Tetanus in adults: results of the multicenter ID-IRI study.

Tetanus is an acute, severe infection caused by a neurotoxin secreting bacterium. Various prognostic factors affecting mortality in tetanus patients have been described in the literature. In this study, we aimed to analyze the factors affecting mortality in hospitalized tetanus patients in a large case series. This retrospective multicenter study pooled data of tetanus patients from 25 medical centers. The hospitals participating in this study were the collaborating centers of the Infectious Diseases International Research Initiative (ID-IRI). Only adult patients over the age of 15 years with tetanus were included. The diagnosis of tetanus was made by the clinicians at the participant centers. Izmir Bozyaka Education and Research Hospital's Review Board approved the study. Prognostic factors were analyzed by using the multivariate regression analysis method. In this study, 117 adult patients with tetanus were included. Of these, 79 (67.5%) patients survived and 38 (32.5%) patients died. Most of the deaths were observed in patients >60 years of age (60.5%). Generalized type of tetanus, presence of pain at the wound area, presence of generalized spasms, leukocytosis, high alanine aminotransferase (ALT) and C-reactive protein (CRP) values on admission, and the use of equine immunoglobulins in the treatment were found to be statistically associated with mortality (p < 0.05 for all). Here, we describe the prognostic factors for mortality in tetanus. Immunization seems to be the most critical point, considering the advanced age of our patients. A combination of laboratory and clinical parameters indicates mortality. Moreover, human immunoglobulins should be preferred over equine sera to increase survival.

Managing atypical and typical herpetic central nervous system infections: results of a multinational study.

There have been many studies pertaining to the management of herpetic meningoencephalitis (HME), but the majority of them have focussed on virologically unconfirmed cases or included only small sample sizes. We have conducted a multicentre study aimed at providing management strategies for HME. Overall, 501 adult patients with PCR-proven HME were included retrospectively from 35 referral centres in 10 countries; 496 patients were found to be eligible for the analysis. Cerebrospinal fluid (CSF) analysis using a PCR assay yielded herpes simplex virus (HSV)-1 DNA in 351 patients (70.8%), HSV-2 DNA in 83 patients (16.7%) and undefined HSV DNA type in 62 patients (12.5%). A total of 379 patients (76.4%) had at least one of the specified characteristics of encephalitis, and we placed these patients into the encephalitis presentation group. The remaining 117 patients (23.6%) had none of these findings, and these patients were placed in the nonencephalitis presentation group. Abnormalities suggestive of encephalitis were detected in magnetic resonance imaging (MRI) in 83.9% of the patients and in electroencephalography (EEG) in 91.0% of patients in the encephalitis presentation group. In the nonencephalitis presentation group, MRI and EEG data were suggestive of encephalitis in 33.3 and 61.9% of patients, respectively. However, the concomitant use of MRI and EEG indicated encephalitis in 96.3 and 87.5% of the cases with and without encephalitic clinical presentation, respectively. Considering the subtle nature of HME, CSF HSV PCR, EEG and MRI data should be collected for all patients with a central nervous system infection.

Single-kernel analysis of fumonisins and other fungal metabolites in maize from South African subsistence farmers.

Fumonisins are important Fusarium mycotoxins mainly found in maize and derived products. This study analysed maize from five subsistence farmers in the former Transkei region of South Africa. Farmers had sorted kernels into good and mouldy quality. A total of 400 kernels from 10 batches were analysed; of these 100 were visually characterised as uninfected and 300 as infected. Of the 400 kernels, 15% were contaminated with 1.84-1428 mg kg(-1) fumonisins, and 4% (n=15) had a fumonisin content above 100 mg kg(-1). None of the visually uninfected maize had detectable amounts of fumonisins. The total fumonisin concentration was 0.28-1.1 mg kg(-1) for good-quality batches and 0.03-6.2 mg kg(-1) for mouldy-quality batches. The high fumonisin content in the batches was apparently caused by a small number (4%) of highly contaminated kernels, and removal of these reduced the average fumonisin content by 71%. Of the 400 kernels, 80 were screened for 186 microbial metabolites by liquid chromatography-tandem mass spectrometry, detecting 17 other fungal metabolites, including fusaric acid, equisetin, fusaproliferin, beauvericin, cyclosporins, agroclavine, chanoclavine, rugulosin and emodin. Fusaric acid in samples without fumonisins indicated the possibility of using non-toxinogenic Fusaria as biocontrol agents to reduce fumonisin exposure, as done for Aspergillus flavus. This is the first report of mycotoxin profiling in single naturally infected maize kernels.

