg body weight) and piracetam (300 mg/kg body weight) for the last 2 weeks. Behavioral changes including open field test and passive avoidance were examined after drug administration. To determine the brain damage, pathological alterations were measured by hematoxylin and eosin (HE) staining. The activities of lactate dehydrogenase (LDH), glutathione S-transferase (GSH-ST), glutamine synthetase (GS), creatine kinase (CK) in brain cortex and hippocampus were determined using different biochemical methods. Consistent with the cognition deficits, the activities of GSH-ST, GS and CK decreased while the activity of LDH increased in aging mice brain. Administration of catalpol for 2-weeks not only ameliorated cognition deficit, but also reversed the biochemical markers mentioned above and reduced the histological lesions in mouse brain. These results suggest that catalpol has protective effects on memory damage and energy metabolism failure in aging model mice and is worth testing for further preclinical study aimed for senescence or neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD).     

Icariin isolated from Epimedium brevicornum Maxim attenuates learning and memory deficits induced by d-galactose in rats

The effects of icariin (ICA), a major constituent of flavonoids from the Chinese medical herb Epimedium brevicornum Maxim, on spatial memory performances and expressions of hippocampus brain-derived neurotrophic factor (BDNF) and tyrosine kinase TrkB (tropomyosin receptor kinase B) were investigated in d-galactose (d-gal)-treated rats. Subcutaneous injection of d-gal (500 mg/kg/d) for four months caused memory loss as detected by the Morris water maze, morphologic abnormalities of neurons in hippocampus region and the reduced expression of BDNF and TrkB were observed. ICA (60 mg/kg/d) given orally 1 h after subcutaneous injection of d-gal daily for 4 months markedly attenuated d-gal-induced rats behavioral dysfunction and neurodegeneration, as evidenced by shortened escape latency and searching distance and rescued morphologic abnormalities, and also elevated the mRNA levels and the protein expressions of BDNF and TrkB in hippocampus, as evidenced by quantitative real-time RT-PCR and Western blotting analysis. But ICA had no significant influence on normal rats which were not injected d-gal. These results clearly demonstrated that d-gal produced learning and memory deficits after chronic administration, and ICA can protect neuron from d-gal insults and improve the memory loss.     

Naringin alleviates cognitive impairment,mitochondrial dysfunction and oxidative stress induced by d-galactose in mice

Role of mitochondrial dysfunction and oxidative stress has been well documented in aging and related disorders such as Alzheimer’s disease. Bioflavonoids have been reported to have a therapeutic potential against several age related processes. Bioflavonoids are being used as a neuroprotectants in the treatment of various neurological disorders including aging. Therefore, present study has been conducted in order to explore the possible role of naringin against d-galactose induced cognitive dysfunction, oxidative damage and mitochondrial dysfunction in mice. Chronic administration of d-galactose (100 mg/kg) for 6 weeks significantly impaired cognitive performance (both in Morris water maze and elevated plus maze), locomotor activity, oxidative defense and mitochondrial complex (I, II and III) enzymes activities as compared to sham group. Six weeks naringin (40 and 80 mg/kg) treatment significantly improved cognitive performance, oxidative defense and restored mitochondria complex enzyme activities as compared to control (d-galactose). Naringin treatment significantly attenuated acetylcholine esterase activity in d-galactose treated mice. In conclusion, present study highlights the potential role of naringin against d-galactose induced cognitive impairment, biochemical and mitochondrial dysfunction in mice.     

Characterization of SSR103800, a selective inhibitor of the glycine transporter-1 in models predictive of therapeutic activity in schizophrenia

On native human, rat and mouse glycine transporter-1(GlyT1), SSR130800 behaves as a selective inhibitor with IC50 values of 1.9, 5.3 and 6.8 nM, respectively. It reversibly blocked glycine uptake in mouse brain cortical homogenates, increased extracellular levels of glycine in the rat prefrontal cortex, and potentiated NMDA-mediated excitatory postsynaptic currents in rat hippocampal slices. SSR103800 (30 mg/kg, p.o.) decreased MK-801- and PCP-induced locomotor hyperactivity in rodents. SSR103800 (1 and 10 mg/kg, p.o.) attenuated social recognition deficit in adult rats induced by neonatal injections of PCP (10 mg/kg, s.c., on post-natal day 7, 9 and 11). SSR103800 (3 mg/kg, p.o.) counteracted the deficit in short-term visual episodic-like memory induced by a low challenge dose of PCP (1 mg/kg, i.p.), in PCP-sensitized rats (10 mg/kg, i.p.). SSR103800 (30 mg/kg, i.p.) increased the prepulse inhibition of the startle reflex in DBA/1J mice. SSR103800 decreased defensive- and despair-related behaviors in the tonic immobility test in gerbils (10 and 30 mg/kg, p.o.) and in the forced-swimming procedure in rats (1 and 3 mg/kg, p.o.), respectively. These findings suggest that SSR103800 may have a therapeutic potential in the management of the core symptoms of schizophrenia and comorbid depression states.     

