Digestion of proteins

Digestion of proteins. General pathways of amino acids transformation.

Nitrogen balance.

The nitrogen balance index (NBI) is used to evaluate the amount of protein used by the body in comparison with the amount of protein supplied from daily food intake. The body is in the state of nitrogen (or protein) equilibrium when the intake and usage of protein is equal. The body has a positive nitrogen balance when the intake of protein is greater than that expended by the body. In this case, the body can build and develop new tissue. Since the body does not store protein, the overconsumption of protein can result in the excess amount to be converted into fat and stored as adipose tissue.

Blood urea nitrogen can be used in estimating nitrogen balance.

A positive value is often found during periods of growth, tissue repair or pregnancy.

This means that the intake of nitrogen into the body is greater than the loss of nitrogen from the body, so there is an increase in the total body pool of protein.

The body has a negative nitrogen balance when the intake of protein is less than that expended by the body. In this case, protein intake is less than required, and the body cannot maintain or build new tissues.

A negative nitrogen balance represents a state of protein deficiency, in which the body is breaking down tissues faster than they are being replaced. The ingestion of insufficient amounts of protein, or food with poor protein quality, can result in serious medical conditions in which an individual's overall health is compromised. The immune system is severely affected; the amount of blood plasma decreases, leading to medical conditions such as anemia or edema; and the body becomes vulnerable to infectious diseases and other serious conditions. Protein malnutrition in infants is called kwashiorkor, and it poses a major health problem in developing countries, such as Africa, Central and South America, and certain parts of Asia. An infant with kwashiorkor suffers from poor muscle and tissue development, loss of appetite, mottled skin, patchy hair, diarrhea, edema, and, eventually, death (similar symptoms are present in adults with protein deficiency). Treatment or prevention of this condition lies in adequate consumption of protein-rich foods.

A negative value can be associated with burns, fevers, wasting diseases and other serious injuries and during periods of fasting. This means that the amount of nitrogen excreted from the body is greater than the amount of nitrogen ingested.

It can be used in the evaluation of malnutrition.

The difference between the total nitrogen intake by an organism and its total nitrogen loss. A normal, healthy adult has a zero nitrogen balance.

Essential and nonessential amino acids.

THE TWENTY AMINO ACIDS

Name	Abbreviation	Linear structure formula (atom composition and bonding)
SOURCE: Institute for Chemistry
Alanine	ala	CH₃-CH(NH₂)-COOH
Arginine	arg	HN=C(NH₂)-NH-(CH₂)3-CH(NH₂)-COOH
Asparagine	asn	H₂N-CO-CH₂-CH(NH₂)-COOH
Aspartic acid	asp	HOOC-CH₂-CH(NH₂)-COOH
Cysteine	cys	HS-CH₂-CH(NH₂)-COOH
Glutamine	gln	H2N-CO-(CH₂)2-CH(NH₂)-COOH
Glutamic acid	glu	HOOC-(CH₂)2-CH(NH₂)-COOH
Glycine	gly	NH₂-CH₂-COOH
Histidine	his	NH-CH=N-CH=C-CH₂-CH(NH₂)-COOH \|____________\|
Isoleucine	ile	CH₃-CH2-CH(CH₃)-CH(NH₂)-COOH
Leucine	leu	(CH₃)2-CH-CH₂-CH(NH₂)-COOH
Lysine	lys	H₂N-(CH₂)4-CH(NH₂)-COOH
Methionine	met	CH₃-S-(CH₂)2-CH(NH₂)-COOH
Phenylalanine	phe	Ph-CH₂-CH(NH₂)-COOH
Proline	pro	NH-(CH₂)3-CH-COOH \|__________\|
Serine	ser	HO-CH₂-CH(NH₂)-COOH
Threonine	thr	CH₃-CH(OH)-CH(NH₂)-COOH
Tryptophan	trp	Ph-NH-CH=C-CH₂-CH(NH₂)-COOH \|_________\|
Tyrosine	tyr	HO-Ph-CH₂-CH(NH₂)-COOH
Valine	val	(CH₃)2-CH-CH(NH₂)-COOH

consist of a sufficient and balanced supply of both essential and nonessential amino acids in order to ensure high levels of protein production.

