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88-484: γ-Hydroxybutyric acid , also known as gamma -hydroxybutyric acid , GHB , or 4-hydroxybutanoic acid , is a naturally occurring neurotransmitter and a depressant drug . It is a precursor to GABA , glutamate , and glycine in certain brain areas. It acts on the GHB receptor and is a weak agonist at the GABA B receptor. GHB has been used in the medical setting as a general anesthetic and as treatment for cataplexy , narcolepsy , and alcoholism . The substance

176-507: A gland or muscle cell . Neurotransmitters are released from synaptic vesicles into the synaptic cleft where they are able to interact with neurotransmitter receptors on the target cell. Some neurotransmitters are also stored in large dense core vesicles . The neurotransmitter's effect on the target cell is determined by the receptor it binds to. Many neurotransmitters are synthesized from simple and plentiful precursors such as amino acids , which are readily available and often require

264-421: A withdrawal syndrome of insomnia , anxiety, and tremor that usually resolves within three to twenty-one days. The withdrawal syndrome can be severe producing acute delirium and may require hospitalization in an intensive care unit for management. Management of GHB dependence involves considering the person's age, comorbidity and the pharmacological pathways of GHB. The mainstay of treatment for severe withdrawal

352-425: A better understanding of GHB's mode of action. Analogues of GHB such as 3-methyl-GHB, 4-methyl-GHB , and 4-phenyl-GHB have been shown to produce similar effects to GHB in some animal studies, but these compounds are even less well researched than GHB itself. Of these analogues, only 4-methyl-GHB (γ-hydroxyvaleric acid, GHV) and a prodrug form γ-valerolactone (GVL) have been reported as drugs of abuse in humans, and on

440-788: A date-rape drug that received national attention in the United States. In early 1999, a 15-year-old girl, Samantha Reid of Rockwood, Michigan , died from GHB poisoning. Reid's death inspired the legislation titled the "Hillory J. Farias and Samantha Reid Date-Rape Drug Prohibition Act of 2000". This is the law that made GHB a Schedule 1 controlled substance. In the United Kingdom, British serial killer Stephen Port administered GHB to his victims by adding it to drinks given to them, raping them, and murdering four of them in his flat in Barking , East London . GHB can be detected in hair. Hair testing can be

528-465: A diagnosis of poisoning in hospitalized patients, to provide evidence in an impaired driving, or to assist in a medicolegal death investigation. Blood or plasma GHB concentrations are usually in a range of 50–250 mg/L in persons receiving the drug therapeutically (during general anesthesia), 30–100 mg/L in those arrested for impaired driving, 50–500 mg/L in acutely intoxicated patients and 100–1000 mg/L in victims of fatal overdosage. Urine

616-699: A feeling of euphoria, and larger doses create deleterious effects such as reduced motor function and drowsiness. The sodium salt of GHB has a salty taste. Other salt forms such as calcium GHB and magnesium GHB have also been reported, but the sodium salt is by far the most common. Some prodrugs , such as γ-butyrolactone (GBL), convert to GHB in the stomach and bloodstream. Other prodrugs exist, such as 1,4-butanediol (1,4-B). GBL and 1,4-B are normally found as pure liquids, but they can be mixed with other more harmful solvents when intended for industrial use (e.g. as paint stripper or varnish thinner). GHB can be manufactured with little knowledge of chemistry, as it involves

704-448: A few seconds. The most prevalent transmitter is glutamate , which is excitatory at well over 90% of the synapses in the human brain. The next most prevalent is gamma-Aminobutyric Acid, or GABA, which is inhibitory at more than 90% of the synapses that do not use glutamate. Although other transmitters are used in fewer synapses, they may be very important functionally: the great majority of psychoactive drugs exert their effects by altering

792-471: A minor portion (1–5%) of the administered GHB dose is excreted unchanged in the urine. Studies have shown that the maximum concentration of GHB in urine appears within 1 hour and rapidly declines thereafter. The vast majority (95–98%) undergoes extensive metabolism in the liver. GHB is broken down through a series of enzymatic pathways. The primary route involves conversion to succinic semialdehyde (SSA) by either GHB dehydrogenase (ADH) or GHB transhydrogenase. SSA

880-403: A modulatory effect. Purine neurotransmitters, like ATP , are derived from nucleic acids. Metabolic products such as nitric oxide and carbon monoxide have also been reported to act like neurotransmitters. Neurotransmitters are generally stored in synaptic vesicles , clustered close to the cell membrane at the axon terminal of the presynaptic neuron. However, some neurotransmitters, like

