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At least 73 records · Page 4Linked to original sources
PubMed2005

Facilitation of conditioned fear extinction by d-cycloserine is mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase cascades and requires de novo protein synthesis in basolateral nucleus of amygdala.

Recent results showed that either systemic or intra-amygdala administration of d-cycloserine, a partial agonist at the glycine modulatory site on the glutamate N-methyl-d-aspartate receptor facilitates the extinction of conditioned fear. Here we evaluated the role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase in the basolateral nucleus of amygdala on the effect of d-cycloserine. The facilitation effect of d-cycloserine on fear extinction and mitogen-activated protein kinase activation was completely blocked by intra-amygdala administration of mitogen-activated protein kinase inhibitor PD98059 (500 ng/side, bilaterally) or U0-126 (20 microM/side, bilaterally). Furthermore, phosphatidylinositol 3-kinase inhibitor (wortmannin, 5.0 microg/side, bilaterally) infused into the basolateral nucleus of amygdala significantly reduced both facilitation effect of d-cycloserine and phosphatidylinositol 3-kinase activation. Intra-amygdala administration of a transcription inhibitor (actinomycin D, 10 microg dissolved in 1.6 microl vehicle; 0.8 microl per side) and a translation inhibitor (anisomycin, 125 microg dissolved in 1.6 microl vehicle; 0.8 microl per side) completely blocked the facilitation effect of d-cycloserine. Control experiments indicated the blockage by actinomycin D or anisomycin were not due to lasting damage to the basolateral nucleus of amygdala or state dependency. In addition, none of the active drugs used here altered the expression of conditioned fear. These results suggested that phosphatidylinositol 3-kinase and mitogen-activated protein kinase-dependent signaling cascades and new protein synthesis within the basolateral nucleus of amygdala played important roles in the d-cycloserine facilitation of the extinction of conditioned fear.

Amygdala↗
PubMed1998

Tetrahydroaminoacridine and D-cycloserine stimulate acquisition of water maze spatial navigation in aged rats.

We investigated the effect of tetrahydroaminoacridine, a cholinesterase inhibitor and D-cycloserine (a partial glycine-B agonist of the NMDA receptor complex) on the defect of water maze spatial navigation in rats induced by aging. Tetrahydroaminoacridine (3 mg/kg, i.p.) or D-cycloserine (10 mg/kg, i.p.) enhanced acquisition of the water maze task. A combination of subthreshold doses of tetrahydroaminoacridine (1 mg/kg) and D-cycloserine (3 mg/kg) improved water maze acquisition, but a combination of lower subthreshold doses (tetrahydroaminoacridine 0.3 mg/kg + D-cycloserine 1 mg/kg) was ineffective. Consolidation in water maze test was not improved by tetrahydroaminoacridine (3 mg/kg) and/or D-cycloserine (10 mg/kg). The results suggest that tetrahydroaminoacridine and D-cycloserine synergistically enhance acquisition of spatial navigation in aged rats.

Aging↗
PubMed2003

A side reaction of alanine racemase: transamination of cycloserine.

Alanine racemase (EC 5.1.1.1) catalyzes the interconversion of alanine enantiomers, and thus represents the first committed step involved in bacterial cell wall biosynthesis. Cycloserine acts as a suicide inhibitor of alanine racemase and as such, serves as an antimicrobial agent. The chemical means by which cycloserine inhibits alanine racemase is unknown. Through spectroscopic assays, we show here evidence of a pyridoxal derivative (arising from either isomer of cycloserine) saturated at the C4' carbon position. We additionally report the L- and D-cycloserine inactivated crystal structures of Bacillus stearothermophilus alanine racemase, which corroborates the spectroscopy via evidence of a 3-hydroxyisoxazole pyridoxamine derivative. Upon the basis of the kinetic and structural properties of both the L- and D-isomers of the inhibitor, we propose a mechanism of alanine racemase inactivation by cycloserine. This pathway involves an initial transamination step followed by tautomerization to form a stable aromatic adduct, a scheme similar to that seen in cycloserine inactivation of aminotransferases.

