European Chemicals Agency
The European Chemicals Agency is an agency of the European Union which manages the technical and administrative aspects of the implementation of the European Union regulation called Registration, Evaluation and Restriction of Chemicals. ECHA is the driving force among regulatory authorities in implementing the EU's chemicals legislation. ECHA helps companies to comply with the legislation, advances the safe use of chemicals, provides information on chemicals and addresses chemicals of concern, it is located in Finland. The agency headed by Executive Director Bjorn Hansen, started working on 1 June 2007; the REACH Regulation requires companies to provide information on the hazards and safe use of chemical substances that they manufacture or import. Companies register this information with ECHA and it is freely available on their website. So far, thousands of the most hazardous and the most used substances have been registered; the information is technical but gives detail on the impact of each chemical on people and the environment.
This gives European consumers the right to ask retailers whether the goods they buy contain dangerous substances. The Classification and Packaging Regulation introduces a globally harmonised system for classifying and labelling chemicals into the EU; this worldwide system makes it easier for workers and consumers to know the effects of chemicals and how to use products safely because the labels on products are now the same throughout the world. Companies need to notify ECHA of the labelling of their chemicals. So far, ECHA has received over 5 million notifications for more than 100 000 substances; the information is available on their website. Consumers can check chemicals in the products. Biocidal products include, for example, insect disinfectants used in hospitals; the Biocidal Products Regulation ensures that there is enough information about these products so that consumers can use them safely. ECHA is responsible for implementing the regulation; the law on Prior Informed Consent sets guidelines for the import of hazardous chemicals.
Through this mechanism, countries due to receive hazardous chemicals are informed in advance and have the possibility of rejecting their import. Substances that may have serious effects on human health and the environment are identified as Substances of Very High Concern 1; these are substances which cause cancer, mutation or are toxic to reproduction as well as substances which persist in the body or the environment and do not break down. Other substances considered. Companies manufacturing or importing articles containing these substances in a concentration above 0,1% weight of the article, have legal obligations, they are required to inform users about the presence of the substance and therefore how to use it safely. Consumers have the right to ask the retailer whether these substances are present in the products they buy. Once a substance has been identified in the EU as being of high concern, it will be added to a list; this list is available on ECHA's website and shows consumers and industry which chemicals are identified as SVHCs.
Substances placed on the Candidate List can move to another list. This means that, after a given date, companies will not be allowed to place the substance on the market or to use it, unless they have been given prior authorisation to do so by ECHA. One of the main aims of this listing process is to phase out SVHCs where possible. In its 2018 substance evaluation progress report, ECHA said chemical companies failed to provide “important safety information” in nearly three quarters of cases checked that year. "The numbers show a similar picture to previous years" the report said. The agency noted that member states need to develop risk management measures to control unsafe commercial use of chemicals in 71% of the substances checked. Executive Director Bjorn Hansen called non-compliance with REACH a "worry". Industry group CEFIC acknowledged the problem; the European Environmental Bureau called for faster enforcement to minimise chemical exposure. European Chemicals Bureau Official website
Cannabidiol is a phytocannabinoid discovered in 1940. It is one of some 113 identified cannabinoids in cannabis plants, accounting for up to 40% of the plant's extract; as of 2018, preliminary clinical research on cannabidiol included studies of anxiety, movement disorders, pain. Cannabidiol can be taken into the body in multiple ways, including by inhalation of cannabis smoke or vapor, as an aerosol spray into the cheek, by mouth, it may be supplied as CBD oil containing only CBD as the active ingredient, a full-plant CBD-dominant hemp extract oil, dried cannabis, or as a prescription liquid solution. CBD does not have the same psychoactivity as THC, may affect the actions of THC. Although in vitro studies indicate CBD may interact with different biological targets, including cannabinoid receptors and other neurotransmitter receptors, as of 2018 the mechanism of action for its biological effects has not been determined. In the United States, the cannabidiol drug Epidiolex has been approved by the Food and Drug Administration for treatment of two epilepsy disorders.