Radiofrequency ablation of colorectal liver metastases: long-term survival.

PURPOSE: To evaluate the results of radiofrequency ablation (RFA) therapy with regard to long-term survival and rate of complications in patients with liver metastases from colorectal carcinoma. MATERIAL AND METHODS: A total of 102 patients were included and treated with RFA. In 100 patients, resection was not possible; two patients refused surgery. The patients had a total of 332 colorectal liver metastases. Pre- and post-treatment evaluation was performed with contrast-enhanced computed tomography. Survival from time of diagnosis of liver metastases was calculated by Kaplan-Meier analysis. Complications were recorded as minor or major in accordance with the definitions of the Society for Cardiovascular and Interventional Radiology. RESULTS: Estimated median survival from time of diagnosis of liver metastases was 52 months (95% CI 34-82). Estimated 1-, 2-, 3-, 4-, and 5-year survival was 96%, 79%, 64%, 52%, and 44%, respectively. Minor complications were recorded following seven RFA treatments (4.0%) and major complications following 12 RFA treatments (6.9%). CONCLUSION: RFA is an effective method to treat liver metastases from colorectal carcinoma. Survival is improved and comparable with survival following surgical resection. The rate of complications is low.

[Complications of transligamental knee arthroscopy. The frequency of pain and ultrasonographic changes in the inferior patellar tendon]. / Komplikationer til transligamentaer knaeledsartroskopi. Hyppigheden af smerter og UL-forandringer i ligamentum patellae inferius.

INTRODUCTION: We wanted to investigate whether the transtendineous portal for arthroscopy was causing damage to the patellar tendon (PT). We also wanted to assess postoperative complaints related to the patellar tendon. METHODS: Out of 59 consecutive patients, who had neither anterior knee pain nor ultrasonographic changes in the tendon, and who had a planned transtendineous arthroscopy of the knee because of a suspected meniscal lesion or osteoarthritis, 36 patients were given both a clinical examination and ultrasonography of the PT before surgery and at two and six months. RESULTS: At the six months follow-up, 20 patients had tenderness of the PT, which was fewer than at the two-month follow-up. Ten patients had signs of granuloma formation of the patellar tendon and four had signs of perifibrosis/peritendinitis on ultrasonography. There was no statistical correlation between tenderness of the patellar tendon and granuloma formation (p = 0.48, Fisher's exact test) or perifibrosis/peritendinitis (p = 0.78, Fisher's exact test). DISCUSSION: More than 25% of the patients showed granuloma formation on ultrasonography and more than 50% had complaints from the patellar tendon, but both the symptoms and the complaints seemed to decline over time. The consequences of the postoperative changes in the patellar tendon six months postoperatively are uncertain, as there was no statistical correlation between tenderness of the PT and the findings at ultrasonography. Further studies are recommended to investigate the changes in the PT when this method is used.

Effect of AMPA receptor modulators on hippocampal and cortical function.

Attention has focused on drugs that modulate AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid) receptors because of their potential for enhancing memory and treating certain pathologies that involve glutamatergic neurotransmission. The aim of this study was to compare and contrast the functionality of positive allosteric modulators of AMPA receptors in the hippocampus and medial prefrontal cortex. Electrically stimulated EPSPs (excitatory postsynaptic potential) in the hippocampus were augmented by CX516 [(1-quinoxaline-6-ylcarbonyl)piperidine], aniracetam and 1-BCP [(1-(1,3-benzodioxol-5-ylcarbonyl)piperidine] and not by cyclothiazide. Using grease gap electrophysiology, it was found that the mode of application dramatically altered the effect of the modulators of AMPA-induced depolarization. When added simultaneously with AMPA, aniracetam, 1-BCP and CX516 augmented the response in the frontal cortex. However, in the hippocampus, only aniracetam and cyclothiazide augmented the response when simultaneously added to AMPA. Therefore, in addition to regional variations, there appears to be differences in modulator response dependent upon whether a response is generated endogenously or exogenously by AMPA.