Alanine Racemase↗
PubMed2003

D-cycloserine-Naloxone interactions in opioid-dependent humans under a novel-response naloxone discrimination procedure.

Six participants currently in opioid maintenance treatment were trained to distinguish between naloxone (0.15 mg/70 kg, intramuscularly [i.m.]) and placebo under an instructed novel-response drug-discrimination procedure. Doses of the partial glycine agonist D-cycloserine (0-500 mg/70 kg, per os [P.O.]) alone and combined with naloxone (0.15 mg/70 kg) were then tested. D-cycloserine alone produced minimal drug-appropriate responding, no significant changes in self-reported effects, and increases only in systolic blood pressure. When combined with the naloxone, D-cycloserine partially attenuated naloxone-appropriate responding. D-cycloserine attenuated naloxone-induced increases in visual analog scale ratings of "like naloxone" and scores on the Lysergic Acid Diethyl Amide subscale of the Addiction Research Center Inventory (D. R. Jasinski, 1977; W. R. Martin, J. W. Sloan, J. D. Sapiro, & D. R. Jasinski, 1971). Naloxone attenuated D-cycloserine-induced increases in systolic blood pressure. These results suggest that D-cycloserine at doses up to 500 mg/70 kg may have some limited usefulness in relieving symptoms of opioid withdrawal.

Adult↗
PubMed1996

D-cycloserine adjuvant therapy to molindone in the treatment of schizophrenia.

This preliminary investigation examined the therapeutic efficacy of two doses of oral D-cycloserine (5 and 15 mg p.o. b.i.d.) administered as an adjuvant to molindone (150 mg p.o. q.d.) in the treatment of schizophrenia. D-Cycloserine is an agonist at the N-methyl-D-aspartate (NMDA) subclass of glutamate receptor complex. An NMDA agonist intervention was studied because of the schizophreniform psychosis precipitated by phencyclidine (PCP), which is a noncompetitive antagonist at the NMDA glutamate receptor. The PCP model of schizophrenia is regarded as the most comprehensive pharmacological model of this disorder. In this preliminary, placebo-controlled, double-blind, parallel-group study, the measures of treatment efficacy were the Brief Psychiatric Rating Scale, Schedule for the Assessment of Negative Symptoms, and Clinical Global Impression Scale. The final scores for each item of the outcome measures employed were based on the consensus of at least two trained raters who were present during each rating interview. In the 13 subjects evaluated, although the D-cycloserine was well tolerated, neither dose seemed to possess adjuvant therapeutic efficacy. However, since another recent report of nine patients with schizophrenia treated for 2 weeks with a slightly higher dose of D-cycloserine (50 mg/day) described significant clinical and neuropsychological improvement, further study of the adjuvant potential of slightly higher doses of D-cycloserine seems warranted. Additionally, there might be a therapeutic window for D-cycloserine dosing, as daily doses of 250 mg have been associated with symptom worsening.

Administration, Oral↗
PubMed1988

Regulation of Bacillus subtilis macrofiber twist development by D-cycloserine.

The effect of D-cycloserine on the establishment of twist states in Bacillus subtilis macrofibers was examined. Macrofibers produced in the presence of the drug differed in twist compared with those produced in its absence. The degree of twist alteration was dependent on the concentration of D-cycloserine in the growth medium. Macrofibers of different twist states representative of the entire twist spectrum from tight left-handedness to tight right-handedness were produced in strains FJ7 and C6D in four different ways: by control of the concentration of D-alanine, magnesium sulfate, or ammonium sulfate in the growth medium or by control of the growth temperature. The structures so produced were used to determine the effect of D-cycloserine on twist establishment starting from different twist states throughout the twist spectrum. In all but one case, twist resulting from growth in the presence of D-cycloserine was further towards the left-hand end of the twist spectrum than that produced in its absence, the exception being the unusual left-handed twist states produced in strains C6D and the closely related RHX 11S at high D-alanine concentrations described here. Studies of the interaction between D-cycloserine and D-alanine both used alone and used independently with the other twist-modifying systems (temperature, magnesium sulfate, and ammonium sulfate) revealed that changes in twist resulting from D-cycloserine were always in the opposite direction from those resulting from D-alanine. This antagonism suggests that the biochemical mechanism of twist regulation involves the metabolism of peptidoglycan, particularly reactions involving D-alanine or the dipeptide D-alanyl-D-alanine. This antagonism suggests that the biochemical mechanism of twist regulation involves the metabolism of peptidoglycan, particularly reactions involving D-alanine or the dipeptide D-alanyl-D-alanine. The possibility that peptidoglycan cross-linking is involved is discussed.

