CTTNBP2 Controls Synaptic Expression of Zinc-Related Autism-Associated Proteins and Regulates Synapse Formation and Autism-like Behaviors.

Synaptic dysregulation is a critical feature of autism spectrum disorders (ASDs). Among various autism-associated genes, cortactin binding protein 2 (CTTNBP2) is a cytoskeleton regulator predominantly expressed in neurons and highly enriched at dendritic spines. Here, using Cttnbp2 knockout and ASD-linked mutant mice, we demonstrate that Cttnbp2 deficiency reduces zinc levels in the brain, alters synaptic protein targeting, impairs dendritic spine formation and ultrastructure of postsynaptic density, and influences neuronal activation and autism-like behaviors. A link to autism, the NMDAR-SHANK pathway, and zinc-related regulation are three features shared by CTTNBP2-regulated synaptic proteins. Zinc supplementation rescues the synaptic expression of CTTNBP2-regulated proteins. Moreover, zinc supplementation and administration of D-cycloserine, an NMDAR coagonist, improve the social behaviors of Cttnbp2-deficient mice. We suggest that CTTNBP2 controls the synaptic expression of a set of zinc-regulated autism-associated genes and influences NMDAR function and signaling, providing an example of how genetic and environmental factor crosstalk controls social behaviors.

The impact of D-cycloserine and sarcosine on in vivo frontal neural activity in a schizophrenia-like model.

BACKGROUND: N-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed to underlie the pathogenesis of schizophrenia. Specifically, reduced function of NMDARs leads to altered balance between excitation and inhibition which further drives neural network malfunctions. Clinical studies suggested that NMDAR modulators (glycine, D-serine, D-cycloserine and glycine transporter inhibitors) may be beneficial in treating schizophrenia patients. Preclinical evidence also suggested that these NMDAR modulators may enhance synaptic NMDAR function and synaptic plasticity in brain slices. However, an important issue that has not been addressed is whether these NMDAR modulators modulate neural activity/spiking in vivo. METHODS: By using in vivo calcium imaging and single unit recording, we tested the effect of D-cycloserine, sarcosine (glycine transporter 1 inhibitor) and glycine, on schizophrenia-like model mice. RESULTS: In vivo neural activity is significantly higher in the schizophrenia-like model mice, compared to control mice. D-cycloserine and sarcosine showed no significant effect on neural activity in the schizophrenia-like model mice. Glycine induced a large reduction in movement in home cage and reduced in vivo brain activity in control mice which prevented further analysis of its effect in schizophrenia-like model mice. CONCLUSIONS: We conclude that there is no significant impact of the tested NMDAR modulators on neural spiking in the schizophrenia-like model mice.

Accumulation of ceramide in slow-twitch muscle contributes to the development of insulin resistance in the obese JCR:LA-cp rat.

NEW FINDINGS: What is the central question of this study? The aim was to determine whether the accumulation of ceramide contributes to skeletal muscle insulin resistance in the JCR obese rat. What is the main finding and its importance? Our main new finding is that ceramides accumulate only in slow-twitch skeletal muscle in the JCR obese rat and that reducing ceramide content in this muscle type by inhibition of serine palmitoyl transferase-1 halts the progression of insulin resistance in this rat model predisposed to early development of type 2 diabetes. Our findings highlight the importance of assessing insulin signalling/sensitivity and lipid intermediate accumulation in different muscle fibre types. It has been postulated that insulin resistance results from the accumulation of cytosolic lipid metabolites (i.e. diacylglycerol/ceramide) that impede insulin signalling and impair glucose homeostasis. De novo ceramide synthesis is catalysed by serine palmitoyl transferase-1. Our aim was to determine whether de novo ceramide synthesis plays a role during development of insulin resistance in the JCR:LA-cp obese rat. Ten-week-old JCR:LA-cp obese rats were supplemented with either vehicle or the serine palmitoyl transferase-1 inhibitor l-cycloserine (360 mg l(-1) ) in their drinking water for a 2 week period, and glycaemia was assessed by meal tolerance testing. Treatment of JCR:LA-cp obese rats with l-cycloserine improved their plasma glucose and insulin levels during a meal tolerance test. Examination of muscle lipid metabolites and protein phosphorylation patterns revealed differential signatures in slow-twitch (soleus) versus fast-twitch muscle (gastrocnemius), in that ceramide levels were increased in soleus but not gastrocnemius muscles of JCR:LA-cp obese rats. Likewise, improved glycaemia in l-cycloserine-treated JCR:LA-cp obese rats was associated with enhanced Akt and pyruvate dehydrogenase signalling in soleus but not gastrocnemius muscles, probably as a result of l-cycloserine reducing elevated ceramides in this muscle type. Potential mechanisms of ceramide-mediated insulin resistance involve activation of atypical protein kinase Cζ/λ and protein phosphatase 2A; however, neither of these was altered in muscles of JCR:LA-cp obese rats. Our results suggest a key role for ceramide in the development of insulin resistance in the JCR:LA-cp obese rat, while supporting serine palmitoyl transferase-1 inhibition as a novel target for treatment of obesity-associated insulin resistance.