Essential vs. Nonessential Amino Acids

Nonessential	Essential
Alanine	Arginine*
Asparagine	Histidine
Aspartate	Isoleucine
Cysteine	Leucine
Glutamate	Lysine
Glutamine	Methionine*
Glycine	Phenylalanine*
Proline	Threonine
Serine	Tryptophan
Tyrosine	Valine
The amino acids arginine, methionine and phenylalanine are considered essential for reasons not directly related to lack of synthesis. Arginine is synthesized by mammalian cells but at a rate that is insufficient to meet the growth needs of the body and the majority that is synthesized is cleaved to form urea. Methionine is required in large amounts to produce cysteine if the latter amino acid is not adequately supplied in the diet. Similarly, phenyalanine is needed in large amounts to form tyrosine if the latter is not adequately supplied in the diet.

The quality of protein depends on the level at which it provides the nutritional amounts of essential amino acids needed for overall body health, maintenance, and growth. Animal proteins, such as eggs, cheese, milk, meat, and fish, are considered high-quality, or complete, proteins because they provide sufficient amounts of the essential amino acids. Plant proteins, such as grain, corn, nuts, vegetables and fruits, are lower-quality, or incomplete, proteins because many plant proteins lack one or more of the essential amino acids, or because they lack a proper balance of amino acids. Incomplete proteins can, however, be combined to provide all the essential amino acids, though combinations of incomplete proteins must be consumed at the same time, or within a short period of time (within four hours), to obtain the maximum nutritive value from the amino acids. Such combination diets generally yield a high-quality protein meal, providing sufficient amounts and proper balance of the essential amino acids needed by the body to function.

Digestion of proteins in stomach and small intestine.

Chemical composition of digestive juices.

Proteolytic enzymes and their activation.

Digestion in the stomach

Chemical digestion begins in the stomach. The stomach is a large, hollow, pouched-shaped muscular organ. Food in the stomach is broken down by the action of gastric juice, which contains hydrochloric acid and pepsin (an enzyme that digests protein). The stomach begins its production of gastric juice while food is still in the mouth. Nerves from the cheeks and tongue are stimulated and send messages to the brain. The brain in turn sends messages to nerves in the stomach wall, stimulating the secretion of gastric juice before the arrival of food. The second signal for gastric juice production occurs when food arrives in the stomach and touches the lining.

Gastric juice is secreted from the linings of the stomach walls, along with mucus that helps to protect the stomach lining from the action of the acid. Three layers of powerful stomach muscles churn food into a thick liquid called chyme (pronounced KIME). From time to time, chyme is passed through the pyloric sphincter, the opening between the stomach and the small intestine.

Protein digestion begins when the food reaches the stomach and stimulates the release of hydrochloric acid (HCl) by the parietal cells located in the gastric mucosa of the GI (gastrointestinal) tract. Hydrochloric acid provides for a very acidic environment, which helps the protein digestion process in two ways:

(1) through an acid-catalyzed hydrolysis reaction of breaking peptide bonds (the chemical process of breaking peptide bonds is referred to as a hydrolysis reaction because water is used to break the bonds); and (2) through conversion of the gastric enzyme pepsinogen (an inactive precursor) to pepsin (the active form). Pepsinogen is stored and secreted by the "chief cells" that line the stomach wall. Once converted into the active form, pepsin attacks the peptide bonds that link amino acids together, breaking the long polypeptide chain into shorter segments of amino acids known as dipeptides and tripeptides.

These protein fragments are then further broken down in the duodenum of the small intestines.

(2) The brush border enzymes, which work on the surface of epithelial cells of the small intestines, hydrolyze the protein fragments into amino acids.

Digestion and absorption in the small intestine

The small intestine is a long, narrow tube running from the stomach to the large intestine. The small intestine is greatly coiled and twisted. Its full length is about 20 feet (6 meters). The small intestine is subdivided into three sections: the duodenum (pronounced do-o-DEE-num), the jejunum (pronounced je-JOO-num), and the ileum (pronounced ILL-ee-um).The cells of the small intestine actively absorb the amino acids through a process that requires energy.