Alanine↗
PubMed1996

D-cycloserine added to clozapine for patients with schizophrenia.

OBJECTIVE: The effects of D-cycloserine added to clozapine were assessed and compared with previous results for D-cycloserine plus conventional neuroleptics. METHOD: Ten schizophrenic outpatients receiving clozapine entered consecutive 2-week trials of placebo and D-cycloserine at 5, 15, 50, and 250 mg/day. Clinical evaluations were videotaped and scored by a rater blind to the sequence of assessments. RESULTS: There was a significant dose effect of D-cycloserine on scores on the Scale for the Assessment of Negative Symptoms (SANS); the 50-mg dose produced a mean 21% increase in SANS score. The patients had significantly higher baseline serum glutamate concentrations than the patients receiving typical neuroleptics in the previous trial. Baseline glutamate level and change in glycine level significantly correlated with response of negative symptoms to 50-mg D-cycloserine. CONCLUSIONS: The improvement of negative symptoms with D-cycloserine previously observed in patients receiving typical neuroleptics did not occur in patients treated with clozapine.

Adult↗
PubMed2002

Cycloserine fatty acid derivatives as prodrugs: synthesis, degradation and in vitro skin permeability.

Various 4,5-dihydroisoxazol-3-yl fatty acid ester derivatives of cycloserine were synthesized to improve skin permeation of cycloserine. The ester derivatives were prepared by using the tert-butoxycarbonyl (t-Boc) protection strategy. The 4,5-dihydroisoxazol-3-yl esters were readily hydrolysed in an aqueous buffer solution, and the degradation profiles showed both specific acid and specific base catalysis. In 50% human serum the formation of cycloserine was observed, but enzymatic catalysis was limited. Delivery through hairless mouse skin was investigated, and the apparent permeability coefficient was measured based on the flux of cycloserine into the receptor phase. The skin permeation of cycloserine across the hairless mouse skin was increased up to 20-fold by the fatty acid esters. The 4,5-dihydroisoxazol-3-yl fatty acid esters of cycloserine can therefore be considered as new topical prodrugs with the potential use in treatment of various skin infections.

Animals↗
PubMed1963

INHIBITION OF THE GROWTH OF AGENTS OF THE PSITTACOSIS GROUP BY D-CYCLOSERINE AND ITS SPECIFIC REVERSAL BY D-ALANINE.

Moulder, James W. (University of Chicago, Chicago, Ill.), Dorothy L. Novosel, and Julius E. Officer. Inhibition of the growth of agents of the psittacosis group by d-cycloserine and its specific reversal by d-alanine. J. Bacteriol. 85:707-711. 1963.-d-Cycloserine inhibited multiplication of four members of the psittacosis group in chick embryo yolk sac. d-Alanine reversed each inhibition. In infections with the agent of mouse pneumonitis, the most sensitive member of the psittacosis group tested, d-alanine competitively antagonized the growth inhibition produced by d-cycloserine. Of a number of other potential reversing agents, only dl-alanyl-dl-alanine reversed the effect of d-cycloserine on mouse pneumonitis agent. The significance of the susceptibility of the psittacosis group to d-cycloserine is discussed in light of the known mode of action of this antibiotic on bacteria.

Alanine↗
PubMed1988

Spectrophotometric determination of cycloserine with 9-methoxyacridine.