D-Cycloserine ameliorates social alterations that result from prenatal exposure to valproic acid.

Prenatal exposure to valproic acid (VPA) alters rodent social interactions in a dose-dependent way: exposure to a high dose of VPA (>500 mg/kg) mid-gestation decreases social interactions whereas a moderate dose of VPA (350 mg/kg) increases peer-directed social behavior. The moderate dose also decreases expression of the mRNA for serine in amygdala and orbitofrontal cortex. In this study, we examined whether d-cycloserine could ameliorate VPA-induced alterations in ultrasonic vocalizations (USVs), social interactions, and locomotor activity. Pregnant Sprague Dawley rats were given intraperintoneal injections of VPA (200mg/kg each) on gestational days 12, 12.5 and 13; controls were injected with saline. Offspring received a subcutaneous injection of saline or d-cycloserine (32 or 64 mg/kg) either acutely (1h prior to testing) or repeatedly (once per day for four days). Social interactions were assessed during late adolescence, and USVs were recorded concomitantly. Male and female rats that were exposed to VPA demonstrated more locomotor activity than control animals during habituation to the testing chamber. VPA-exposed males showed increased play fighting. d-Cycloserine normalized the VPA-induced increase in play fighting in males and also increased social motivation in females. When the pair contained a VPA-exposed rat, significantly fewer USVs were emitted and 16% of the vocalizations were of a novel waveform. These effects were not seen in pairs containing VPA-exposed animals that were treated with d-cycloserine. Overall, these findings are consistent with data from other laboratories suggesting that d-cycloserine may be a promising pharmacotherapeutic compound for improving social behavior disorders.

Cycloserine as an alternative urinary tract infection therapy: susceptibilities of 500 urinary pathogens to standard and alternative therapy antimicrobials.

PURPOSE: Cycloserine has been used previously in some areas of the world for the treatment of urinary tract infections. The emergence of multi-resistant strains of Enterobacteriaceae and the lack of new agents in the development pipeline has prompted a need to review the activity of older agents. Susceptibility testing of cycloserine has traditionally been problematic owing to testing in standard media, containing competitive alanine, thus presenting falsely elevated minimum inhibitory concentrations (MICs). This study tests urinary coliforms against cycloserine in both standard and minimal media. METHODS: Susceptibilities were performed on 500 "wild type" UTI coliforms using Mueller-Hinton broth in the range 0.008-128 µg/ml in accordance with ISO guidelines. Cycloserine was also tested in Minimal Salts medium + 2 % 1 M glucose + 0.2 % 1 M magnesium sulphate. MICs were recorded after 18 h of incubation at 35 °C and interpreted with EUCAST breakpoints (where available). RESULTS: Cycloserine MIC50 for the "wild type" coliforms was 32 µg/ml in Mueller-Hinton broth compared with 2 µg/ml in Minimal Salts. Eighty-seven per cent of "wild type" UTI coliforms show cycloserine MICs < = 8 µg/ml in Minimal Salts. The epidemiological cut-off values for cycloserine for E. coli in this study were 64 µg/ml using Mueller-Hinton broth and 8 µg/ml using Minimal Salts medium. Ninety-four per cent of trimethoprim-resistant and 82 % of third generation cephalosporin-resistant E. coli had MICs in Minimal Salts ≤ 8 µg/ml. CONCLUSION: Cycloserine is still licensed in some countries for the treatment of urinary infections and the data presented here suggest that it may play a role in the management of infections resistant to trimethoprim and third generation cephalosporins.