The side effects of long-term use of the drug include somnolence, decreased appetite, fatigue, weakness, sleeping problems. The U. S. Drug Enforcement Administration has assigned Epidiolex a Schedule V classification, while non-Epidiolex CBD remains a Schedule I drug prohibited for any use. Cannabidiol is not scheduled under any United Nations drug control treaties, in 2018 the World Health Organization recommended that it remain unscheduled. There has been little high-quality research into the use of cannabidiol for epilepsy, what there is is limited to refractory epilepsy in children. While the results of using medical-grade cannabidiol in combination with conventional medication shows some promise, they did not lead to seizures being eliminated, were associated with some minor adverse effects. An orally administered cannabidiol solution was approved by the US Food and Drug Administration in June 2018 as a treatment for two rare forms of childhood epilepsy, Lennox-Gastaut syndrome and Dravet syndrome.
Preliminary research on other possible therapeutic uses for cannabidiol include several neurological disorders, but the findings have not been confirmed by sufficient high-quality clinical research to establish such uses in clinical practice. Preliminary research indicates that cannabidiol may reduce adverse effects of THC those causing intoxication and sedation, but only at high doses. Safety studies of cannabidiol showed it is well-tolerated, but may cause tiredness, diarrhea, or changes in appetite as common adverse effects. Epidiolex documentation lists sleepiness and poor quality sleep, decreased appetite and fatigue. Laboratory evidence indicated that cannabidiol may reduce THC clearance, increasing plasma concentrations which may raise THC availability to receptors and enhance its effect in a dose-dependent manner. In vitro, cannabidiol inhibited receptors affecting the activity of voltage-dependent sodium and potassium channels, which may affect neural activity. A small clinical trial reported that CBD inhibited the CYP2C-catalyzed hydroxylation of THC to 11-OH-THC.
Little is known about potential drug interactions but CBD-mediates decrease in clobazam metabolism. Cannabidiol has low affinity for the cannabinoid CB2 receptors. Cannabidiol may be an antagonist of GPR55, a G protein-coupled receptor and putative cannabinoid receptor, expressed in the caudate nucleus and putamen in the brain, it may act as an inverse agonist of GPR3, GPR6, GPR12. CBD has been shown to act as a serotonin 5-HT1A receptor partial agonist, this action may be involved in its antidepressant and neuroprotective effects, it is an allosteric modulator of the μ- and δ-opioid receptors as well. The pharmacological effects of CBD may involve PPARγ intracellular calcium release; the oral bioavailability of CBD is 13 to 19%, while its bioavailability via inhalation is 11 to 45%. The elimination half-life of CBD is 18–32 hours. Cannabidiol is metabolized in the liver as well as in the intestines by CYP2C19 and CYP3A4 enzymes, UGT1A7, UGT1A9, UGT2B7 isoforms. CBD may have a wide margin in dosing.
Nabiximols is a patented medicine containing THC in equal proportions. The drug was approved by Health Canada in 2005 for prescription to treat central neuropathic pain in multiple sclerosis, in 2007 for cancer related pain. In New Zealand, Sativex is "approved for use as an add-on treatment for symptom improvement in people with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication." Cannabidiol is soluble in organic solvents such as pentane. At room temperature, it is a colorless crystalline solid. In basic media and the presence of air, it is oxidized to a quinone. Under acidic conditions it cyclizes to THC, which occurs during pyrolysis; the synthesis of cannabidiol has been accomplished by several research groups. Cannabis produces CBD-carboxylic acid through the same metabolic pathway as THC, until the next to last step, where CBDA synthase performs catalysis instead of THCA synthase. Cannabinoids were isolated from the cannabis plant in 1940 by Roger Adams, its chemical structure was established in 1963.
Cannabidiol is the generic name of the drug and its INN. Food and beverage products containing CBD were introduced in the United States in 2017. Similar to energy drinks and protein bars which may contain vitamin or herbal additives and beverage items can be infused with CBD as an alternative means of ingesting the substance. In the United S
The melting point of a substance is the temperature at which it changes state from solid to liquid. At the melting point the solid and liquid phase exist in equilibrium; the melting point of a substance depends on pressure and is specified at a standard pressure such as 1 atmosphere or 100 kPa. When considered as the temperature of the reverse change from liquid to solid, it is referred to as the freezing point or crystallization point; because of the ability of some substances to supercool, the freezing point is not considered as a characteristic property of a substance. When the "characteristic freezing point" of a substance is determined, in fact the actual methodology is always "the principle of observing the disappearance rather than the formation of ice", that is, the melting point. For most substances and freezing points are equal. For example, the melting point and freezing point of mercury is 234.32 kelvins. However, certain substances possess differing solid-liquid transition temperatures.