The duodenum is about 10 inches (25 centimeters) long and connects with the lower portion of the stomach. When chyme reaches the duodenum, it is further broken down by intestinal juices and through the action of the pancreas and gall bladder. The pancreas is a large gland located below the stomach that secretes pancreatic juice into the duodenum through the pancreatic duct. There are three enzymes in pancreatic juice that break down carbohydrates, fats, and proteins. The gall bladder, located next to the liver, stores bile produced by the liver. While bile does not contain enzymes, it contains bile salts that help to dissolve fats. The gall bladder empties bile into the duodenum when chyme enters that portion of the intestine.

The amino acids travel through the hepatic portal vein to the liver, where the nutrients are processed into glucose or fat (or released into the bloodstream). The tissues in the body take up the amino acids rapidly for glucose production, growth and maintenance, and other vital cellular functioning. For the most part, the body does not store protein, as the metabolism of amino acids occurs within a few hours.

Breakdown of Food

Amino acids are metabolized in the liver into useful forms that are used as building blocks of protein in tissues. The body may utilize the amino acids for either anabolic or catabolic reactions. Anabolism refers to the chemical process through which digested and absorbed products are used to effectively build or repair bodily tissues, or to restore vital substances broken down through metabolism. Catabolism, on the other hand, is the process that results in the release of energy through the breakdown of nutrients, stored materials, and cellular substances. Anabolic and catabolic reactions work hand-in-hand, and the energy produced in catabolic processes is used to fuel essential anabolic processes. The vital biochemical reaction of glycolysis (in which glucose is oxidized to produce carbon dioxide, water, and cellular energy) in the form of adenosine triphosphate, or ATP, is a prime example of a catabolic reaction. The energy released, as ATP, from such a reaction is used to fuel important anabolic processes, such as protein synthesis.

Absorption and elimination in the large intestine

Rotting of proteins in a large intestine, products.

The large intestine performs the following functions:

- reabsorbs water and maintains the fluid balance of the body

· - absorbs certain vitamins

· - processes undigested material (fibre)

· - stores waste before it is eliminated.

The large intestine is wider and heavier than the small intestine. However, it is much shorter—only about 5 feet (1.5 meters) long. It rises up on the right side of the body (the ascending colon), crosses over to the other side underneath the stomach (the transverse colon), descends on the left side, (the descending colon), then forms an s-shape (the sigmoid colon) before reaching the rectum and anus. The muscular rectum, about 6 inches (16 centimeters) long, expels feces (stool) through the anus, which has a large muscular sphincter that controls the passage of waste matter.

The large intestine removes water from the waste products of digestion and returns some of it to the bloodstream. Fecal matter contains undigested food, bacteria, and cells from the walls of the digestive tract. Millions of bacteria in the large intestine help to produce certain B vitamins and vitamin K. These vitamins are absorbed into the bloodstream along with the water.

Caecum

The caecum is the first part of the large intestine. Shaped like a small pouch and located in the right lower abdomen, it is the connection between the small intestine and the colon.

The caecum accepts and stores processed material from the small intestine and moves it towards the colon. As the processed food approaches the end of the small intestine, a valve separating the small and large intestines opens, the caecum expands and the material enters. At this stage, the mixture normally contains:

· undigested food (fibre)

· a little bit of water

· some vitamins

· some minerals or salts

The metabolism of amino acids can be understood from the dynamic catabolic and anabolic processes. In the process referred to as deamination, the nitrogen-containing amino group (NH₂) is cleaved from the amino acid unit. In this reaction, which requires vitamin B6 as a cofactor, the amino group is transferred to an acceptor keto-acid, which can form a new amino acid. Through this process, the body is able to make the nonessential amino acids not provided by one's diet. The keto-acid intermediate can also be used to synthesize glucose to ultimately yield energy for the body, and the cleaved nitrogen-containing group is transformed into urea, a waste product, and excreted as urine.

Proteins are vital to basic cellular and body functions, including cellular regeneration and repair, tissue maintenance and regulation, hormone and enzyme production, fluid balance, and the provision of energy.

The kinds of gastric juice acidity

Your stomach is where the food you eat is broken down into smaller pieces. This action is called digestion.

Stomach (gastric) juice is the term used to describe the chemicals that break down food in the stomach. These include hydrochloric acid and an enzyme called pepsin. Gastric juice is sometimes referred to as stomach acid, although not all of the substances in gastric juice are acidic.