968-406: A neuron may release more than one transmitter from its synaptic terminal . Various techniques and experiments such as staining , stimulating, and collecting can be used to identify neurotransmitters throughout the central nervous system . Neurons communicate with each other through synapses , specialized contact points where neurotransmitters transmit signals. When an action potential reaches

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1056-463: A receptor agonist is morphine , an opiate that mimics effects of the endogenous neurotransmitter β-endorphin to relieve pain. Other drugs interfere with the deactivation of a neurotransmitter after it has been released, thereby prolonging the action of a neurotransmitter. This can be accomplished by blocking re-uptake or inhibiting degradative enzymes. Lastly, drugs can also prevent an action potential from occurring, blocking neuronal activity throughout

1144-423: A selective GABA B antagonist, quickly reverses GHB overdose in mice. However, this treatment has yet to be tried in humans, and it is unlikely that it will be researched for this purpose in humans due to the illegal nature of clinical trials of GHB and the lack of medical indemnity coverage inherent in using an untested treatment for a life-threatening overdose. GHB may be quantitated in blood or plasma to confirm

1232-496: A sleeping agent, wherein they awake suddenly after several hours of GHB-induced deep sleep. That is to say that, over time, the concentration of GHB in the system decreases below the threshold for significant GABA B receptor activation and activates predominantly the GHB receptor, leading to wakefulness. Recently, analogs of GHB, such as 4-hydroxy-4-methylpentanoic acid (UMB68) have been synthesised and tested on animals, in order to gain

1320-497: A small number of biosynthetic steps for conversion. Neurotransmitters are essential to the function of complex neural systems. The exact number of unique neurotransmitters in humans is unknown, but more than 100 have been identified. Common neurotransmitters include glutamate , GABA , acetylcholine , glycine , dopamine and norepinephrine . Neurotransmitters are generally synthesized in neurons and are made up of, or derived from, precursor molecules that are found abundantly in

1408-679: A survey in the Netherlands published in 2010 found that the proportion of drug-related rapes where GHB was used appeared to be greatly overestimated by the media. More recently, a study in Western Australia reviewed the pre-hospital context given in medical records around emergency department presentations with analytical confirmation of GHB exposure. This study found that most cases reported daily dosing and subsequent accidental overdose rather than their presentation being associated with date-rape. There have been several high-profile cases of GHB as

1496-747: A topical anesthetic (eye drops) Prevents destruction of dopamine Prodrug Prodrugs are often designed to improve bioavailability when a drug itself is poorly absorbed from the gastrointestinal tract . A prodrug may be used to improve how selectively the drug interacts with cells or processes that are not its intended target. This reduces adverse or unintended effects of a drug, especially important in treatments like chemotherapy , which can have severe unintended and undesirable side effects. Compound that undergoes biotransformation before exhibiting pharmacological effects. Note 1 : Modified from ref. Note 2 : Prodrugs can thus be viewed as drugs containing specialized nontoxic protective groups used in

1584-495: A transient manner to alter or to eliminate undesirable properties in the parent molecule. Many herbal extracts historically used in medicine contain glycosides (sugar derivatives) of the active agent, which are hydrolyzed in the intestines to release the active and more bioavailable aglycone . For example, salicin is a β-D-glucopyranoside that is cleaved by esterases to release salicylic acid . Aspirin , acetylsalicylic acid, first made by Felix Hoffmann at Bayer in 1897,

1672-429: A useful tool in court cases or for the victim's own information. Most over-the-counter urine test kits test only for date-rape drugs that are benzodiazepines , which GHB is not. To detect GHB in urine, the sample must be taken within four hours of GHB ingestion, and cannot be tested at home. In humans, GHB has been shown to reduce the elimination rate (thus increasing the elimination time ) of alcohol. This may explain

1760-429: Is a disease that causes GHB to accumulate in the blood. GHB is used for medical purposes in the treatment of narcolepsy and, more rarely, alcohol dependence , although there remains uncertainty about its efficacy relative to other pharmacotherapies for alcohol dependence. The authors of a 2010 Cochrane review concluded that "GHB appears better than NTX and disulfiram in maintaining abstinence and preventing craving in

1848-464: Is a synthetic prodrug of salicylic acid. However, in other cases, such as codeine and morphine , the administered drug is enzymatically activated to form sugar derivatives (morphine- glucuronides ) that are more active than the parent compound. The first synthetic antimicrobial drug, arsphenamine , discovered in 1909 by Sahachiro Hata in the laboratory of Paul Ehrlich , is not toxic to bacteria until it has been converted to an active form by

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1936-406: Is also produced as a result of fermentation and so is found in small quantities in some beers and wines, in particular fruit wines. The amount found in wine is pharmacologically insignificant and not sufficient to produce psychoactive effects. GHB has at least two distinct binding sites in the central nervous system. GHB acts as an agonist at the inhibitory GHB receptor and as a weak agonist at