For example, agar melts at 85 °C and solidifies from 31 °C. The melting point of ice at 1 atmosphere of pressure is close to 0 °C. In the presence of nucleating substances, the freezing point of water is not always the same as the melting point. In the absence of nucleators water can exist as a supercooled liquid down to −48.3 °C before freezing. The chemical element with the highest melting point is tungsten, at 3,414 °C; the often-cited carbon does not melt at ambient pressure but sublimes at about 3,726.85 °C. Tantalum hafnium carbide is a refractory compound with a high melting point of 4215 K. At the other end of the scale, helium does not freeze at all at normal pressure at temperatures arbitrarily close to absolute zero. Many laboratory techniques exist for the determination of melting points. A Kofler bench is a metal strip with a temperature gradient. Any substance can be placed on a section of the strip, revealing its thermal behaviour at the temperature at that point. Differential scanning calorimetry gives information on melting point together with its enthalpy of fusion.
A basic melting point apparatus for the analysis of crystalline solids consists of an oil bath with a transparent window and a simple magnifier. The several grains of a solid are placed in a thin glass tube and immersed in the oil bath; the oil bath is heated and with the aid of the magnifier melting of the individual crystals at a certain temperature can be observed. In large/small devices, the sample is placed in a heating block, optical detection is automated; the measurement can be made continuously with an operating process. For instance, oil refineries measure the freeze point of diesel fuel online, meaning that the sample is taken from the process and measured automatically; this allows for more frequent measurements as the sample does not have to be manually collected and taken to a remote laboratory. For refractory materials the high melting point may be determined by heating the material in a black body furnace and measuring the black-body temperature with an optical pyrometer. For the highest melting materials, this may require extrapolation by several hundred degrees.
The spectral radiance from an incandescent body is known to be a function of its temperature. An optical pyrometer matches the radiance of a body under study to the radiance of a source, calibrated as a function of temperature. In this way, the measurement of the absolute magnitude of the intensity of radiation is unnecessary. However, known temperatures must be used to determine the calibration of the pyrometer. For temperatures above the calibration range of the source, an extrapolation technique must be employed; this extrapolation is accomplished by using Planck's law of radiation. The constants in this equation are not known with sufficient accuracy, causing errors in the extrapolation to become larger at higher temperatures. However, standard techniques have been developed to perform this extrapolation. Consider the case of using gold as the source. In this technique, the current through the filament of the pyrometer is adjusted until the light intensity of the filament matches that of a black-body at the melting point of gold.
This establishes the primary calibration temperature and can be expressed in terms of current through the pyrometer lamp. With the same current setting, the pyrometer is sighted on another black-body at a higher temperature. An absorbing medium of known transmission is inserted between this black-body; the temperature of the black-body is adjusted until a match exists between its intensity and that of the pyrometer filament. The true higher temperature of the black-body is determined from Planck's Law; the absorbing medium is removed and the current through the filament is adjusted to match the filament intensity to that of the black-body. This establishes a second calibration point for the pyrometer; this step is repeated to carry the calibration to hi
The nucleus accumbens known as the accumbens nucleus, or as the nucleus accumbens septi is a region in the basal forebrain rostral to the preoptic area of the hypothalamus. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum; the ventral striatum and dorsal striatum collectively form the striatum, the main component of the basal ganglia. The dopaminergic neurons of the mesolimbic pathway project onto the GABAergic medium spiny neurons of the nucleus accumbens and olfactory tubercle; each cerebral hemisphere has its own nucleus accumbens, which can be divided into two structures: the nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions. Different NAcc subregions and neuron subpopulations within each region are responsible for different cognitive functions; as a whole, the nucleus accumbens has a significant role in the cognitive processing of motivation, aversion and reinforcement learning. In addition, part of the nucleus accumbens core is centrally involved in the induction of slow-wave sleep.