Hypoaciditas, hyperaciditas, anaciditas, hypochlorhydria, hyperchlorhydria, achlorhydria.

HYPOCHLORHYDRIA (Obvious) is the lack of adequate production of Hydrochloric Acid (HCL) by the Stomach Parietal Cells.

Many people, in the process of aging, develop various stages of Hypochlorhydria; however, it is not confined to this aging group. Many young people also develop this problem. Bear in mind that the presence of HCL in the Stomach generally inhibits (slows down or stops) the reflex of “rapid-dumping” of foods out of the Stomach, rendering the critical First Stage of Digestion partially or totally incomplete. Also, HCL performs a natural sterilization of the foods that we swallow. This is quite important, because nothing that we eat is sterile. In the pre-digestion phase of the Stomach, HCL, Pepsin, certain Enzymes, plus the Intrinsic Factor, which is essential for the absorption of Vitamin B-12, play key rolls in the conversion processes of Proteins to Amino Acids and Starches to Sugars that can be utilized by our bodies (in conjunction with the Duodenal, 2nd Phase of Digestion).

ACHLORHYDRIA

ACHLORHYDRIA is the total absence of HCL production in the stomach.

Patients with Achlorhydria May Have a form of Pernicious Anemia. This will also show in a routine Blood test. When the Anemia is corrected the Stomachs Parietal Function will generally return to Normal.

HYPERCHLORHYDRIA

HYPERCHLORHYDRIA, The above Graph indicates the excess production of Hydrochloric Acid (HCL). This condition may cause Delayed, or Marked-delayed, emptying time of the Stomach's contents. In many cases, Patients with Delayed and Marked-delayed emptying, will retain food in their Stomachs for 6 to 24 hours, or much longer in many cases.

Mechanism of amino acid absorption.

Intestinal barrier function regulates transport and host defense mechanisms at the mucosal interface with the outside world. Transcellular and paracellular fluxes are tightly controlled by membrane pumps, ion channels and tight junctions, adapting permeability to physiological needs. Permeability greatly defines the absorbance of compounds in the intestine. In case of high permeability compounds it is unlikely that the absorption will be modified by transporters, yet the test compound might be involved in transporter mediated drug-drug interactions. The absorption of medium and low permeability compounds can be affected by membrane transporters located at the endothelial cells of the intestinal barrier.

In the intestine transporters are localized in the brush border membrane and on the basolateral side of intestinal cells. Four major ABC efflux transporters have been shown to localize at the apical/luminal membrane of enterocytes, and thus are thought to form a barrier to intestinal absorption of substrate drugs.

General pathways of amino acids transformation

Deamination of amino acids, it kinds. The role of vitamins in deamination of amino acids.

Oxidative Deamination Reaction

Deamination is also an oxidative reaction that occurs under aerobic conditions in all tissues but especially the liver. During oxidative deamination, an amino acid is converted into the corresponding keto acid by the removal of the amine functional group as ammonia and the amine functional group is replaced by the ketone group. The ammonia eventually goes into the urea cycle.

Oxidative deamination occurs primarily on glutamic acid because glutamic acid was the end product of many transamination reactions.

The glutamate dehydrogenase is allosterically controlled by ATP and ADP. ATP acts as an inhibitor whereas ADP is an activator.

Central Role for Glutamic Acid:

Apparently most amino acids may be deaminated but this is a significant reaction only for glutamic acid. If this is true, then how are the other amino acids deaminated? The answer is that a combination of transamination and deamination of glutamic acid occurs which is a recycling type of reaction for glutamic acid. The original amino acid loses its amine group in the process. The general reaction sequence is shown on the left.

Synthesis of New Amino Acids:

The same reaction works in reverse for the synthesis of amino acids. In this situation alpha-ketoglutaric acid first uses transamination of a different amino acid to make glutamic acid, which then reacts with a keto acid to make a new amino acid. In effect, the interconversion of alpha-ketoglutaric acid and glutamic acid lies at the very heart of nitrogen metabolism. These molecules serve as the "collection and receiving agent" for nitrogen. The subsequent fate of the amino group is in new amino acids, any nitrogen bases, or any other nitrogen containing compounds.

Transamination of amino acids, mechanism, role of enzymes and coenzymes.