Terpene alcohols inhibit de novo sphingolipid biosynthesis.

The terpene alcohols geranyllinalool, phytol (diterpene alcohol), and farnesol (sesquiterpene alcohol) were newly found to inhibit sphingolipid de novo biosynthesis in LLC-PK1 cells (pig kidney epithelial cells). A simple chromatographic bioassay was established for the screening of inhibitory compounds able to reduce the amount of sphinganine, an intermediate metabolite of sphingolipid biosynthesis. The screening strategy was based on the degree of suppression of fumonisin B1 (FB1-induced sphinganine accumulation following co-treatment with selected terpene alcohols. L-cycloserine and ISP-1, specific serine palmitoyltransferase (SPT) inhibitors, were used as positive controls. Our results show that measuring reduced sphinganine levels after treatment with 2 µM FB1 in combination with the putative inhibitory compounds provides a useful screening bioassay for evaluating compounds causing sphingolipid depletion. Intracellular sphinganine concentrations were analyzed using the fluorescent peak areas of the O-phthalaldehyde (OPA) derivatives of sphinganine eluted with 87 % acetonitrile on a reversed-phase column. Geranyllinalool, phytol, and farnesol were identified as novel SPT inhibitors that reduce FB1-induced sphinganine accumulation and thus inhibit the first step of sphingolipid de novo synthesis.

D-cycloserine facilitates extinction the first time but not the second time: an examination of the role of NMDA across the course of repeated extinction sessions.

Extinction of learned fear is facilitated by the partial NMDA agonist D-cycloserine (DCS). However, some studies suggest that the involvement of NMDA in learning differs depending on whether learning is for the first or second time. The current study aimed to extend these findings by examining the role of NMDA in extinction for the first and the second time. Specifically, the present series of experiments used Pavlovian fear conditioning and extinction paradigms to compare the effect of DCS on extinction of fear to a light CS the first and second time around. As found previously, DCS facilitated extinction of learned fear (Experiment 1). A novel finding, however, was that DCS did not facilitate the re-extinction of fear to this same CS following retraining (Experiments 2A and 2B). Finally, it was demonstrated that the transition from NMDA-dependent to NMDA-independent extinction was stimulus specific (Experiment 3). That is, rats were first trained to fear a CS (light); this fear was then extinguished. Following this, rats were then retrained to fear the same CS (light) or a new CS (white noise). When given a second extinction session, DCS was found to facilitate extinction of the new CS but not the original CS. The results of this series of experiments suggest that the role of NMDA in extinction depends on whether extinction is new learning (first extinction) or retrieval of a previous extinction memory (re-extinction).

Absence of significant interactive effects of high-dose D-cycloserine and ethanol in healthy human subjects: preliminary insights into ethanol actions at the glycine B site of NMDA glutamate receptors.