The nucleus accumbens plays a lesser role in processing fear and the placebo effect. It is involved in the encoding of new motor programs as well; the nucleus accumbens is an aggregate of neurons, described as having an outer shell and an inner core. Major glutamatergic inputs to the nucleus accumbens include the prefrontal cortex, basolateral amygdala, ventral hippocampus, thalamic nuclei, glutamatergic projections from the ventral tegmental area; the nucleus accumbens receives dopaminergic inputs from the ventral tegmental area, which connect via the mesolimbic pathway. The nucleus accumbens is described as one part of a cortico-basal ganglia-thalamo-cortical loop. Dopaminergic inputs from the VTA modulate the activity of GABAergic neurons within the nucleus accumbens; these neurons are activated directly or indirectly by euphoriant drugs and by participating in rewarding experiences. Another major source of input comes from the CA1 and ventral subiculum of the hippocampus to the dorsomedial area of the nucleus accumbens.
Slight depolarizations of cells in the nucleus accumbens correlates with positivity of the neurons of the hippocampus, making them more excitable. The correlated cells of these excited states of the medium spiny neurons in the nucleus accumbens are shared between the subiculum and CA1; the subiculum neurons are found to hyperpolarize while the CA1 neurons "ripple" in order to accomplish this priming. The nucleus accumbens is one of the few regions that receive histaminergic projections from the tuberomammillary nucleus; the output neurons of the nucleus accumbens send axonal projections to the basal ganglia and the ventral analog of the globus pallidus, known as the ventral pallidum. The VP, in turn, projects to the medial dorsal nucleus of the dorsal thalamus, which projects to the prefrontal cortex as well as the striatum. Other efferents from the nucleus accumbens include connections with the tail of the ventral tegmental area, substantia nigra, the reticular formation of the pons; the nucleus accumbens shell is a substructure of the nucleus accumbens.
The shell and core together form the entire nucleus accumbens. Location: The shell is the outer region of the nucleus accumbens, – unlike the core – is considered to be part of the extended amygdala, located at its rostral pole. Cell types: Neurons in the nucleus accumbens are medium spiny neurons containing D1-type or D2-type dopamine receptors. A subpopulation of MSNs contain both D1-type and D2-type receptors, with 40% of striatal MSNs expressing both DRD1 and DRD2 mRNA; these mixed-type NAcc MSNs with both D1-type and D2-type receptors are confined to the NAcc shell. The neurons in the shell, as compared to the core, have a lower density of dendritic spines, less terminal segments, less branch segments than those in the core; the shell neurons project to the subcommissural part of the ventral pallidum as well as the ventral tegmental area and to extensive areas in the hypothalamus and extended amygdala. Function: The shell of the nucleus accumbens is involved in the cognitive processing of reward, including subjective "liking" reactions to certain pleasurable stimuli, motivational salience, positive reinforcement.
That NAcc shell has been shown to mediate specific Pavlovian-instrumental transfer, a phenomenon in which a classically conditioned stimulus modifies operant behavior. A "hedonic hotspot" or pleasure center, responsible for the pleasurable or "liking" component of some intrinsic rewards is located in a small compartment within the medial NAcc shell; the D1-type medium spiny neurons in the Nacc shell mediate reward-related cognitive processes, whereas the D2-type medium spiny neurons in the NAcc shell mediate aversion-related cognition. Addictive drugs have a larger effect on dopamine release in the shell than in the core; the nucleus accumbens core is the inner substructure of the nucleus accumbens. Location: The nucleus accumbens core is part of the ventral striatum, located within the basal ganglia. Cel
The 5-HT3 receptor belongs to the Cys-loop superfamily of ligand-gated ion channels and therefore differs structurally and functionally from all other 5-HT receptors receptors which are G protein-coupled receptors. This ion channel is cation-selective and mediates neuronal depolarization and excitation within the central and peripheral nervous systems; as with other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore, permeable to sodium and calcium ions. Binding of the neurotransmitter 5-hydroxytryptamine to the 5-HT3 receptor opens the channel, which, in turn, leads to an excitatory response in neurons; the activating, inward current is predominantly carried by sodium and potassium ions. 5-HT3 receptors have a negligible permeability to anions. They are most related by homology to the nicotinic acetylcholine receptor; the 5-HT3 receptor differs markedly in structure and mechanism from the other 5-HT receptor subtypes, which are all G-protein-coupled.