Transamination as the name implies, refers to the transfer of an amine group from one molecule to another. This reaction is catalyzed by a family of enzymes called transaminases. Actually, the transamination reaction results in the exchange of an amine group on one acid with a ketone group on another acid. It is analogous to a double replacement reaction.

Pyridoxine is an example of a vitamin which is required for the synthesis of a coenzyme. Other examples which you have met in this course are listed in the table below.

vitamin	cofactor	example enzymes
pyridoxine (vit b6)	pyridoxal phosphate	transaminases
niacin (nicotinamide)	NAD⁺/ NADP⁺	malate dehydrogenase
riboflavin (vit b2)	FAD	succinate dehydrogenase
thiamine (vit b1)	TPP	pyruvate dehydrogenase
pantothenate	Coenzyme A	fatty acid metabolism

The most usual and major keto acid involved with transamination reactions is alpha-ketoglutaric acid, an intermediate in the citric acid cycle. A specific example is the transamination of alanine to make pyruvic acid and glutamic acid.

Other amino acids which can be converted after several steps through transamination into pyruvic acid include serine, cysteine, and glycine.

Other Transamination Reactions:

Aspartic acid can be converted into oxaloacetic acid, another intermediate of the citric acid cycle. Other amino acids such as glutamine, histidine, arginine, and proline are first converted into glutamic acid.

Glutamine and asparagine are converted into glutamic acid and aspartic acid by a simple hydrolysis of the amide group.

All of the amino acids can be converted through a variety of reactions and transamination into a keto acid which is a part of or feeds into the citric acid cycle. The interrelationships of amino acids with the citric acid cycle are illustrated in the graphic on the left.

Amino Acids in Overall Metabolism:

Once the keto acids have been formed from the appropriate amino acids by transamination, they may be used for several purposes. The most obvious is the complete metabolism into carbon dioxide and water by the citric acid cycle.

However, if there are excess proteins in the diet those amino acids converted into pyruvic acid and acetyl CoA can be converted into lipids by the lipogenesis process. If carbohydrates are lacking in the diet or if glucose cannot get into the cells (as in diabetes), then those amino acids converted into pyruvic acid and oxaloacetic acids can be converted into glucose or glycogen.

The hormones cortisone and cortisol from the adrenal cortex stimulate the synthesis of glucose from amino acids in the liver and also function as antagonists to insulin

Synthesis of New Amino Acids:

In addition to the catabolic function of transamination reactions, these reactions can also be used to synthesize amino acids needed or not present in the diet. An amino acid may be synthesized if there is an available "root" ketoacid with a synthetic connection to the final amino acid. Since an appropriate "root" keto acid does not exist for eight amino acids, (lys, leu, ile, met, thr, try, val, phe), they are essential and must be included in the diet because they cannot be synthesized.

Glutamic acid usually serves as the source of the amine group in the transamination synthesis of new amino acids. The reverse of the reactions mentioned earlier are the most obvious methods for producing the amino acids alanine and aspartic acid.

Several nonessential amino acids are made by processes other than transamination. Cysteine is made from methionine, and serine and glycine are synthesized from phosphoglyceric acid - an intermediate of glycolysis

The correlation between transamination and deamination.

Pathways

Decarboxylisation of amino acids, role of enzymes and co-enzymes.

Decarboxylation is any chemical reaction in which a carboxyl group (-COOH) is split off from a compound as carbon dioxide (CO₂).

Common biosynthetic decarboxylations of amino acids to amines are:

Other decarboxylation reactions from the citric acid cycle include:

Enzymes that catalyze decarboxylations are called decarboxylases or, more formally, carboxy-lyases . Carboxy-lyases, also known as decarboxylases, are carbon-carbon lyases that add or remove a carboxyl group from organic compounds. These enzymes catalyze the decarboxylation of amino acids, beta-keto acids and alpha-keto acids

Heating or pyrolysis of Δ9-Tetrahydrocannabinolic acid yields the psychoactive compound

Main bioactive amines, their source and role in organism.

Fig. 1. The formation of biogenic amines with an example of tyramine production.