On the effect of neonatal nitric oxide synthase inhibition in rats: a potential neurodevelopmental model of schizophrenia.

NADPH-d (nicotinamide-adenine dinucleotide phosphate-diaphorase) neurons are thought to migrate improperly during development in the brains of schizophrenic patients. This enzyme is a nitric oxide synthase (NOS). Nitric oxide (NO) is known to affect neurodevelopmental processes in the CNS. Therefore, we hypothesized that interference of NO generation during development may produce some aspects of schizophrenia symptomatology in a rat model. In these experiments, neonatal rats were challenged with a NOS inhibitor (L-nitroarginine 1-100 mg/kg s.c.) daily on post-natal days 3-5. L-Nitroarginine (L-NoArg) treated male rats developed a hypersensitivity to amphetamine in adulthood versus vehicle treated controls, whereas female rats did not. However, L-NoArg treated female rats developed a hypersensitivity to phencyclidine (PCP) at juvenile and adult ages versus vehicle treated controls, whereas male animals did not. L-NoArg treated male rats also had deficits in pre-pulse inhibition of startle whereas adult female rats did not. The results are discussed in terms of a new neurodevelopmental model of schizophrenia and male/female differences inherent in this disease.

The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA antagonist- than dopamine agonist-induced hyperactivity in mice.

The purpose of the present study was to compare the effectiveness of the selective 5-HT2A antagonist M100907 in different psychosis models. The classical neuroleptic haloperidol was used as reference compound. Two hyperdopaminergia and two hypoglutamatergia mouse models were used. Hyperdopaminergia was produced by the DA releaser d-amphetamine or the DA uptake inhibitor GBR 12909. Hypoglutamatergia was produced by the un-competitive NMDA receptor antagonist MK-801 or the competitive NMDA receptor antagonist D-CPPene. M100907 was found to counteract the locomotor stimulant effects of the NMDA receptor antagonists MK-801 and D-CPPene, but spontaneous locomotion, d-amphetamine- and GBR-12909-induced hyperactivity were not significantly affected. Haloperidol, on the other hand, antagonized both NMDA antagonist- and DA agonist-induced hyperactivity, as well as spontaneous locomotion in the highest dose used. Based on the present and previous results we draw the conclusion that 5-HT2A receptor antagonists are particularly effective against behavioural anomalies resulting from hypoglutamatergia of various origins. The clinical implications of our results and conclusions would be that a 5-HT2A receptor antagonist, due to i a the low side effect liability, could be the preferable treatment strategy in various disorders associated with hypoglutamatergia; such conditions might include schizophrenia, childhood autism and dementia disorders.

Mixed D2/5-HT2A antagonism of cocaine-induced facilitation of brain stimulation reward.

Previous behavioral, neurochemical and neurophysiological experiments have shown that selective 5-HT2A and mixed D2/5-HT2A antagonists can attenuate some, but not all, responses to amphetamine. The generality of these findings were determined in the present experiment by assessing the effect of mixed D2/5-HT2A antagonists on cocaine-induced facilitation of ventral tegmental area self-stimulation in rats. Although amphetamine and cocaine influence activity in monoaminergic neurons through different mechanisms, our previous research has shown that selective D2 and 5-HT2A antagonists have similar effects on behavioral responses to these psychostimulants. Therefore, we expected a similar pattern of results using mixed D2/5-HT2A antagonists. As shown previously, cocaine decreased self-stimulation threshold in a dose-dependent manner. Haloperidol and the mixed D2/5-HT2A antagonists risperidone and MDL 28, 133A antagonized cocaine-induced facilitation of self-stimulation, but only at doses that increased baseline self-stimulation threshold. There was a significant correlation (r = 0.87, p < 0.001) between antagonist-induced change in baseline threshold and attenuation of cocaine's effect on threshold. Taken together, the results of this and previous experiments support the importance of D2 receptors in the mechanisms of brain stimulation reward. 5-HT2A receptors appear not to be involved in mediation of both brain stimulation reward and amphetamine- and cocaine-induced facilitation of brain stimulation reward.

Mixed D2/5-HT2A antagonism of amphetamine-induced facilitation of brain stimulation reward.