BACKGROUND: Ethanol reduces N-methyl-d-aspartate (NMDA) glutamate receptor function via multiple cellular targets. It is not yet clear whether direct ethanol antagonism of the glycine(B) co-agonist site of NMDA receptors is relevant to this effect. The purpose of this study was to evaluate whether ethanol effects at the glycine(B) co-agonist site was clinically relevant by evaluating some aspects of the psychopharmacologic interactions between the glycine(B) partial agonist, D-cycloserine (DCS), and ethanol in healthy human subjects. METHODS: All subjects completed 4 test days under double-blind conditions in which DCS or placebo was administered orally prior to ethanol or an ethanol-tainted placebo drink. Two groups of healthy subjects were studied. A first group of subjects (n = 25) were pretreated orally with DCS 500 mg or placebo 4 hours prior to ethanol (0.8 g/kg, p.o. or placebo) administration. A second group of subjects (n = 20) were pretreated with DCS 1000 mg or placebo prior to ethanol administration. Outcomes included subjective and cognitive responses to the experimental interventions. RESULTS: Predictable ethanol responses were observed in both groups of subjects, although the response to ethanol and the breath alcohol levels, but not plasma alcohol levels, were slightly but significantly lower in the group that received the higher DCS dose. DCS produced mild sedative effects that were greater for the lower than the higher dose. It also produced a mild impairment of verbal fluency without impairing attention. No statistically significant interactions between ethanol and DCS emerged in analyses. However, the combination of ethanol and DCS produced significantly greater impairment than both ethanol or DCS administered alone on a test of verbal fluency and aspects of memory function. IMPLICATIONS: DCS and ethanol both produced sedative and cognitive effects, consistent with their ability to reduce NMDA receptor function. However, the absence of interactive effects observed in this study raises questions about the clinical significance of the glycine(B) site as a target for ethanol in the brain at levels of ethanol intoxication associated with social drinking. However, it should be noted that this conclusion is limited to the dependent measures evaluated and the doses of ethanol and DCS studied.

Selective increase in the extracellular D-serine contents by D-cycloserine in the rat medial frontal cortex.

A partial agonist of the N-methyl-D-aspartate (NMDA) receptor, D-cycloserine, acting at its glycine modulatory site, ameliorates the neuropsychiatric symptoms that are mimicked by NMDA antagonists and include cognitive disturbances, antipsychotic-resistant schizophrenic symptoms and cerebellar ataxia. To obtain a further insight into the mechanisms of the therapeutic efficacies of D-cycloserine, we investigated the effects of the systemic administration of D-cycloserine on the extracellular contents of an endogenous NMDA co-agonist, D-serine, in the medial frontal cortex of the rat using an in vivo dialysis technique. An acute intraperitoneal injection of D-cycloserine (50 and 100 mg/kg) caused an increase in extracellular concentrations of D-serine without significant effects on those of L-serine, glycine, L-glutamate, L-aspartate, L-glutamine, L-asparagine, L-alanine, L-threonine and taurine in the medial frontal cortex. The selective increase in the extracellular D-serine contents may, at least partially, be associated with the facilitating effects of D-cycloserine on the NMDA receptor functions in addition to its direct stimulation of the NMDA receptor glycine site.

D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury.

Traumatic brain injury triggers a massive glutamate efflux, activation of NMDA receptor channels, and cell death. Recently, we reported that NMDA receptors in mice are down-regulated from hours to days following closed head injury (CHI), and treatment with NMDA improved recovery of motor and cognitive functions up to 14 d post-injury. Here we show that a single injection of a low dose of D-cycloserine (DCS), a partial NMDA receptor agonist, in CHI mice 24 h post-injury, resulted in a faster and greater recovery of motor and memory functions as assessed by neurological severity score and object recognition tests, respectively. Moreover, DCS treatment of CHI mice led to a significant improvement of hippocampal long-term potentiation (LTP) in the CA1 region that was completely blunted in CHI control mice. However, DCS did not improve CHI-induced impairment in synaptic glutamate release measured by paired pulse facilitation (PPF) ratio in hippocampal CA1 region. Finally, CHI-induced reduction of brain-derived neurotrophic factor (BDNF) was fully restored following DCS treatment. Since DCS is in clinical use for other indications, the present study offers a novel approach to treat human brain injury.

Treatment and follow-up of HIV-negative multidrug-resistant tuberculosis patients in an infectious diseases reference hospital, Buenos Aires, Argentina.