A functional channel may be composed of five identical 5-HT3A subunits or a mixture of 5-HT3A and one of the other four 5-HT3B, 5-HT3C, 5-HT3D, or 5-HT3E subunits. It appears. All other subunit subtypes must heteropentamerize with 5-HT3A subunits to form functional channels. Additionally, there has not been any pharmacological difference found between the heteromeric 5-HT3AC, 5-HT3AD, 5-HT3AE, the homomeric 5-HT3A receptor. N-terminal glycosylation of receptor subunits is critical for subunit assembly and plasma membrane trafficking; the subunits surround a central ion channel in a pseudo-symmetric manner. Each subunit comprises an extracellular N-terminal domain which comprises the orthosteric ligand-binding site. Whereas extracellular domain is the site of action of agonists and competitive antagonists, the transmembrane domain contains the central ion pore, receptor gate, principle selectivity filter that allows ions to cross the cell membrane; the 5-HT3 receptor gene is located on human chromosomal region 11q23.1-q23.2.
It is similar in structure to the mouse gene, spread over ~ 13 kb. Four of its introns are in the same position as the introns in the homologous α7-acetylcholine receptor gene proving their evolutionary relationship. Additional genes that code for the subunits of the 5-HT3 receptor have been identified. HTR3A and HTR3B for the 5-HT3A and 5-HT3B subunits and in addition HTR3C, HTR3D and HTR3E genes encoding 5-HT3C, 5-HT3D and 5-HT3E subunits. HTR3C and HTR3E do not seem to form functional homomeric channels, but when co-expressed with HTR3A they form heteromeric complex with decreased or increased 5-HT efficacies; the pathophysiological role for these additional subunits has yet to be identified. Expression; the 5-HT3C, 5-HT3D and 5-HT3E genes tend to show peripherally restricted pattern of expression, with high levels in the gut. In human duodenum and stomach, for example, 5-HT3C and 5-HT3E mRNA might be greater than for 5-HT3A and 5-HT3B. Polymorphism. In patients treated with chemotherapeutic drugs, certain polymorphism of the HTR3B gene could predict successful antiemetic treatment.
This could indicate that the 5-HTR3B receptor subunit could be used as biomarker of antiemetic drug efficacy. The 5-HT3 receptor is expressed throughout the central and peripheral nervous systems and mediates a variety of physiological functions. On a cellular level, it has been shown that postsynaptic 5-HT3 receptors mediate fast excitatory synaptic transmission in rat neocortical interneurons and hippocampus, in ferret visual cortex. 5-HT3 receptors are present on presynaptic nerve terminals. There is some evidence for a role in modulation of neurotransmitter release, but evidence is inconclusive; when the receptor is activated to open the ion channel by agonists, the following effects are observed: CNS: nausea and vomiting center in brain stem, seizure propensity, pro-nociception PNS: neuronal excitation, emesis Agonists for the receptor include: Cereulide 2-methyl-5-HT Alpha-Methyltryptamine Bufotenin Chlorophenylbiguanide Ethanol Ibogaine Phenylbiguanide Quipazine RS-56812: Potent and selective 5-HT3 partial agonist, 1000x selectivity over other serotonin receptors SR-57227 Varenicline YM-31636 Antagonists for the receptor include: Antiemetics AS-8112 Granisetron Ondansetron Tropisetron Gastroprokinetics Alosetron Batanopride Metoclopramide Renzapride Zacopride M1, the major active metabolite of mosapride Antidepressants Mianserin Mirtazapine Vortioxetine Antipsychotics Clozapine Olanzapine Quetiapine Antimalarials Quinine Chloroquine Mefloquine Others 3-Tropanyl indole-3-carboxylate Lamotrigine Memantine Menthol Thujone These agents are not agonists at the receptor, but increase the affinity or efficacy of the receptors for an agonist: Indole Derivatives 5-chloroindole Small Organic Anaesthetics Ethanol Chloroform Halothane Isoflurane Identification of the 5-HT3 receptor did not take place until 1986 because of a lack of selective pharmacological tool.