Recent experiments have demonstrated that 5-HT2A antagonists can modify electrophysiological, neurochemical, and behavioral responses to psychostimulants. These findings led to an interest in using 5-HT2A antagonists to block the effects of psychostimulants on brain reward mechanisms. The present experiments assessed the ability of mixed D2/5-HT2A antagonists to reverse amphetamine-induced facilitation of self-stimulation. The D2/5-HT2A antagonists MDL 28,133A and risperidone attenuated the effects of cocaine and amphetamine, but only at antagonist doses that elevated baseline self-stimulation thresholds. A comparison of the effects of the mixed antagonists to those of haloperidol and eticlopride revealed that all four antagonists produced similar anti-stimulant effects when the influence of the drugs on baseline responding was considered. The D2 activity of the antagonists appears to account for their ability to reduce the effects of psychostimulants on self-stimulation. 5-HT2A antagonism makes a negligible contribution to the anti-amphetamine effects.

The role of 5-HT2A receptors in antipsychotic activity.

The correlation between the clinical activity of antipsychotic agents and their affinity for the D2 dopamine receptor has been the mainstay of the hypothesis that schizophrenia is due to excessive dopaminergic function. More recently, the unique clinical profile of the atypical antipsychotic clozapine has been proposed to involve actions on additional receptor systems. In particular, the high affinity of clozapine for the 5HT2A receptor subtype has been suggested to contribute to its reduced side-effect liability, greater efficacy and its activity in therapy-resistant schizophrenia. We have used the highly selective 5-HT2A antagonist MDL 100,907 to explore the contribution of 5-HT2A receptor blockade to antipsychotic activity. Biochemical, electrophysiological and behavioral studies reveal that selective 5HT2A receptor antagonists have the preclinical profile of an atypical antipsychotic. The limited clinical evidence available also suggests that compounds producing 5-HT2A receptor blockade are effective, in particular, against the negative symptoms of schizophrenia.

Characterization of the 5-HT2 receptor antagonist MDL 100907 as a putative atypical antipsychotic: behavioral, electrophysiological and neurochemical studies.

Progress toward understanding the role of the 5-hydroxytryptamine (5-HT)2 receptor in the therapy for schizophrenia has been hampered by the lack of highly selective antagonists. We now report on the effects of MDL 100,907 [R(+)-alpha-(2,3-dimethoxyphenyl)-1- [2-(4-fluorophenylethyl)]-4-piperidine-methanol], a highly selective and potent 5-HT2 receptor antagonist, in behavioral, electrophysiological and neurochemical models of antipsychotic activity and extrapyramidal side-effect liability. In mice, MDL 100,907 blocked amphetamine-stimulated locomotion at doses that did not significantly affect apomorphine-stimulated climbing behavior. Neither MDL 100,907 nor clozapine reduced apomorphine-induced stereotypies or produced catalepsy in rats. MDL 100,907 blocked the slowing of ventral tegmental area (A10) dopaminergic neurons by amphetamine but, like clozapine, produced only small increases in the number of active substantia nigra zona compacta (A9) and A10 dopamine neurons after acute administration. When administered chronically, MDL 100,907 and clozapine selectively reduced the number of spontaneously active A10 neurons, whereas haloperidol reduced activity in both the A9 and A10 regions. Consistent with their acute effect on A9 and A10 activity, neither MDL 100,907 nor clozapine increased dopamine metabolism in the striatum or nucleus accumbens, whereas acute haloperidol accelerated dopamine turnover in both regions. The administration of the dopamine uptake blocker amfonelic acid with haloperidol produced a massive increase in DA metabolism characteristic of typical antipsychotics. In contrast, MDL 100,907 and clozapine were without effect on dopamine turnover when given in the presence of amfonelic acid. These data indicate that MDL 100,907 has a clozapine-like profile of potential antipsychotic activity with low extrapyramidal sid-effect liability.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiological, biochemical and behavioral evidence for 5-HT2 and 5-HT3 mediated control of dopaminergic function.

Several lines of evidence have suggested a link between serotonergic and dopaminergic systems in the brain. The interpretation of much of these early data needs careful reevaluation in light of the recent understanding of the plethora of serotonin receptor subtypes, their distribution in the brain and the new findings with more selective serotonin antagonists. Electrophysiological, biochemical and behavioral evidence obtained using highly selective antagonists of the 5-HT2 or 5-HT3 receptor subtypes, MDL 100,907 or MDL 73,147EF, respectively, supports the thesis that serotonin modulates the dopaminergic system. This modulation is most evident when the dopaminergic system has been activated.