SETTING: An Argentinean reference hospital specialising in infectious diseases. OBJECTIVE: To assess the outcomes of all human immunodeficiency virus (HIV) negative multidrug-resistant tuberculosis (MDR-TB) patients referred to or diagnosed at Hospital Muñiz. DESIGN: Clinical study for the period 1996-1999, with follow-up until June 2002. RESULTS: One hundred and forty-one adult patients (52.5% female) with resistance to two to seven drugs were studied. Fifty patients (35.5%) had not been treated previously. The most frequently used second-line drugs were 5-F-quinolones, cycloserine and ethionamide in susceptibility based individually tailored three- to five-drug regimens. Hospital admission was associated with treatment success. Forty-five episodes of severe toxicity occurred. Treatment was successful in 51.8% of cases, but follow-up of 73 patients yielded 11.9% relapse. The mortality rate was 19.1% and default was 19.9%. Logistic regression analysis was statistically significant for treatment success in relation to patient admission, residence and resistance pattern. CONCLUSION: The burden of MDR-TB in this setting--prolonged infection, treatment cost and difficulties, low rates of cure and treatment adherence and high rates of fatality and relapse--can be improved by strengthening TB control programme activities and fighting against poverty and HIV/AIDS.

Glycine and D-cycloserine attenuate vacuous chewing movements in a rat model of tardive dyskinesia.

Presently there is no established treatment for antipsychotic drugs-induced tardive dyskinesia (TD), which remains a major clinical issue in psychiatry. Based on the principles of the glutamatergic hypothesis of schizophrenia, the amino acid glycine (GLY) and the antituberculosis drug D-cycloserine (DCS) have been assessed, during the last decade, as adjuvants to antipsychotic drugs. Observations stemming from these studies suggest that, in addition to improving schizophrenia symptoms, these compounds may also be beneficial against drug-induced dyskinesias. In order to investigate this hypothesis, GLY and DCS effects were studied using the putative TD analogue vacuous chewing movements (VCM) rat model. Following 24 weeks of treatment with haloperidol decanoate (0.38 mg/kg/4 weeks) rats (N=40) were randomized to receive one intraperitoneal injection with 1.6 g/kg GLY, 10 mg/kg ("low dose") DCS; 100 mg/kg ("high dose") DCS or saline ("placebo"), respectively. Behavior was videotaped at intervals during the experiment and all VCM, rearing, grooming and immobility episodes were analyzed and scored. A control group (N=9) received saline for 24 weeks. Haloperidol administration decreased motor activity and significantly induced VCM. High dose DCS significantly reduced VCM without affecting other motor parameters. GLY treatment resulted in significantly less VCM but also reduced rearing, grooming and mobility. In contrast, low dose DCS and placebo did not significantly affect any of these parameters. These findings indicate that the use of GLY and DCS results in attenuation of VCM in rats and may have an effect on TD in humans. Clinical trials with this type of compounds for patients suffering from TD are warranted.

Characterization of a fish antimicrobial peptide: gene expression, subcellular localization, and spectrum of activity.

Antimicrobial peptides are proposed to act as the first line of mucosal host defense by exerting broad-spectrum microbicidal activity against pathogenic microbes. Pleurocidin, a new 25-residue linear antimicrobial peptide, was recently isolated from the skin secretions of winter flounder (Pleuronectes americanus). The present study identifies the cDNA and gene encoding pleurocidin. The pleurocidin gene comprises four exons. Its upstream region demonstrates consensus binding sequences for transcription factors found in host defense genes in mammals, including sequences identical to the NF-IL6 and alpha and gamma interferon response elements. Pleurocidin is predicted to exist as a 68-residue prepropeptide that undergoes proteolytic cleavage of its amino-terminal signal and carboxy-terminal anionic propiece to form the active, mature peptide. Transmission electron microscopy localized pleurocidin to the mucin granules of skin and intestinal goblet cells. Significant synergy was shown to occur between pleurocidin and D-cycloserine targeting Mycobacterium smegmatis. Pleurocidin was functionally active at physiologic concentrations of magnesium and calcium; however, high concentrations of these divalent cations ablated pleurocidin's activity against a standard test strain, Escherichia coli D31. Pleurocidin was tested against bacterial and fungal clinical isolates and showed broad-spectrum antimicrobial activity. Together, these data support the hypothesis that pleurocidin participates in innate mucosal immunity, and it may prove to be a beneficial therapeutic agent.

Effects of the partial glycine agonist D-cycloserine on cognitive functioning in chronic low dose MPTP-treated monkeys.