Spectrophotometric assay for cycloserine based on the interaction of the drug with 9-methoxyacridine as a chromogenic agent is described. The highly colored substituted acridine product was identified as 9-(d-4-imino-3-isoxazolidinone)acridine. Color development was affected by time and temperature of heating and by the quantity of 9-methoxyacridine reagent utilized. The absorbance at 438 nm is linearly proportional to concentrations of cycloserine with a detection limit of 0.3 microgram/mL. The optimum range for the assay of cycloserine was from 5.0 X 10(-6) to 3.0 X 10(-4) M (correlation coefficient = 0.9999, n = 6). When applied to cycloserine capsules labeled to contain 250 mg, the proposed method gave mean recoveries of 101.84 +/- 0.48%. The procedure is sufficiently sensitive, precise, and accurate for the determination of cycloserine in its dosage form.

Acridines↗
PubMed1991

Actions of D-cycloserine at the N-methyl-D-aspartate-associated glycine receptor site in vivo.

The antibiotic, D-cycloserine has been shown to be a partial agonist at the N-methyl-D-aspartate (NMDA)-coupled, strychnine-insensitive glycine receptor by in vitro receptor binding. This partial agonism was further investigated in an in vivo system, by monitoring changes in levels of cyclic guanosine-monophosphate (cGMP), a well characterized second messenger response, mediated by the NMDA receptor complex, in the cerebellum of the mouse. Parenteral injections of D-cycloserine produced a biphasic dose-response curve which suggested partial agonism. In support of this contention, when intracerebellar injections were made together with D-serine, a glycine agonist, D-cycloserine attenuated the N-methyl-D-aspartate receptor-mediated increase in levels of cGMP. Likewise, systemic administration of D-cycloserine attenuated increases in cGMP induced by pentylenetetrazol. These data are relevant to the study of N-methyl-D-aspartate-mediated neurotransmission, since D-cycloserine is a parenterally bioavailable compound, with both agonist and depressant properties at the N-methyl-D-aspartate-associated glycine receptor.

Animals↗
PubMedDate not supplied

D-cycloserine, a novel cognitive enhancer, improves spatial memory in aged rats.

D-cycloserine, a partial agonist of the NMDA receptor-associated glycine site, can enhance cognition. The present experiment examines the behavioral effects of D-cycloserine on cognitive deficits in male Fischer-344 rats, 24 months old. Rats 24 months old (n = 42) received either vehicle or one of 3 doses of D-cycloserine prior to testing. Young rats, 4 months old (n = 13), received vehicle prior to testing. Place discrimination and repeated acquisition were tested in the water maze and a variety of sensorimotor tasks were given. Aging impaired performance in all tasks. D-cycloserine improved performance in place discrimination and repeated acquisition. No doses affected sensorimotor function. These results support the hypothesis that D-cycloserine has cognition enhancing properties and that it may be useful in treating disorders involving cognitive impairment.

Aging↗
PubMed1989

D-cycloserine: a ligand for the N-methyl-D-aspartate coupled glycine receptor has partial agonist characteristics.

We have previously shown that D-cycloserine displaces [3H]glycine binding to a recognition site with properties consistent with an N-methyl-D-aspartate (NMDA) receptor modulatory site. Additionally, D-cycloserine positively modulates the NMDA receptor as evidenced by its dose-dependent enhancement of [3H]1-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP) binding to the NMDA receptor-coupled ionophore. Further evaluation of this compound indicates that the maximal stimulation of [3H]TCP binding induced by D-cycloserine is lower than that produced by other compounds acting at the NMDA receptor associated glycine modulatory site (glycine and D-serine). Moreover, the stimulation of [3H]TCP binding induced by D-cycloserine in the presence of various fixed concentrations of glycine results in a family of dose-response curves which asymptotically converge to 40-50% of the maximal stimulation induced by glycine alone. These results are consistent with D-cycloserine acting as a partial agonist of the NMDA receptor via its interaction with the coupled glycine modulatory site.

Animals↗
PubMed1984

L-cycloserine inhibition of sphingolipid synthesis in the anaerobic bacterium Bacteroides levii.