Determination of the l-isomer in d-penicillamine by derivatization liquid chromatography

A method for a fast quantitative determination of the l-isomer in d-penicillamine is described. l-Leucine is coupled to d,l-penicillamine and the resulting diastereomers separated by reversed phase liquid chromatography. The mild conditions for the derivatization cause no racemization. For detection the UV-absorption of the derivatives at a wavelength of 215 nm is used. A linear signal was gained in a concentration range of 0.05–10% l-isomer in d-penicillamine. One complete determination can be carried out in 1.5–2 h. A comparison of products from different manufacturers resulted in the detection of l-penicillamine in the material of only one producer.     

d-Penicillamine toxicity in mice I. Pathological findings

DDD mice were fed 4, 2, or 0.5 g of d-penicillamine/kg of commercial diet from 3 weeks of age for periods ranging from 10 to 48 weeks. In male mice fed 4 g/kg diet, subcutaneous hemorrhage, dorsal hernia, priapism, and paralysis of the digits were observed. In a few mice, there was a ruptured aortic aneurysm. In most advanced cases, ataxia due to hindleg paralysis was observed. In male mice fed 2 g/kg diet, priapism and paralysis of the digits were noted at a lower incidence. No abnormalities were observed also in the mice fed 0.5 g/kg diet. Subcutaneous hemorrhage, dorsal hernia, and priapism were observed exclusively in males and orchidectomy significantly reduced the incidence. The incidence of digit paralysis, however, showed no sex difference and was not prevented by orchidectomy and administration of estrogen. Histologically, nerves, such as the optic and sciatic, showed moderate to marked demyelination and axonal degeneration, and spinal ganglion cells showed degenerative changes in mice fed the 4 g/kg diet. Back muscle covering the herniated area became thin or almost disappeared, and was replaced by a thin layer of collagenous tissue. When the onset of penicillamine feeding was delayed until 3 months of age, all the toxicities were remarkably reduced. Copper supplementation significantly prevented the toxicity while pyridoxine hydrochloride did not.     

Palmatine attenuates d-galactosamine/lipopolysaccharide-induced fulminant hepatic failure in mice

Palmatine is an isoquinoline alkaloid from Coptis chinensis, an herbal medicine used to treat various inflammatory diseases such as gastritis, edema and dermatitis. The present study examined the cytoprotective properties of palmatine on d(+)-galactosamine (GalN)/lipopolysaccharide (LPS)-induced fulminant hepatic failure. Mice were intraperitoneally given GalN (700 mg/kg)/LPS (10 μg/kg). Palmatine (25, 50, 100, and 200 mg/kg) was administered 1 h before GalN/LPS. GalN/LPS increased the mortality and serum aminotransferase activities. These increases were attenuated by palmatine. GalN/LPS increased hepatic lipid peroxidation and decreased the contents of reduced glutathione. Palmatine did not affect the lipid peroxidation and glutathione content. GalN/LPS increased the circulating levels of tumor necrosis factor (TNF)-α, interleukin-6 (IL-6) and IL-10. Palmatine prevented the increase of serum TNF-α and augmented that of serum IL-10. GalN/LPS treatment also increased the levels of TNF-α, IL-6 and IL-10 mRNA expression in liver tissue. Palmatine decreased the TNF-α mRNA expression and increased the IL-10 mRNA expression. Palmatine attenuated the apoptosis of hepatocytes, as evidenced by the TUNEL method and capase-3 analysis. Our data suggest that palmatine alleviates GalN/LPS-induced liver injury by modulating the cytokine response and inhibiting apoptosis.     

