User:Hifzasakhi/Cycloserine

Cycloserine is a second-line drug used in the treatment of tuberculosis. It is restricted for extremely drug resistant strains. Interestingly, it was found that this drug can also penetrate into the central nervous system (CNS). Since then, cycloserine has also been found to aid in the treatment of various neurological disorders, due to its effects as a selective partial agonist of the N-methyl-D-aspartate (NMDA) glutamatergic receptors. Specifically, it affects the glycine-binding sites which are important for opening NMDA channels. . Cycloserine is stable under basic conditions but breaks down into serine and hydroylamine under acidic conditions. .

Cerebral lobes

Antibiotic Use

It has been used in the treatment of tuberculosis and occasionally, for urinary tract infections (UI).

Mechanism of Action As An Antibiotic

DCS works an antibiotic by inhibiting cell-wall biosynthesis in bacteria. As a cyclic analogue of D-alanine, it acts against two crucial enzymes important in the cytosolic stages of peptidoglycan synthesis: alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl). The first enzyme is a pyridoxal 5-phosphate-dependent enzyme which converts the L-alanine to the D-alanine form. The second enzyme is involved in joining of these two residues by catalyzing the formation of the ATP-dependant D-alanine-D-alanine dipeptide bond between the resulting D-alanine molecules.

Neurocognitive Use

D-Cycloserine

This is the dextrorotatory form of the drug. This type has been investigated in numerous studies focusing on fear extinction and addictions in the human and animal models.

Implications in Fear Extinction and Memory Consolidation

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. These disorders and phobias result from and get perpetuated through pathological fear memory. Pavlovian fear conditioning is a notable animal model to induce this conditioning during studies and provides an avenue to examine mechanisms of learning and memory. In this conditioning model, a neutral and non-aversive 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). After these two stimuli are presented together a few times, the animals quickly learn to associate the two stimuli together, and elicit a learned response, such as freezing (termed as the conditioned response, CR).

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

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

Interaction with the NMDA Receptor

Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system. One of the ionotropic receptors that glutamate activates is the NMDA receptor. NMDA glutamatergic receptors are tetrameric, consisting of two NR1 subunits (which bind glycine) and NR2 subunits (which bind glutamate). These receptors are important for synaptic plasticity and development processes in the brain. D-Cycloserine (DCS) acts as a partial agonist at NMDA receptors with NR2A,NR2B, or NR2D subunits. DCS has lower efficacy than the endogenous agonists glycine or D-serine at NR1/NR2A, NR1/NR2B and NR1/NR2D. However, at the NR1/NR2C receptors, DCS has higher efficacy than endogenous glycine or D-serine. It has been hypothesized that the efficacy of glycine agonists entails the differential communication between the NR2 subtypes and the NR1 receptors, where the residues of the NR1 domain may interact differently with the NR2 subtypes, especially during instances of intra-protein conformational changes at the dimer interface. 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. Similarly, recordings performed with a continuous saturating concentration of the endogenous agonists glycine and glutamate showed that DCS decreased efficiency of gating by slowing forward rate constant preceding rapid pore openings.

Phobias

These refer to various things which elicit fear in people.

Acrophobia

Acrophobia is the fear of heights.

Ophidiophobia

Ophidiophobia refers to the phobia of snakes.

Social Anxiety Disorder

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

Obsessive-Compulsive Disorder

This refers to when people want to do certain tasks.

Depression

This is the mental state when people feel down and sad.

Drug Addiction

Cocaine addictions result in drug-seeking and drug-taking behaviors. These behaviors result from pairing cocaine use with the external cues which results in conditioning and memory consolidation. The conditioned response are cravings and relapse. Although cue exposure (extinction) therapy is currently being employed to help patients counter the motivation for drug seeking and seeking 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 impacted with cocaine use). Plus, there are no promising pharmaceuticals for treating drug addictions in the market currently and since cocaine addiction is a major problem in modern society, it is imperative that better therapeutics can be created to reverse this problem.

There is considerable interest in using DCS, which has already been found to help with fear extinction in various animal as well as human model systems. Extinction of drug addiction is analogous to extinction of fear, in which active learning processes are involved. 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.

Studies employing various animal model systems to assess the efficacy of DCS in treatment of cocaine addictions have yielded mixed results. For instance, in a study conducted in 2009, it was 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. 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. The study also found that DCS was effective only when used administered in conjunction with explicit extinction therapy.

L-Cycloserine

This is the levorotary version of the drug.

Reduction of Cerebroside Levels

This is implicated in the formation of myelin, although the results of some studies have been conflicting.

Increased GABA Levels

L-cycloserine has been shown to irreversibly inhibit GABA pyridoxal 5′-phosphate (PLP)-dependent aminitransferase in E.Coli, as well in the brains of various animals, such as pirgs, cats, and monkeys in a time-dependent manner. Likewise, L-cycloserineincreades levels of the r gamma-aminobutyric acid (GABA) , an inhibitory neurotransmitter in vivo.