L-cycloserine was found to significantly inhibit the activity of the first enzyme of the sphingolipid pathway when added to growing cultures of Bacteroides levii. The effect of cycloserine on the synthesis of the sphingolipids showed that ceramidephosphorylethanolamine was inhibited to a greater degree than ceramidephosphorylglycerol, although synthesis of both was significantly inhibited by cycloserine as determined by [32P] incorporation and phosphorus determination. In contrast, synthesis of phosphatidylethanolamine and phosphatidylglycerol was not inhibited by L-cycloserine at 100 micrograms/ml. Peturbation of sphingolipid synthesis by L-cycloserine may therefore provide a useful tool for the study of the function of these membrane lipids.

Anaerobiosis↗
PubMed2000

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.

Animals↗
PubMed2003

D-cycloserine for the treatment of ataxia in spinocerebellar degeneration.

We studied the effects of D-cycloserine, a partial NMDA receptor allosteric agonist, on ataxia in patients with spinocerebellar degeneration. Fifteen Japanese ataxic patients enrolled in a 14-day single-blind trial of D-cycloserine (daily oral dose of 50 mg) following a 14-day single-blind placebo phase. At the end of the D-cycloserine administration, there was a significant reduction in the posture, gait and total score of the international cooperative ataxia rating scale and in the time for walking and speech tasks. D-Cycloserine was well-tolerated and no adverse effect was observed. D-Cycloserine may have therapeutic efficacy for spinocerebellar ataxia.

Adult↗
PubMed1997

Behavioral and neuroendocrine effects of the partial NMDA agonist D-cycloserine in healthy subjects.

The effect of D-cycloserine, a partial agonist of the N-Methyl-D-Aspartate (NMDA) receptor, were assessed in a (neuroendocrine) challenge paradigm to to examine NMDA systems in male healthy volunteers, using a double-blind, placebo-controlled crossover design. Oral D-cycloserine (15, 50, and 150 mg) was readily absorbed and its plasma concentration increased dose-dependently. Behavioral and hormonal responses were measured for 240 minutes after administration of the drug. D-cycloserine was well tolerated and did not induce side-effects according to the Visual Analog Scales (VAS), the Brief Psychiatric Rating Scale (BPRS) and the Adverse Events Checklist (AEC) & codes. D-cycloserine failed to elicit a neuroendocrine response as evaluated by cortisol, prolactin, and luteinizing hormone (LH) plasma levels. The present result suggests that D-cycloserine can readily be administered to healthy volunteers but that, in the dosages used, neuroendocrine secretion fails to serve as a model for testing NMDA receptor function in humans.

Adult↗
PubMed2004

Comparative effects of glycine and D-cycloserine on persistent negative symptoms in schizophrenia: a retrospective analysis.

Phencyclidine (PCP), ketamine and other N-methyl-D-aspartate (NMDA) antagonists induce schizophrenia-like symptoms in normal volunteers, suggesting that endogenous dysfunction or dysregulation of NMDA receptors may contribute to the pathophysiology of schizophrenia. Glycine and D-cycloserine are potential treatments for persistent negative symptoms of schizophrenia. Seventeen patients were identified who participated in double-blind trials of both agents. Significant clinical improvement was observed during both trials. However, the degree of improvement was significantly larger during glycine, than D-cycloserine, treatment on both an individual subject and group level. Previous analyses have documented effectiveness of glycine, and to a lesser extent D-cycloserine, within separate patient populations. This analysis provides the first direct comparison of glycine and D-cycloserine effects within the same population, and suggests first, that NMDA agonists are effective in treatment of persistent negative symptoms of schizophrenia, and, second, that full agonists, such as glycine and D-serine, may be more effective than partial agonists such as D-cycloserine. Similar findings are apparent when data are considered from all trials with NMDA agonists performed to date. Overall, the findings indicate that agents which potentiate NMDA transmission may be therapeutically beneficial in treatment of persistent symptoms of schizophrenia.

Adult↗