However, with the discovery that the 5-HT3 receptor plays a prominent role in chemotherapy- and radiotherapy-induced vomiting, the conc
Regulation of therapeutic goods
The regulation of therapeutic goods, drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency. In other jurisdictions they are regulated at the state level, or at both state and national levels by various bodies, as is the case in Australia; the role of therapeutic goods regulation is designed to protect the health and safety of the population. Regulation is aimed at ensuring the safety and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered. There is some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers. Modern drug regulation has historical roots in the response to the proliferation of universal antidotes which appeared in the wake of Mithridates' death. Mithridates had brought together physicians and shamans to concoct a potion that would make him immune to poisons.
Following his death, the Romans became keen on further developing the Mithridates potion's recipe. Mithridatium re-entered western society through multiple means; the first was through the Leechbook of the Bald, written somewhere between 900 and 950, which contained a formula for various remedies, including for a theriac. Additionally, theriac became a commercial good traded throughout Europe based on the works of Greek and Roman physicians; the resulting proliferation of various recipes needed to be curtailed in order to ensure that people were not passing off fake antidotes, which led to the development of government involvement and regulation. Additionally, the creation of these concoctions took on ritualistic form and were created in public and the process was observed and recorded, it was believed that if the concoction proved unsuccessful, it was due to the apothecaries’ process of making them and they could be held accountable because of the public nature of the creation. In the 9th century, many Muslim countries established an office of the hisba, which in addition to regulating compliance to Islamic principles and values took on the role of regulating other aspects of social and economic life, including the regulation of medicines.
Inspectors were appointed to employ oversight on those who were involved in the process of medicine creation and were given a lot of leigh weigh to ensure compliance and punishments were stringent. The first official'act', the'Apothecary Wares and Stuffs' Act was passed in 1540 by Henry VIII and set the foundation for others. Through this act, he encouraged physicians in his College of Physicians to appoint four people dedicated to inspecting what was being sold in apothecary shops. In conjunction with this first piece of legislation, there was an emergence of standard formulas for the creation of certain ‘drugs’ and ‘antidotes’ through Pharmacopoeias which first appeared in the form of a decree from Frederick II of Sicily in 1240 to use consistent and standard formulas; the first modern pharmacopoeias were the Florence Pharmacopoeia published in 1498, the Spanish Pharmacopoeia published in 1581 and the London Pharmacopoeia published in 1618. In the United States, regulation of drugs was a state right, as opposed to federal right.
But with the increase in fraudulent practices due to private incentives to maximize profits and poor enforcement of state laws, increased the need for stronger federal regulation. President Roosevelt signed the Federal Food and Drug Act in 1906 which established stricter standards. A 1911 Supreme Court decision, United States vs. Johnson, established that misleading statements were not covered under the FFDA; this directly led to Congress passing the Sherley Amendment which established a clearer definition of ‘misbranded’. Another key catalyst for advances in drug regulation were certain catastrophes that served as calls to the government to step in and impose regulations that would prevent repeats of those instances. One such instance occurred in 1937 when more than a hundred people died from using sulfanilamide elixir which had not gone through any safety testing; this directly led to the passing of the Federal, Food and Cosmetic Act in 1938. One other major catastrophe occurred in the late 1950s when Thalidomide, sold in Germany and sold around the world, led to 100,000 babies being born with various deformities.
The UK's Chief Medical Officer had established a group to look into safety of drugs on the market in 1959 prior to the crisis and was moving in the direction of address the problem of unregulated drugs entering the market. The crisis created a greater sense of emergency to establish safety and efficacy standards around the world; the UK started a temporary Committee on Safety of Drugs while they attempted to pass more comprehensive legislation. Though compliance and submission of drugs to the Committee on Safety of Drugs was not mandatory after, the pharmaceutical industry larger complied due to the thalidomide situation; the European Economic Commission passed a directive in 1965 in order to impose greater efficacy standards before marketing a drug. The United States congress passed the Drug Amendments Act of 1962 The Drug Amendments Act required the FDA to ensure that new drugs being introduced to the market had passed certain tests and standards. Both the EU and US acts introduced the requirements to ensure efficacy.