2024-497: Is also used illicitly for various reasons, including as a performance-enhancing drug , date rape drug , and as a recreational drug . It is commonly used in the form of a salt, such as sodium γ-hydroxybutyrate (NaGHB, sodium oxybate , or Xyrem) or potassium γ-hydroxybutyrate (KGHB, potassium oxybate). GHB is also produced as a result of fermentation, and is found in small quantities in some beers and wines, beef, and small citrus fruits. Succinic semialdehyde dehydrogenase deficiency

2112-453: Is further oxidized by succinic semialdehyde dehydrogenase (SSADH) to succinic acid , which enters the Krebs cycle and is ultimately converted into carbon dioxide and water. Neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse . The cell receiving the signal, or target cell, may be another neuron, but could also be

2200-416: Is illegal, and little is known about them beyond their delayed onset and longer duration of action. The intermediate compound γ-hydroxybutyraldehyde (GHBAL) is also a prodrug for GHB; however, as with all aliphatic aldehydes this compound is caustic and is strong-smelling and foul-tasting; actual use of this compound as an intoxicant is likely to be unpleasant and result in severe nausea and vomiting. Only

2288-530: Is important to keep the victim awake and moving; the victim must not be left alone due to the risk of death through vomiting. Frequently the victim will be in a good mood but this does not mean the victim is not in danger. GHB overdose is a medical emergency and immediate assessment in an emergency department is needed. Convulsions from GHB can be treated with the benzodiazepines diazepam or lorazepam . Even though these benzodiazepines are also CNS depressants, they primarily modulate GABA A receptors whereas GHB

2376-479: Is in a Type II, and the Type I synaptic cleft is wider. Finally, the active zone on a Type I synapse is larger than that on a Type II synapse. The different locations of Type I and Type II synapses divide a neuron into two zones: an excitatory dendritic tree and an inhibitory cell body. From an inhibitory perspective, excitation comes in over the dendrites and spreads to the axon hillock to trigger an action potential . If

2464-588: Is needed. Baclofen was first suggested as an adjunct because benzodiazepines do not affect GABA B receptors and therefore have no cross-tolerance with GHB while baclofen, which works via GABA B receptors, is cross-tolerant with GHB and may be more effective in alleviating withdrawal effects of GHB. GHB withdrawal is not widely discussed in textbooks and some psychiatrists, general practitioners, and even hospital emergency physicians may not be familiar with this withdrawal syndrome. Overdose of GHB can sometimes be difficult to treat because of its multiple effects on

2552-651: Is often the preferred specimen for routine drug abuse monitoring purposes. Both γ-butyrolactone (GBL) and 1,4-butanediol are converted to GHB in the body. In January 2016, it was announced scientists had developed a way to detect GHB, among other things, in saliva. Cells produce GHB by reduction of succinic semialdehyde via succinic semialdehyde reductase (SSR). This enzyme appears to be induced by cAMP levels, meaning substances that elevate cAMP, such as forskolin and vinpocetine , may increase GHB synthesis and release. Conversely, endogeneous GHB production in those taking valproic acid will be inhibited via inhibition of

2640-489: Is one that is bioactivated at multiple sites, either in parallel or sequential steps. For example, a prodrug, which is bioactivated concurrently in both target cells and metabolic tissues, could be designated as a "Type IA/IB" prodrug (e.g., HMG Co-A reductase inhibitors and some chemotherapy agents; note the symbol " / " applied here). When a prodrug is bioactivated sequentially, for example initially in GI fluids then systemically within

2728-487: Is primarily a GABA B receptor agonist, and so do not worsen CNS depression as much as might be expected. Because of the faster and more complete absorption of GBL relative to GHB, its dose-response curve is steeper, and overdoses of GBL tend to be more dangerous and problematic than overdoses involving only GHB or 1,4-B. Any GHB/GBL overdose is a medical emergency and should be cared for by appropriately trained personnel. A newer synthetic drug, SCH-50911 , which acts as

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2816-466: Is respiratory arrest. Other relatively common causes of death due to GHB ingestion include aspiration of vomitus, positional asphyxia, and trauma sustained while intoxicated (e.g., motor vehicle accidents while driving under the influence of GHB). The risk of aspiration pneumonia and positional asphyxia risk can be reduced by laying the patient down in the recovery position . People are most likely to vomit as they become unconscious, and as they wake up. It

2904-434: Is supportive care and benzodiazepines for control of acute delirium , but larger doses are often required compared to acute delirium of other causes (e.g. > 100 mg/d of diazepam ). Baclofen has been suggested as an alternative or adjunct to benzodiazepines based on anecdotal evidence and some animal data. However, there is less experience with the use of baclofen for GHB withdrawal, and additional research in humans