The glycine/NMDA receptor antagonist,L-701,324 reverses isolation-induced deficits in prepulse inhibition in the rat

Previous studies have demonstrated that the glycine/NMDA receptor antagonist, L-701,324 (7-chloro-4-hydroxy-3(3-phenoxy)phenyl-2(H)quinolone) blocks the activation of mesolimbic dopamine systems induced following psychostimulant administration in the rat (Bristow et al. 1994). In the present study, pretreatment with L-701,324 also reversed the deficit in prepulse inhibition (PPI) observed in rats reared in social isolation after weaning. Given that PPI is also attenuated in schizophrenic patients and that isolation rearing induces both neurochemical and behavioural abnormalities suggestive of a physiologically induced state of dopaminergic hyperactivity, these results suggest that blockade of the glycine/NMDA receptor may offer a new strategy for the development of novel antipsychotic agents.     

High molecular weight persimmon tannin ameliorates cognition deficits and attenuates oxidative damage in senescent mice induced by d-galactose

Mice were subcutaneously injected with d-galactose (d-gal, 150mg/kg per day) for 6 weeks and were administered high molecular weight persimmon condensed tannin (HMWPT) simultaneously. After 6 weeks of treatment, the animal behavior was observed in the open field test and water maze test, and the morphology of hippocampus and skin were checked. Meanwhile, the activities of antioxidant enzymes, the levels of non-enzymatic antioxidants, as well as malondialdehyde (MDA) were evaluated. The results indicated that HMWPT markedly inhibited the d-gal induced learning and memory impairment in both open field test and Morris water maze. Biochemical examination revealed that HMWPT significantly increased the decreased activities of superoxide dismutase (SOD), catalase (CAT), elevated the lowered total anti-oxidation capability (T-AOC), glutathione (GSH) and hydroxyproline (Hyp) contents (p < 0.01 or p < 0.05), and decreased the raised monoamine oxidase (MAO), total cholinesterase (TChE) activities and MDA level (p < 0.01) in serum, liver or brain of aging mice induced by d-gal in a dose-dependent fashion. Furthermore, HMWPT significantly and (p < 0.01) attenuated the d-gal induced number decrease, neuronal degeneration and karyopycnosis in cells in the hippocampus and decrease of thickness of skin epidermis and dermis.     

d-Cycloserine attenuates reactivity to smoking cues in nicotine dependent smokers: A pilot investigation

Increasing evidence indicates that smoking cues contribute to nicotine self-administration and attenuating conditioned reactivity to smoking cues may aid abstinence of smoking and prevention of smoking relapse in individuals with nicotine dependence. Based on prior studies showing that the partial N-methyl-d-aspartate (NMDA) agonist d-cycloserine (DCS) facilitates extinction of learned fear during behavioral exposure therapy in humans and facilitates extinction of cocaine-induced conditioned place preference in animals, we evaluated whether DCS would have potential for reducing reactivity to smoking cues when combined with cue exposure treatment in humans with nicotine dependence. In this double-blind placebo-controlled pilot laboratory study, 25 smokers were recruited from the general community and randomized to DCS or placebo, plus cue exposure therapy. DCS significantly attenuated smoking cue reactivity in response to in-vivo smoking cues based on physiological reactivity and subjective urge-to-smoke ratings and led to a significantly smaller expired carbon monoxide (CO) level at the one-week follow-up compared to placebo, although exploratory analyses indicated no effect on smoking behavior overall. These findings provide promising support for DCS combined with cue exposure therapy in attenuating conditioned reactivity to smoking cues.     

Effects of liposome-entrapped D-myo-inositol 1,4,5-trisphosphate and D-myo-inositol 1,3,4,5-tetrakisphosphate in the isolated rat aorta

This study examined the effects of D-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P₃)- and D-myo-inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P₄)-loaded liposomes upon the contractile activity of vascular smooth muscle, using the isolated (endothelium removed) rat aortic ring as an in vitro model. While control liposomes had no effect, the administration of Ins(1,4,5)P₃-containing liposomes contracted the smooth muscle preparation. Furthermore, a similar effect was seen with the administration of Ins(1,3,4,5)P₄-filled liposomes but, in this case, the rings developed a significantly higher level of active tension. Pretreatment of the aortic preparation with heparin-loaded liposomes blocked the contractions induced by both Ins(1,4,5)P₃- and Ins(1,3,4,5)P₄-containing liposomes.