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Title: Cycloserine  
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Subject: Serine, Cell envelope antibiotic, Tuberculosis, Hypotaurine, 2-Oxazolidone
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Systematic (IUPAC) name
Clinical data
Trade names Seromycin
Licence data US FDA:
Pregnancy cat.
  • C
Legal status
Pharmacokinetic data
Bioavailability ~70% to 90%
Metabolism Hepatic
Half-life 10 hrs (normal renal function)
Excretion Renal
CAS number  YesY
ATC code J04
ChemSpider  YesY
Chemical data
Formula C3H6N2O2 
Mol. mass 102.092 g/mol

Cycloserine (4-amino-3-isoxazolidinone) is a drug sold under the brand name Seromycin. It is an antibiotic effective against Mycobacterium tuberculosis. Since the discovery that cycloserine is able to penetrate into the central nervous system, numerous studies have been conducted to assess the efficacy of cycloserine for psychiatric disorders. It has been found to be effective in the treatment of some neurological disorders, due to its effect as a selective partial agonist of the N-methyl-D-aspartic acid (NMDA) glutamatergic receptors found in the basolateral nucleus of the amygdala. Specifically, cycloserine affects the glycine-binding sites which are important for opening these NMDA channels.[1][2] Cycloserine is stable under basic conditions, with the greatest stability at pH = 11.5.[3] Under mildly acidic conditions, it breaks down into hydroxylamine and D-serine, whereas under prolonged hydrolysis, it breaks down into hydroxylamine and DL-serine.[3][4]

The name "cycloserine" is a misnomer because the compound has an extra nitrogen atom compared to serine. (It also has one fewer oxygen atom and one fewer hydrogen atom than serine.)

Antibiotic uses


For the treatment of tuberculosis, cycloserine is classified as a second-line drug, i.e. its use is only considered if one or more first-line drugs cannot be used. Hence, cycloserine is restricted for use only against multiple drug-resistant and extensively drug-resistant strains of M. tuberculosis. Another reason for limited use of this drug is the neurological side effects it causes, since it is able to penetrate into the central nervous system (CNS) and cause headaches, drowsiness, depression, dizziness, vertigo, confusion, paresthesias, dysarthria, hyperirritability, psychosis, convulsions, and shaking (tremors).[1][5] Overdose of cycloserine may result in paresis, seizures, and coma, while alcohol consumption may increase the risk of seizures.[5] Coadministration of pyridoxine can reduce the incidence of some of these CNS side effects (e.g. convulsions) caused by cycloserine.

Mechanism of antibiotic action

Cycloserine works as an antibiotic by inhibiting cell-wall biosynthesis in bacteria.[6][7] As a cyclic analogue of D-alanine, cycloserine acts against two crucial enzymes important in the cytosolic stages of peptidoglycan synthesis: alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl).[7] The first enzyme is a pyridoxal 5'-phosphate-dependent enzyme which converts the L-alanine to the D-alanine form.[7] The second enzyme is involved in joining two of these D-alanine residues together by catalyzing the formation of the ATP-dependent D-alanine-D-alanine dipeptide bond between the resulting D-alanine molecules.[7] If both of these enzymes are inhibited, then D-alanine residues cannot form and previously formed D-alanine molecules cannot be joined together.[7] This effectively leads to inhibition of peptidoglycan synthesis.[7]

Psychiatric uses


The dextrorotary form of cycloserine has been investigated in numerous studies focusing on fear extinction and addictions in the human and animal model systems.

Implications in fear conditioning, memory consolidation, and extinction

D-Cycloserine, when used in conjunction with exposure-based cognitive behavior therapy, helps with fear extinction in an array of anxiety- and stress-inducing disorders.[8][9] These disorders and phobias are a result of and get perpetuated through pathological fear memory.[8][9] Pavlovian fear conditioning is a notable animal model to induce this form of conditioning in the laboratory and provides an avenue to examine mechanisms of learning and memory.[8][9] In this conditioning model, a neutral and nonaversive stimulus such as light or tone (termed as the conditioned stimulus, CS) is paired with an aversive stimulus, such as an electrical shock to the foot (termed as the unconditioned stimulus, US).[8][9] After these two stimuli are presented together a few times, the animals quickly learn to associate these stimuli together, and elicit a learned response, such as freezing or sweaty fingers (termed as the conditioned response, CR).[8][9]