2992-434: Is then increased via the GHB receptor. Both the inhibition and increase of dopamine release by GHB are inhibited by opioid antagonists such as naloxone and naltrexone . Dynorphin may play a role in the inhibition of dopamine release via kappa opioid receptors . This explains the paradoxical mix of sedative and stimulatory properties of GHB, as well as the so-called "rebound" effect, experienced by individuals using GHB as

3080-453: The blood–brain barrier . GHB induces the accumulation of either a derivative of tryptophan or tryptophan itself in the extracellular space, possibly by increasing tryptophan transport across the blood–brain barrier. The blood content of certain neutral amino-acids, including tryptophan, is also increased by peripheral GHB administration. GHB-induced stimulation of tissue serotonin turnover may be due to an increase in tryptophan transport to

3168-578: The central nervous system . Single ions (such as synaptically released zinc ) are also considered neurotransmitters by some, as well as some gaseous molecules such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H 2 S). The gases are produced in the neural cytoplasm and are immediately diffused through the cell membrane into the extracellular fluid and into nearby cells to stimulate production of second messengers. Soluble gas neurotransmitters are difficult to study, as they act rapidly and are immediately broken down, existing for only

3256-458: The cerebral cortex and possibly other areas as well. In addition, the neu­ro­tox­icity appears to be caused by oxidative stress . Addiction occurs when repeated drug use disrupts the normal balance of brain circuits that control rewards, memory and cognition, ultimately leading to compulsive drug taking. Rats forced to consume massive doses of GHB will intermittently prefer GHB solution to water. GHB has also been associated with

3344-456: The inhibitory GABA B receptor. GHB is a naturally occurring substance that acts in a similar fashion to some neurotransmitters in the mammalian brain. GHB is probably synthesized from GABA in GABAergic neurons , and released when the neurons fire. GHB has been found to activate oxytocinergic neurons in the supraoptic nucleus . If taken orally, GABA itself does not effectively cross

3432-422: The presynaptic terminal , the action potential can trigger the release of neurotransmitters into the synaptic cleft. These neurotransmitters then bind to receptors on the postsynaptic membrane, influencing the receiving neuron in either an inhibitory or excitatory manner. If the overall excitatory influences outweigh the inhibitory influences, the receiving neuron may generate its own action potential, continuing

3520-438: The synaptic cleft , was discovered. The presence of such a gap suggested communication via chemical messengers traversing the synaptic cleft, and in 1921 German pharmacologist Otto Loewi confirmed that neurons can communicate by releasing chemicals. Through a series of experiments involving the vagus nerves of frogs, Loewi was able to manually slow the heart rate of frogs by controlling the amount of saline solution present around

3608-496: The synaptic cleft , where they bind to specific receptors on the membrane of the postsynaptic neuron. After being released into the synaptic cleft, neurotransmitters diffuse across the synapse where they are able to interact with receptors on the target cell. The effect of the neurotransmitter is dependent on the identity of the target cell's receptors present at the synapse. Depending on the receptor, binding of neurotransmitters may cause excitation , inhibition , or modulation of

γ-Hydroxybutyric acid - Misplaced Pages Continue

3696-462: The 1990s, as small doses of GHB can act as a euphoriant and are believed to be aphrodisiac. Slang terms for GHB include liquid ecstasy , lollipops , liquid X or liquid E due to its tendency to produce euphoria and sociability and its use in the dance party scene. Some athletes have used GHB or its analogs because of being marketed as anabolic agents, although there is no evidence that it builds muscle or improves performance. GHB became known to

3784-407: The GHB receptor in the behavioural effects induced by GHB is more complex. GHB receptors are densely expressed in many areas of the brain, including the cortex and hippocampus, and these are the receptors that GHB displays the highest affinity for. There has been somewhat limited research into the GHB receptor; however, there is evidence that activation of the GHB receptor in some brain areas results in

3872-466: The actions of some neurotransmitter systems, often acting through transmitters other than glutamate or GABA. Addictive drugs such as cocaine and amphetamines exert their effects primarily on the dopamine system. The addictive opiate drugs exert their effects primarily as functional analogs of opioid peptides , which, in turn, regulate dopamine levels. Neurons expressing certain types of neurotransmitters sometimes form distinct systems, where activation of

3960-414: The available evidence seem to be less potent but more toxic than GHB, with a particular tendency to cause nausea and vomiting. Other prodrug ester forms of GHB have also rarely been encountered by law enforcement, including 1,4-butanediol diacetate (BDDA/DABD), methyl-4-acetoxybutanoate (MAB), and ethyl-4-acetoxybutanoate (EAB), but these are, in general, covered by analogue laws in jurisdictions where GHB