D-Cycloserine, a partial agonist at the glycine recognition site of the N-methyl-D-aspartate (NMDA) receptor complex, has been shown to facilitate certain forms of memory formation and to improve visual recognition memory in normal monkeys. In the present study, the effects of D-cycloserine on spatial short-term memory deficits in monkeys induced by chronic low-dose 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) administration were examined. Chronic low-dose MPTP administration resulted in deficits in the performance of a variable delayed-response task (VDR). Single administration of D-cycloserine (320 or 1000 microgram/kg) significantly improved the performance on this task. High-dose D-cycloserine (8000 microgram/kg) or MK-801 (10-32 microgram/kg) administration had no effects on delayed-response performance but impaired performance on a visual discrimination (VD) task that was not adversely affected by MPTP administration. These results show that at low doses, D-cycloserine has cognition-enhancing properties in this model of early Parkinsonism.

IV glycine and oral D-cycloserine effects on plasma and CSF amino acids in healthy humans.

BACKGROUND: The amino acid glycine, modulates neurotransmission via actions at GLY-A receptor and GLY-B receptor. The latter are coagonist sites associated with N-Methyl-D-Aspartate (NMDA) glutamate receptors. The central bioavailability of peripherally administered glycine has not been adequately characterized in humans. METHODS: Healthy human subjects were administered either oral D-cycloserine (50 mg or placebo) and intravenous glycine (saline, 100 mg/kg or 200 mg/kg) in random order over 4 test days under double-blind conditions. Cerebrospinal fluid was collected by lumbar puncture performed on the first test day was analyzed to determine amino acid levels. The acoustic startle response was measured on the second test day. RESULTS: Intravenous glycine dose-dependently increased both serum and CSF glycine and serine levels. Neither glycine nor DCS produced any significant effects on behavior, cognition or the acoustic startle response. Neither IV glycine nor DCS were associated with any toxicity. CONCLUSIONS: Thus, peripheral glycine administration raised CSF glycine levels without producing any clear central nervous system effects. Glycine and D-cycloserine did not worsen cognitive test performance and did not induce behavioral symptoms on their own. The possibility that glycine and D-cycloserine enhanced cognitive test performance cannot be excluded given the psychometric limitations of the test battery.

Prepulse inhibition of the startle reflex in rats: effects of compounds acting at various sites on the NMDA receptor complex.

Prepulse inhibition (PPI) of the startle reflex in rats is disrupted by N-methyl-D-aspartate (NMDA) receptor non-competitive antagonists (phencyclidine-like compounds). In order to explore more thoroughly the control exerted by NMDA receptors on PPI, we assessed the effects of i.p. administration, in Sprague-Dawley rats, of compounds acting as antagonists or agonists at the five binding sites of the NMDA receptor complex. The non-competitive NMDA receptor antagonists phencyclidine (1-6 mg/kg) and MK-801 (dizocilpine: 0.05-0.2 mg/kg) robustly and dose-dependently disrupted PPI. A similar effect was obtained with the competitive NMDA receptor antagonists CGS 19755 (1-20 mg/kg) and CPP (3-20 mg/kg), but not with the cation Mg2+ (100 and 200 mg/kg), the glycine/NMDA binding site antagonist L-701,324 (1-10 mg/kg), or the polyamine/NMDA binding site antagonist eliprodil (3-20 mg/kg). Potentiation of glutamatergic neurotransmission by NMDA (10-50 mg/kg), and the glycine/NMDA site partial agonist d-cycloserine (1-30 mg/kg) also failed to modify PPI, though d-cycloserine diminished PPI at higher doses (50-200 mg/kg). Co-administration of sub-threshold doses of CPP (3 mg/kg) and phencyclidine (2 mg/kg) resulted in an additive effect, disrupting PPI. In contrast, co-administration of L-701,324 (6 mg/kg) with phencyclidine (2 mg/kg), eliprodil (20 mg/kg), or CPP (3 mg/kg), did not disrupt PPI. These results demonstrate that PPI-disrupting effects can only be obtained with phencyclidine-like compounds and NMDA receptor competitive antagonists. Treatment with compounds that potentially augment glutamatergic tone were without effect. Finally, despite the permissive control of the glycine/NMDA binding site on glutamatergic neurotransmission, the glycine/NMDA binding site antagonist L-701,324 did not produce synergistic activity when combined with antagonists at the glutamate, polyamine/NMDA or phencyclidine-like compound binding sites.