The process of extinction (associative learning) entails unlearning this association between the CS and US, and results in a decrease in the frequency of the CR being elicited.[8][9] This occurs by repeatedly presenting the CS without the US.[8][9] By repeating this numerous times, the animals learn to not associate the stimuli together, which can be examined by the decrease in frequency of the CR being elicited.[8][9] Similar to fear conditioning, extinction can be broken down into several categories, such as acquisition (training), consolidation, and retrieval of extinction memory.[8][9] Understanding the circuitry and mechanisms of extinction has strong implications for development of novel therapeutics to be used in conjunction with exposure-based cognitive behavioral therapy for patients suffering from anxiety and stress inducing disorders.[8][9] Another reason for development of pharmacological therapeutics is due to the fact that a decrease in exhibition of the CR may not always be permanent since episodes of renewal can also result.[8][9] Relapse of CR can also occur gradually with time, in lieu of other aversive events or with reinstatement (re-presentation) of the US.[8][9] Likewise, with exposure-based cognitive therapies, an impending limitation is the high rates of relapse.[8][9] For all of these reasons, there is considerable interest in the creation of pharmacological treatments to enhance extinction and reduce relapse rates.[8][9]

Many studies have shown the extinction process is dependent upon N-methyl-D-aspartate (NMDA) receptors in the basolateral amygdala (BLA).[8][9] D-Cycloserine (DCS) is a partial agonist of the NMDA receptor, where it increases excitatory NMDA neurotransmission by binding to the glycine-binding sites.[8][9] DCS has been shown to enhance extinction retention in rats.[8][9] It enhances fear extinction during within-sessions which suggests that DCS facilitates the learning aspect of extinction.[8][9] Though DCS has been shown to reduce some occurrences of relapse and reinstatement in humans and rats, it does not seem to prevent renewal.[8][9] Nevertheless, considerable interest exists in employing DCS as a treatment for psychiatric disorders, due to its beneficial therapeutic effects in several studies which have employed DCS for anxiety disorders, acrophobia, post-traumatic stress disorder, obsessive-compulsive disorder, and panic disorders.[8][9]

Interaction with the NMDA receptor

NMDA receptor

Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system. One of the ionotropic receptors which glutamate activates is the NMDA receptor.[10] NMDA glutamatergic receptors are tetrameric, consisting of two NR1 subunits (which bind glycine) and two NR2 subunits (which bind glutamate).[10] These receptors are important for synaptic plasticity and development processes in the brain.[10] D-Cycloserine acts as a partial agonist at NMDA receptors with NR2A, NR2B, NR2C, or NR2D subunits.[10] DCS has lower efficacy than the endogenous agonists glycine or D-serine at the NR1/NR2A, NR1/NR2B and NR1/NR2D receptors.[10] However, at the NR1/NR2C receptors, DCS has higher efficacy than endogenous glycine or D-serine.[10] The efficacy of glycine agonists is hypothesized to entail the differential communication between the NR2 subtypes and the NR1 receptors.[10] This is due to the fact that residues of the NR1 domain may interact differently with the NR2 domain subtypes, especially during instances of intra-protein conformational changes at the dimer interface.[10] This differential dimer interface interaction may explain why DCS has a higher relative efficacy than the endogenous agonists glycine or D-serine at NR1/NR2C receptors.[10] Likewise, recordings performed with a continuous saturating concentration of the endogenous agonists glycine and glutamate have also shown that DCS decreases efficiency of gating by slowing forward rate constant preceding rapid pore openings.[10] These psychotropic responses are related to D-cycloserine's action as a partial agonist of the neuronal NMDA receptor for glutamate and have been examined in implications with sensory-related fear extinction in the amygdala, and extinction of cocaine seeking in the nucleus accumbens.[11][12]

Use for social anxiety disorder


Typically, exposure therapy is employed as a psychotherapy to help patients suffering from social anxiety disorder.[2] Nevertheless, many patients still exude symptoms even after therapy.[2] To help such patients, in 2006, a study found that when 50 mg of DCS was administered an hour prior to exposure-based cognitive behavior therapy (CBT) sessions, it resulted in a much higher anxiety reduction as compared to the administration of a placebo with CBT.[2] Additionally, the researchers also found that when DCS was given with exposure-based CBT for social performance situations such as public speaking, this also resulted in reduction of social anxiety.[2]

Use for substance dependence disorder (drug addiction)