4048-536: The body converts the prodrug into the final active drug form: Both major types can be further categorized into subtypes, based on factors such as (Type I) whether the intracellular bioactivation location is also the site of therapeutic action, or (Type 2) whether or not bioactivation occurs in the gastrointestinal fluids or in the circulation system. Type IA prodrugs include many antimicrobial and chemotherapy agents (e.g., 5-flurouracil). Type IB agents rely on metabolic enzymes, especially in hepatic cells, to bioactivate

4136-402: The body. Likewise, prontosil , the first sulfa drug (discovered by Gerhard Domagk in 1932), must be cleaved in the body to release the active molecule, sulfanilamide . Since that time, many other examples have been identified. Terfenadine , the first non-sedating antihistamine , had to be withdrawn from the market because of the small risk of a serious side effect. However, terfenadine

4224-470: The body. GHB tends to cause rapid unconsciousness at doses above 3500 mg, with single doses over 7000 mg often causing life-threatening respiratory depression , and higher doses still inducing bradycardia and cardiac arrest . Other side-effects include convulsions (especially when combined with stimulants ), and nausea/vomiting (especially when combined with alcohol). The greatest life threat due to GHB overdose (with or without other substances)

4312-531: The brain and in its uptake by serotonergic cells. As the serotonergic system may be involved in the regulation of sleep, mood, and anxiety, the stimulation of this system by high doses of GHB may be involved in certain neuropharmacological events induced by GHB administration. However, at therapeutic doses, GHB reaches much higher concentrations in the brain and activates GABA B receptors, which are primarily responsible for its sedative effects. GHB's sedative effects are blocked by GABA B antagonists. The role of

4400-627: The brain via signaling through trace amine-associated receptor 1 . A brief comparison of these systems follows: Caudal nuclei (CN): Raphe magnus , raphe pallidus , and raphe obscurus Rostral nuclei (RN): Nucleus linearis , dorsal raphe , medial raphe , and raphe pontis Forebrain cholinergic nuclei (FCN): Nucleus basalis of Meynert , medial septal nucleus , and diagonal band Striatal tonically active cholinergic neurons (TAN) Brainstem cholinergic nuclei (BCN): Pedunculopontine nucleus , laterodorsal tegmentum , medial habenula , and parabigeminal nucleus Understanding

4488-404: The cell. Classes of neurotransmitters include amino acids , monoamines , and peptides . Monoamines are synthesized by altering a single amino acid. For example, the precursor of serotonin is the amino acid tryptophan. Peptide neurotransmitters, or neuropeptides , are protein transmitters which are larger than the classical small-molecule neurotransmitters and are often released together to elicit

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4576-455: The central and peripheral nervous system . Drugs such as tetrodotoxin that block neural activity are typically lethal. Drugs targeting the neurotransmitter of major systems affect the whole system, which can explain the complexity of action of some drugs. Cocaine , for example, blocks the re-uptake of dopamine back into the presynaptic neuron, leaving the neurotransmitter molecules in the synaptic gap for an extended period of time. Since

4664-498: The conversion from succinic acid semialdehyde to GHB. People with the disorder known as succinic semialdehyde dehydrogenase deficiency, also known as γ-hydroxybutyric aciduria , have elevated levels of GHB in their urine , blood plasma and cerebrospinal fluid . The precise function of GHB in the body is not clear. It is known, however, that the brain expresses a large number of receptors that are activated by GHB. These receptors are excitatory, however, and therefore not responsible for

4752-772: The dangers of the two drugs were similar. At higher doses, GHB may induce nausea , dizziness , drowsiness , agitation , visual disturbances, depressed breathing , amnesia , unconsciousness , and death. One potential cause of death from GHB consumption is polydrug toxicity. Co-administration with other CNS depressants such as alcohol or benzodiazepines can result in an additive effect (potentiation), as they all bind to gamma-aminobutyric acid (or "GABA") receptor sites. The effects of GHB can last from 1.5 to 4 hours, or longer if large doses have been consumed. Consuming GHB with alcohol can cause respiratory arrest and vomiting in combination with unarousable sleep, which can lead to death. Recreational doses of 1–2 g generally provide

4840-450: The dopamine remains in the synapse longer, the neurotransmitter continues to bind to the receptors on the postsynaptic neuron, eliciting a pleasurable emotional response. Physical addiction to cocaine may result from prolonged exposure to excess dopamine in the synapses, which leads to the downregulation of some post-synaptic receptors. After the effects of the drug wear off, an individual can become depressed due to decreased probability of