The 5-HT2 receptor antagonist, MDL 28,133A, disrupts the serotonergic-dopaminergic interaction mediating the neurochemical effects of 3,4-methylenedioxymethamphetamine.

The selective 5-HT2 receptor antagonist MDL 28,133A dose dependently-blocked the long-term deficits in rat brain 5-HT concentrations produced by the substituted amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA). This protective effect of MDL 28,133A could be abolished by coadministration of the dopamine precursor, L-dihydroxyphenylalanine (L-DOPA). Electrophysiological experiments demonstrated that the ability of MDL 28,133A to block the MDMA-induced slowing of A9 dopaminergic neurons was also sensitive to L-DOPA administration. Both sets of experiments suggest an interaction of MDL 28,133A at the level of dopamine synthesis. Consistent with this explanation, MDL 28,133A antagonized the MDMA-induced stimulation of dopamine synthesis in vivo. MDMA-induced 5-HT release did not reduce the firing rate of dopaminergic neurons as assessed by dopamine depletion following synthesis inhibition with alpha-methyl-p-tyrosine (alpha-MPT). This indicates that the effect of 5-HT2 receptor antagonists on MDMA-induced dopamine synthesis is not due simply to the removal of an inhibitory serotonergic input followed by an increase in dopamine cell firing and autoreceptor activation. MDL 28,133A was also shown to be without effect on the sensitivity of terminal dopamine autoreceptors. The results are consistent with the hypothesis that 5-HT2 receptors are permissive for the stimulation of dopamine synthesis necessary to support MDMA-induced transmitter efflux.

MDL 26,479: a potential cognition enhancer with benzodiazepine inverse agonist-like properties.

1. The present study investigated biochemical, electrophysiological and behavioural properties of the novel cognition enhancer, MDL 26,479 (5-(3-fluorophenyl)-2,4-dimethyl-3H-1,2,4-triazole-3-thione). 2. The 5-aryl-1,2,4-triazole, MDL 26,479, potently (0.22 +/- 0.05 mg kg-1) inhibited [3H]-flumazenil (Ro15-1788) binding in mouse cortex but was ineffective in vitro at displacing radioligand binding to the GABAA receptor complex. 3. Parenteral administration of MDL 26,479 (1 mg kg-1) or the benzodiazepine (BZD) inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (0.3 mg kg-1) increased cortical ex vivo binding of [3H]-hemicholinium-3 ([3H]-HC-3), a marker for cholinergic activation. This effect of MDL 26,479 was blocked by pretreatment with the antagonist flumazenil (1 mg kg-1). 4. MDL 26,479 (20 microM) and DMCM (1 microM) increased excitation in the hippocampal long-term potentiation (LTP) slice preparation; however, unlike DMCM, the effect of MDL 26,479 was not blocked by flumazenil. 5. In behavioural studies, MDL 26,479 did not exhibit adverse properties characteristic of drugs associated with the GABAA receptor complex. It lacked convulsant, anxiogenic, anxiolytic, or depressant effects. Since MDL 26,479 lacks activity with the BZD receptor in vitro we suggest that it acts via the GABAA receptor complex at another site on this receptor or in an as yet undefined manner or an active metabolite is formed in vivo. 6. Previous work showed that MDL 26,479 enhances learning acquisition in animal models.The present study suggests that at least some of the cognition enhancing properties are due to the enhancement of cortical and hippocampal cholinergic function and LTP.

5-HT2 receptor antagonists reverse amphetamine-induced slowing of dopaminergic neurons by interfering with stimulated dopamine synthesis.