Of note, increased regulations and standards for testing led to greater innovation in pharm
Dopamine is an organic chemical of the catecholamine and phenethylamine families. It functions both as a hormone and a neurotransmitter, plays several important roles in the brain and body, it is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical L-DOPA, synthesized in the brain and kidneys. Dopamine is synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to other nerve cells; the brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, many addictive drugs increase dopamine release or block its reuptake into neurons following release. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones; these pathways and cell groups form a dopamine system, neuromodulatory.
In popular culture and media, dopamine is seen as the main chemical of pleasure, but the current opinion in pharmacology is that dopamine instead confers motivational salience. Outside the central nervous system, dopamine functions as a local paracrine messenger. In blood vessels, it acts as a vasodilator. With the exception of the blood vessels, dopamine in each of these peripheral systems is synthesized locally and exerts its effects near the cells that release it. Several important diseases of the nervous system are associated with dysfunctions of the dopamine system, some of the key medications used to treat them work by altering the effects of dopamine. Parkinson's disease, a degenerative condition causing tremor and motor impairment, is caused by a loss of dopamine-secreting neurons in an area of the midbrain called the substantia nigra, its metabolic precursor L-DOPA can be manufactured. There is evidence that schizophrenia involves altered levels of dopamine activity, most antipsychotic drugs used to treat this are dopamine antagonists which reduce dopamine activity.
Similar dopamine antagonist drugs are some of the most effective anti-nausea agents. Restless legs syndrome and attention deficit hyperactivity disorder are associated with decreased dopamine activity. Dopaminergic stimulants can be addictive in high doses, but some are used at lower doses to treat ADHD. Dopamine itself is available as a manufactured medication for intravenous injection: although it cannot reach the brain from the bloodstream, its peripheral effects make it useful in the treatment of heart failure or shock in newborn babies. A dopamine molecule consists of a catechol structure with one amine group attached via an ethyl chain; as such, dopamine is the simplest possible catecholamine, a family that includes the neurotransmitters norepinephrine and epinephrine. The presence of a benzene ring with this amine attachment makes it a substituted phenethylamine, a family that includes numerous psychoactive drugs. Like most amines, dopamine is an organic base; as a base, it is protonated in acidic environments.
The protonated form is water-soluble and stable, but can become oxidized if exposed to oxygen or other oxidants. In basic environments, dopamine is not protonated. In this free base form, it is less water-soluble and more reactive; because of the increased stability and water-solubility of the protonated form, dopamine is supplied for chemical or pharmaceutical use as dopamine hydrochloride—that is, the hydrochloride salt, created when dopamine is combined with hydrochloric acid. In dry form, dopamine hydrochloride is a fine colorless powder. Dopamine is synthesized in a restricted set of cell types neurons and cells in the medulla of the adrenal glands; the primary and minor metabolic pathways are: Primary: L-Phenylalanine → L-Tyrosine → L-DOPA → Dopamine Minor: L-Phenylalanine → L-Tyrosine → p-Tyramine → Dopamine Minor: L-Phenylalanine → m-Tyrosine → m-Tyramine → DopamineThe direct precursor of dopamine, L-DOPA, can be synthesized indirectly from the essential amino acid phenylalanine or directly from the non-essential amino acid tyrosine.
These amino acids are found in nearly every protein and so are available in food, with tyrosine being the most common. Although dopamine is found in many types of food, it is incapable of crossing the blood–brain barrier that surrounds and protects the brain, it must therefore be synthesized inside the brain to perform its neuronal activity. L-Phenylalanine is converted into L-tyrosine by the enzyme phenylalanine hydroxylase, with molecular oxygen and tetrahydrobiopterin as cofactors. L-Tyrosine is converted into L-DOPA by the enzyme tyrosine hydroxylase, with tetrahydrobiopterin, O2, iron as cofactors. L-DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, with pyridoxal phosphate as the cofactor. Dopamine itself is used as precursor in the synthesis o