4928-521: The effects of drugs on neurotransmitters comprises a significant portion of research initiatives in the field of neuroscience . Most neuroscientists involved in this field of research believe that such efforts may further advance our understanding of the circuits responsible for various neurological diseases and disorders, as well as ways to effectively treat and someday possibly prevent or cure such illnesses. Drugs can influence behavior by altering neurotransmitter activity. For instance, drugs can decrease

5016-559: The gates" strategy, the excitatory message is like a racehorse ready to run down the track, but first, the inhibitory starting gate must be removed. As explained above, the only direct action of a neurotransmitter is to activate a receptor. Therefore, the effects of a neurotransmitter system depend on the connections of the neurons that use the transmitter, and the chemical properties of the receptors. There are many different ways to classify neurotransmitters and are commonly classified into amino acids , monoamines and peptides . Some of

5104-410: The general public as a date-rape drug by the late 1990s. GHB is colourless and odorless and has been described as "very easy to add to drinks". When consumed, the victim will quickly feel groggy and sleepy and may become unconscious. Upon recovery they may have an impaired ability to recall events that have occurred during the period of intoxication. In these situations evidence and the identification of

5192-448: The major neurotransmitters are: In addition, over 100 neuroactive peptides have been found, and new ones are discovered regularly. Many of these are co-released along with a small-molecule transmitter. Nevertheless, in some cases, a peptide is the primary transmitter at a synapse. Beta-Endorphin is a relatively well-known example of a peptide neurotransmitter because it engages in highly specific interactions with opioid receptors in

5280-463: The medium term (3 to 12 months)". It is sometimes used off-label for the treatment of fibromyalgia . GHB is the active ingredient of the prescription medication sodium oxybate (Xyrem). Sodium oxybate is approved by the U.S. Food and Drug Administration for the treatment of cataplexy associated with narcolepsy and excessive daytime sleepiness (EDS) associated with narcolepsy. GHB has been shown to reliably increase slow-wave sleep and decrease

5368-437: The message is to be stopped, it is best stopped by applying inhibition on the cell body, close to the axon hillock where the action potential originates. Another way to conceptualize excitatory–inhibitory interaction is to picture excitation overcoming inhibition. If the cell body is normally in an inhibited state, the only way to generate an action potential at the axon hillock is to reduce the cell body's inhibition. In this "open

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5456-482: The metabolic gases carbon monoxide and nitric oxide, are synthesized and released immediately following an action potential without ever being stored in vesicles. Generally, a neurotransmitter is released via exocytosis at the presynaptic terminal in response to an electrical signal called an action potential in the presynaptic neuron. However, low-level "baseline" release also occurs without electrical stimulation. Neurotransmitters are released into and diffuse across

5544-404: The mixing of its two precursors, GBL and an alkali hydroxide such as sodium hydroxide , to form the GHB salt. Due to the ease of manufacture and the availability of its precursors, it is not usually produced in illicit laboratories like other synthetic drugs, but in private homes by low-level producers. GHB is colourless and odourless. GHB has been used as a club drug , apparently starting in

5632-439: The neurons under its influence. Receptors with modulatory effects are spread throughout all synaptic membranes and binding of neurotransmitters sets in motion signaling cascades that help the cell regulate its function. Binding of neurotransmitters to receptors with modulatory effects can have many results. For example, it may result in an increase or decrease in sensitivity to future stimulus by recruiting more or less receptors to

5720-409: The neurotransmitter binding to a receptor. Fluoxetine is a selective serotonin re-uptake inhibitor (SSRI), which blocks re-uptake of serotonin by the presynaptic cell which increases the amount of serotonin present at the synapse and furthermore allows it to remain there longer, providing potential for the effect of naturally released serotonin. AMPT prevents the conversion of tyrosine to L-DOPA ,

5808-851: The parent compound does not have the side effects associated with terfenadine, and so both loratadine and its active metabolite , desloratadine, are currently marketed. Approximately 10% of all marketed drugs worldwide can be considered prodrugs. Since 2008, at least 30 prodrugs have been approved by the FDA . Seven prodrugs were approved in 2015 and six in 2017. Examples of recently approved prodrugs are such as dabigatran etexilate (approved in 2010), gabapentin enacarbil (2011), sofosbuvir (2013), tedizolid phosphate (2014), isavuconazonium (2015), aripiprazole lauroxil (2015), selexipag (2015), latanoprostene bunod (2017), benzhydrocodone (2018), tozinameran (2020) and serdexmethylphenidate (2021). Prodrugs can be classified into two major types, based on how