The role of serotonin in the effect of amphetamine on the firing rate of midbrain dopaminergic neurons was examined using unit recordings of identified A10 dopamine neurons in the chloral hydrate-anesthetized rat. Amphetamine (1 mg/kg, i.v.) reduced the firing rate of these neurons approximately 50 to 60%. This effect was blocked in animals pretreated with the selective serotonin-2 (5-HT2) receptor antagonists, MDL 28,133A (0.2 mg/kg, i.v.) or ritanserin (1 mg/kg, i.v.). Although pretreatment with L-dopa (100 mg/kg, i.v.) plus carbidopa (25 mg/kg, i.p.) alone had no effect on amphetamine-induced slowing of A10 dopamine neurons, when coadministered with the 5-HT2 antagonists, the dopamine precursor completely restored this amphetamine-induced slowing. To verify the role of serotonin in these findings, rats were pretreated with the tryptophan hydroxylase inhibitor, p-chlorophenylalanine (250 mg/kg/day for 2 days) to deplete cortical serotonin levels. Consistent with the results observed with the 5-HT2 receptor antagonists, amphetamine did not produce a significant reduction in the firing rate of A10 neurons in serotonin-depleted rats. These results suggest that, under some conditions, serotonergic input via the activation of 5-HT2 receptors may regulate the availability of the pool of dopamine, which is subject to amphetamine release.

Measurement of anal cross-sectional area and pressure during anal distension in healthy volunteers.

A probe for simultaneous measurement of cross-sectional area and pressure was used to elucidate biomechanical wall properties during anal distension. Measurements in distal sphincter regions demonstrated a high resistance to stretch and a large hysteresis compared to proximal sphincter regions. Resistance to stretch decreased during anal distension indicating an active relaxation mechanism at all recording levels. The zone with high resistance to stretch was located more distal than the high-pressure zone measured by anal-pressure profilometry. In conclusion, biomechanical wall properties of the anal canal cannot be described by classic viscoelastic theories but rather by a loss of sphincter tone caused by reflex mechanism during anal distension.

2,4-Dihydro-3H-1,2,4-triazol-3-ones as anticonvulsant agents.

A series of 5-aryl-2,4-dihydro-3H-1,2,4-triazol-3-ones was evaluated for anticonvulsant activity. In general the members of this series were prepared by the alkaline cyclization of 1-aroyl-4-alkylsemicarbazides. The resulting 2-unsubstituted 3H-1,2,4-triazol-3-ones were then alkylated, yielding 2,4-dialkyl-3H-1,2,4-triazol-3-ones. Approximately one-third of the compounds examined exhibited activity against both maximal electroshock- and pentylenetetrazole-induced seizures in mice. Receptor-binding studies suggest that this activity was not a consequence of activity at either benzodiazepine or NMDA-type glutamate receptors. From this series, compound 45 was selected for further evaluation where it was also found to be active against 3-mercaptopropionic acid, bicuculline, and quinolinic acid induced seizures in mice. In addition, 45 also protected gerbils from hippocampal neuronal degeneration produced by either hypoxia or intrastriatal quinolinic acid injection.

Activity of 5,7-dichlorokynurenic acid, a potent antagonist at the N-methyl-D-aspartate receptor-associated glycine binding site.

5,7-Dichlorokynurenic acid (5,7-DCKA), one of the most potent excitatory amino acid receptor antagonists yet described, binds to a strychnine-insensitive glycine binding site located on the N-methyl-D-aspartate (NMDA) receptor complex (Ki = 79 nM versus [3H]glycine). 5,7-DCKA (10 microM) antagonized the ability of NMDA to stimulate the binding of the radiolabeled ion channel blocker N-[3H][1-(2-thienyl)cyclohexyl]-piperidine ([3]TCP). Glycine was able to overcome this effect and in the presence of 5,7-DCKA enhanced [3H]TCP binding to antagonist-free levels. 5,7-DCKA completely and noncompetitively antagonized several NMDA receptor-mediated biochemical and electrophysiological responses. Thus, micromolar concentrations of 5,7-DCKA inhibited NMDA-stimulated elevation of cytosolic calcium in cultured hippocampal neurons, cGMP accumulation in cerebellar slices, and norepinephrine release from hippocampal slices. The glycine antagonist could also block the action of synaptically released agonist, as shown by its ability to inhibit the increase in the magnitude of the population spike that follows tetanic stimulation of the hippocampus in vitro (long term potentiation). Inclusion of glycine or D-serine prevented all these effects of the antagonist. 5,7-DCKA was a potent anticonvulsant when administered intracerebroventricularly to mice. As in the in vitro experiments, the dose-response curve for the antagonist was shifted rightward in a parallel fashion when D-serine was coinjected. This spectrum of activity displayed by a compound acting at the glycine binding site suggests that the therapeutic utility of glycine antagonists will be similar to those proposed for other types of glutamate receptor antagonists.