Cocaine powder

Cocaine addictions result in drug-seeking and drug-taking behaviors.[13] These behaviors can be explained by the incentive sensitisation theory of addiction, in which constant drug use elicits drug-seeking behaviors due to associative learning processes which occur through Pavlovian conditioning.[14] During this time, drug cues gain 'motivational salience' due to sensitisation of the dopaminergic transmission in the nucleus accumbens/ventral striatal reward pathway.[14] Gradually, this culminates in drug cues taking over attentional processes and results in cravings, drug-seeking, and relapse.[14] A notable instance of this can be seen with cocaine addictions, which arise from pairing cocaine use with the external cues which results in conditioning and memory consolidation. The conditioned responses are cravings and relapse.[13] Although cue exposure (extinction) therapy is currently being employed to help patients counter the motivation for drug-seeking and drug-taking behaviors, this therapy is not effective consistently, possibly due to its context-dependency, as well as reliance on sound memory systems for extinction learning (which are possibly impaired with sustained cocaine use).[13] Plus, no promising pharmaceuticals are available for treating drug addictions in the market currently, and since cocaine addiction is a major problem in modern society, creating better therapeutics is imperative to reverse this problem.[13] As a result, considerable interest in using DCS exists, which has already been found to help with fear extinction in various animal, as well as human, model systems.[13] Extinction of drug addiction is analogous to extinction of fear, in which active learning processes are involved.[13] In particular, animal studies have shown that NMDA receptors are notably important for acquisition and consolidation of cocaine-cue associations in addition to extinction and reconsolidation.[13]

Studies employing various animal model systems to assess the efficacy of DCS in treatment of cocaine addictions have yielded mixed results. For instance, a study in 2009 found that DCS administration two hours prior to each extinction session acutely increased cravings and susceptibility to cocaine cues in cocaine-dependant persons by stimulation of glutamatergic systems.[15] However, in 2010, another study found that taking DCS prior to the extinction training lead to reacquisition of cocaine self-administration in rats and monkeys through augmentation of consolidation of extinction learning.[13] This study also found that DCS was effective only when used administered in conjunction with explicit extinction therapy.[13] More studies must be conducted to reconcile and substantiate these findings.

A similar type of discrepancy is also seen in studies examining the efficacy of DCS on facilitating extinction in participants with nicotine addictions in conjunction with cue exposure therapy.[16] Researchers conducting a study in 2009 hypothesized that when nicotine-dependent persons receive DCS in conjunction with cue exposure therapy, they would exhibit a reduced skin conductance response in comparison to the participants receiving a placebo with cue exposure therapy.[16] Their data suggested, when DCS was administered with cue exposure therapy one hour prior to each of the two 4.5-h experimental sessions, the participants indeed had a lower skin conductance response.[16] Participants receiving the DCS also expressed a reduced urge to smoke in that study, although the evidence did not indicate a change in their smoking behavior.[16] However, another study, conducted in 2011, found thee administration of DCS reduced nicotine self-administration in rats with lower baselines levels of response, but was actually detrimental for rats with higher baseline levels.[17] They found that chronic administration of DCS at 40 mg/kg was effective in creating these responses, implying NMDA receptors may potentially be implicated in individuals who are trying to quit smoking.


Chemical diagram
L-Cycloserine structure

The levorotary version of the drug, L-cycloserine, has been shown to irreversibly inhibit GABA pyridoxal 5′-phosphate-dependent aminitransferase in E. coli, as well in the brains of various animals, such as pigs, cats, and monkeys in a time-dependent manner.[4] This results in increased levels of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in vivo, since its breakdown is halted by the inhibition of GABA transaminase.[4][18] Small doses of LCS have been suggested to reduce hyperexcitability in the brain in acutely treated and subchronically treated animals through GABAnergic inhibition.[19] Furthermore, peak effects of this inhibition can be seen 3-4 hr after a single intraperitoneal injection.[19] LCS has also been implicated in moderately increasing alanine levels and slightly decreasing aspartate, glutamate, and glycine levels in the brain.[19] Small doses of LCS have been shown to reduce levels of cGMP in rat cerebella, whereas small doses administered to cats attentuated the hypothalamically elicited rage reaction.[19] Larger doses of LCS impaired performance of mice in various tests, such as the rotarod, chimney, and horizontal wire tests.[19] In rats, the larger doses resulted in reduction of spontaneous locomotor activity.[19]


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