5896-495: The perpetrator of the rape is often difficult. It is also difficult to establish how often GHB is used to facilitate rape as it is difficult to detect in a urine sample after a day, and many victims may only recall the rape some time after its occurrence; however, a 2006 study suggested that there was "no evidence to suggest widespread date rape drug use" in the UK, and that less than 2% of cases involved GHB, while 17% involved cocaine , and

5984-416: The postsynaptic neuron. In order to avoid continuous activation of receptors on the post-synaptic or target cell, neurotransmitters must be removed from the synaptic cleft. Neurotransmitters are removed through one of three mechanisms: For example, acetylcholine is eliminated by having its acetyl group cleaved by the enzyme acetylcholinesterase ; the remaining choline is then taken in and recycled by

6072-435: The pre-synaptic neuron to synthesize more acetylcholine . Other neurotransmitters are able to diffuse away from their targeted synaptic junctions and are eliminated from the body via the kidneys, or destroyed in the liver. Each neurotransmitter has very specific degradation pathways at regulatory points, which may be targeted by the body's regulatory system or medication. Cocaine blocks a dopamine transporter responsible for

6160-700: The precursor to dopamine; reserpine prevents dopamine storage within vesicles ; and deprenyl inhibits monoamine oxidase (MAO)-B and thus increases dopamine levels. Prevents muscle contractions Stimulates muscle contractions Increases effects of ACh at receptors Used to treat myasthenia gravis Increases attention Reinforcing effects Prevents muscle contractions Toxic Blocks saliva production Causes sedation and depression High dose: stimulates postsynaptic receptors Blocks reuptake Blocks reuptake Enhances attention and impulse control in ADHD Blocks voltage-dependent sodium channels Can be used as

6248-424: The probability that the cell with which it comes in contact will produce an action potential. Synapses containing receptors with excitatory effects are called Type I synapses, while Type II synapses contain receptors with inhibitory effects. Thus, despite the wide variety of synapses, they all convey messages of only these two types. The two types are different appearance and are primarily located on different parts of

6336-469: The prodrugs intracellularly to active drugs. Type II prodrugs are bioactivated extracellularly, either in the milieu of GI fluids (Type IIA), within the systemic circulation and/or other extracellular fluid compartments (Type IIB), or near therapeutic target tissues/cells (Type IIC), relying on common enzymes such as esterases and phosphatases or target directed enzymes. Importantly, prodrugs can belong to multiple subtypes (i.e., Mixed-Type). A Mixed-Type prodrug

6424-452: The rate of synthesis of neurotransmitters by affecting the synthetic enzyme(s) for that neurotransmitter. When neurotransmitter syntheses are blocked, the amount of neurotransmitters available for release becomes substantially lower, resulting in a decrease in neurotransmitter activity. Some drugs block or stimulate the release of specific neurotransmitters. Alternatively, drugs can prevent neurotransmitter storage in synaptic vesicles by causing

6512-598: The release of glutamate, the principal excitatory neurotransmitter. Drugs that selectively activate the GHB receptor cause absence seizures in high doses, as do GHB and GABA B agonists. Activation of both the GHB receptor and GABA B is responsible for the addictive profile of GHB. GHB's effect on dopamine release is biphasic. Low concentrations stimulate dopamine release via the GHB receptor. Higher concentrations inhibit dopamine release via GABA B receptors as do other GABA B agonists such as baclofen and phenibut . After an initial phase of inhibition, dopamine release

6600-503: The respiratory arrest that has been reported after ingestion of both drugs. A review of the details of 194 deaths attributed to or related to GHB over a ten-year period found that most were from respiratory depression caused by interaction with alcohol or other drugs. One publication has investigated 226 deaths attributed to GHB. Of the 226 deaths included, 213 had a cardiorespiratory arrest and 13 had fatal accidents. Seventy-one of these deaths (34%) had no co-intoxicants. Postmortem blood GHB

6688-423: The reuptake of dopamine. Without the transporter, dopamine diffuses much more slowly from the synaptic cleft and continues to activate the dopamine receptors on the target cell. Until the early 20th century, scientists assumed that the majority of synaptic communication in the brain was electrical. However, through histological examinations by Ramón y Cajal , a 20 to 40 nm gap between neurons, known today as

6776-593: The sedative effects of GHB; they have been shown to elevate the principal excitatory neurotransmitter, glutamate . The benzamide antipsychotics— amisulpride , nemonapride , etc.—have been shown to bind to these GHB-activated receptors in vivo. Other antipsychotics were tested and were not found to have an affinity for this receptor. GHB is a precursor to GABA , glutamate, and glycine in certain brain areas. In spite of its demonstrated neurotoxicity, (see relevant section , above), GHB has neuroprotective properties, and has been found to protect cells from hypoxia . GHB