Infusion of D-cycloserine into temporal-hippocampal areas and restoration of mnemonic function in rats with disrupted glutamatergic temporal systems.

Partial transections of the fiber connections between the temporal cortex and the lateral entorhinal cortex at a site of the white matter corresponding to the perirhinal cortex result in impaired visual memory accompanied by reduced concentrations of glutamate in both the temporal cortex and lateral entorhinal cortex. Intraperitoneal administration of the glycinergic receptor agonist D-cycloserine produces complete restoration of memory function, as measured by a brightness discrimination task in rats with temporal cortex/lateral entorhinal cortex transections. The purpose of the present study was to identify in which brain structures the compensatory activity might take place. The results show that infusion of cycloserine into either the temporal cortex or lateral entorhinal cortex fully ameliorated the impairment of temporal cortex/lateral entorhinal cortex lesions, whereas infusion into the hippocampal region caused only a mild improvement of the retention performance. Infusion of cycloserine into the frontal cortex or saline into the temporal cortex or lateral entorhinal cortex had no ameliorating effects on the memory dysfunction of rats bearing temporal cortex/lateral entorhinal cortex transections. It is concluded that the temporal cortex, lateral entorhinal cortex and perirhinal cortex are highly critical in forming visual memory.

Deficits in water escape performance and alterations in hippocampal cholinergic mechanisms associated with neonatal monosodium glutamate treatment in mice.

Mice treated neonatally with monosodium glutamate (MSG) were found to have learning and memory deficits in performing a non-spatial water escape task. Scopolamine impaired the water-escape performance of the control mice but not that of the MSG-treated mice. It was suggested that the water-escape performance deficit in the MSG-treated mice was a result of impaired central cholinergic mechanisms. As such, scopolamine was unable to further incapacitate an already impaired cholinergic system. This is strongly supported by the decreased affinity of the sodium-dependent high-affinity choline uptake observed in the hippocampus. D-Cycloserine, a partial agonist at the glycine site of the NMDA receptor, did not affect the water-escape performance of the MSG-treated and control mice; nor did it alter the effects of scopolamine. This lack of effect of D-Cycloserine may imply that the NMDA receptors are not involved in non-spatial learning, in contrast to their reported involvement in spatial learning.

[Evaluation of cycloserine in the treatment of infections caused by nontuberculous mycobacteria viewed from in vitro experiments].

Evaluation of cycloserine as a drug in the treatment of infections caused by nontuberculous mycobacteria was made from in-vitro studies, in which Mycobacterium tuberculosis strains were used as the standard of the evaluation. The susceptibility testing to cycloserine was made using Ogawa egg medium. Bacterial suspensions, 10 mg wet weight/ml, prepared from 10 day-old cultures (M. tuberculosis, 14 day-old cultures) growing on Ogawa egg medium were used as the source of inoculation. A 0.02 ml-sample of the suspensions was inoculated onto Ogawa egg medium containing cycloserine or containing no drug, and the media inoculated were incubated at 37 degrees C. The minimal inhibitory concentration (MIC) was determined after incubation for 14 days (M. tuberculosis, for 21 days). The MIC was determined as the lowest concentration of the drug, on which the growth of test strains was completely inhibited. However, residual growth was sometimes observed. This was regarded as growth inhibition, because control medium containing no drug showed always abundant, membraneous growth. The results are shown in Fig.. The growth of M. tuberculosis strains was inhibited by the concentrations of 6.25 to 25 micrograms/ml. However, considering our previous observations on the relationship between the cycloserine resistance and the drug efficacy (reference 1), we regarded the MIC 12.5 micrograms/ml as critical concentration for presumable clinical efficacy. The ratios of strains of various mycobacterial species showing the MICs lower than the critical concentration are shown in Table. As seen in this table, clinical efficacy of cycloserine was expected in the treatment of infections caused by Mycobacterium kansasii, M. malmoense, M. simiae, M. scrofulaceum and M. marinum.(ABSTRACT TRUNCATED AT 250 WORDS)