6864-406: The synaptic membrane. Type I (excitatory) synapses are typically located on the shafts or the spines of dendrites, whereas type II (inhibitory) synapses are typically located on a cell body. In addition, Type I synapses have round synaptic vesicles, whereas the vesicles of type II synapses are flattened. The material on the presynaptic and post-synaptic membranes is denser in a Type I synapse than it

6952-450: The synaptic vesicle membranes to leak. Drugs that prevent a neurotransmitter from binding to its receptor are called receptor antagonists . For example, drugs used to treat patients with schizophrenia such as haloperidol, chlorpromazine, and clozapine are antagonists at receptors in the brain for dopamine. Other drugs act by binding to a receptor and mimicking the normal neurotransmitter. Such drugs are called receptor agonists . An example of

7040-404: The system affects large volumes of the brain, called volume transmission . Major neurotransmitter systems include the noradrenaline (norepinephrine) system, the dopamine system, the serotonin system, and the cholinergic system, among others. Trace amines have a modulatory effect on neurotransmission in monoamine pathways (i.e., dopamine, norepinephrine, and serotonin pathways) throughout

7128-471: The target cells, it is designated as a "Type IIA-IA" prodrug (e.g., tenofovir disoproxil ; note the symbol " - " applied here). Many antibody- virus- and gene-directed enzyme prodrug therapies ( ADEPTs , VDEPTs , GDEPTs ) and proposed nanoparticle - or nanocarrier-linked drugs can understandably be Sequential Mixed-Type prodrugs. To differentiate these two Subtypes, the symbol dash " - " is used to designate and to indicate sequential steps of bioactivation, and

7216-654: The tendency for REM sleep in modified multiple sleep latency tests. The FDA-approved labeling for sodium oxybate suggests no evidence GHB has teratogenic , carcinogenic or hepatotoxic properties. Its favorable safety profile relative to ethanol may explain why GHB continues to be investigated as a candidate for alcohol substitution. GHB is a central nervous system depressant used as an intoxicant . It has many street names. Its effects have been described as comparable with ethanol (alcohol) and MDMA use, such as euphoria , disinhibition, enhanced libido and empathogenic states. A review comparing ethanol to GHB concluded that

7304-441: The term "neurotransmitter" can be applied to chemicals that: The anatomical localization of neurotransmitters is typically determined using immunocytochemical techniques, which identify the location of either the transmitter substances themselves or of the enzymes that are involved in their synthesis. Immunocytochemical techniques have also revealed that many transmitters, particularly the neuropeptides , are co-localized, that is,

7392-479: The transmission of information to the next neuron in the network. This process allows for the flow of information and the formation of complex neural networks. A neurotransmitter may have an excitatory, inhibitory or modulatory effect on the target cell. The effect is determined by the receptors the neurotransmitter interacts with at the post-synaptic membrane. Neurotransmitter influences trans-membrane ion flow either to increase (excitatory) or to decrease (inhibitory)

7480-455: The vagus nerve. Upon completion of this experiment, Loewi asserted that sympathetic regulation of cardiac function can be mediated through changes in chemical concentrations. Furthermore, Otto Loewi is credited with discovering acetylcholine (ACh) – the first known neurotransmitter. To identify neurotransmitters, the following criteria are typically considered: However, given advances in pharmacology , genetics , and chemical neuroanatomy ,

7568-402: Was 18–4400 mg/L (median=347) in deaths negative for co-intoxicants. One report has suggested that sodium oxybate overdose might be fatal, based on deaths of three patients who had been prescribed the drug. However, for two of the three cases, post-mortem GHB concentrations were 141 and 110 mg/L, which is within the expected range of concentrations for GHB after death, and the third case

7656-727: Was a patient with a history of intentional drug overdose. The toxicity of GHB has been an issue in criminal trials, as in the death of Felicia Tang , where the defense argued that death was due to GHB, not murder. GHB is produced in the body in very small amounts, and blood levels may climb after death to levels in the range of 30–50 mg/L. Levels higher than this are found in GHB deaths. Levels lower than this may be due to GHB or to postmortem endogenous elevations. In multiple studies, GHB has been found to impair spatial memory , working memory , learning and memory in rats with chronic ad­min­is­tra­tion. These effects are associated with decreased NMDA receptor expression in

7744-431: Was discovered to be the prodrug of the active molecule, fexofenadine , which does not carry the same risks as the parent compound. Therefore, fexofenadine could be placed on the market as a safe replacement for the original drug. Loratadine , another non-sedating antihistamine, is the prodrug of desloratadine , which is largely responsible for the antihistaminergic effects of the parent compound. However, in this case

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