Biogenic amines are basic nitrogenous low molecular weight compounds with biological activity that may be formed or catabolised during the normal metabolism of animals, plants and micro-organisms. Biogenic amines are derived mainly from amino acids through substrate-specific decarboxylase enzymes. Amines may be formed by yeasts during the alcoholic fermentation (mostly putrazine); by lactic acid bacteria (LAB) during malolactic fermentation (MLF. Biogenic amines can also be present in the must, just as putrescine in grapes is associated with potassium deficiencies in the soil. The main biogenic amines are histamine, tyramine, putrescine, cadaverine and phenylethylamine. Microorganisms decarboxylise amino acids in order to provide the cell with energy and to protect the cell against acidic environments by increasing the pH.

Biogenic amines are important because they contain a health risk for sensitive individuals. Symptoms include nausea, respiratorial discomfort, hot flushes, cold sweat, palpitations, headaches, red rash, high or low blood pressure. Alcohol and acetaldehyde have been found to increase the sensitivity to biogenic amines.

Mast cells release histamine when an allergen is encountered.

The histamine response can produce sneezing, itching, hives and watery eyes.

Allergies.
Some antigens, termed allergens trigger the release of IgE antibodies from specialized B cells. The antibodies are inserted into the membrane of leucocytes called mast cells. If the allergen is again presented to an activated mast cell, it binds to the cell surface of the mast cell. This triggers the cell to release histamine and leucotrines that cause allergic reactions

Serotonin

Serotonin is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system (CNS) and enterochromaffin cells in the gastrointestinal tract. Serotonin is synthesized extensively in the human gastrointestinal tract (about 90%), and the major storage place is platelets in the blood stream.

In the central nervous system, serotonin is believed to play an important role in the regulation of body temperature, mood, sleep, vomiting, sexuality, and appetite. Low levels of serotonin have been associated with several disorders, notably clinical depression, migraine, irritable bowel syndrome, tinnitus, fibromyalgia, bipolar disorder, and anxiety disorders.

The pharmacology of 5-HT is extremely complex, with its actions being mediated by a large and diverse range of 5-HT receptors. At least seven different receptor "families" are known to exist, each located in different parts of the body and triggering different responses. As with all neurotransmitters, the effects of 5-HT on the human mood and state of mind, and its role in consciousness, are very difficult to ascertain. Serotonin (5-HT) receptors are also used by other psychoactive drugs, including LSD, DMT, and psilocybin, the active ingredient in psychedelic mushrooms.

Serotonin uptake

The body sometimes deliberately prolongs the transmission of a signal across a synapse by slowing the destruction of neurotransmitters. It does this by releasing into the synapse special long-lasting chemicals called neuromodulators. Some neuromodulators aid the release of neurotransmitters into the synapse; others inhibit the reabsorption of neurotransmitters so that they remain in the synapse; still others delay the breakdown of neurotransmitters after their reabsorption, leaving them in the tip to be released back into the synapse when the next signal arrives.

Mood, pleasure, pain, and other mental states are determined by particular groups of neurons in the brain that use special sets of neurotransmitters and neuromodulators. Mood, for example, is strongly influenced by the neurotransmitter serotonin. Many researchers think that depression results from a shortage of serotonin. Prozac, the world’s bestselling antidepressant, inhibits the reabsorption of serotonin, thus increasing the amount in the synapse.

Drugs alter transmission of impulses across the synapse.

Depression can result from a shortage of the neurotransmitter serotonin. The antidepressant drug Prozac works by blocking reabsorption of serotonin in the synapse, making up for the shortage.

Dopamine - an important transmitter

Arvid Carlsson performed a series of pioneering studies during the late 1950's, which showed that dopamine is an important transmitter in the brain. It was previously believed that dopamine was only a precursor of another transmitter, noradrenaline. Arvid Carlsson developed an assay that made it possible to measure tissue levels of dopamine with high sensitivity. He found that dopamine was concentrated in other areas of the brain than noradrenaline, which led him to the conclusion that dopamine is a transmitter in itself. Dopamine existed in particularly high concentrations in those parts of the brain, called the basal ganglia, which are of particular importance for the control of motor behavior.

Drugs against Parkinson's disease
Arvid Carlsson realized that the symptoms caused by reserpine were similar to the syndrome of Parkinson's disease. This led, in turn, to the finding that Parkinson patients have abnormally low concentrations of dopamine in the basal ganglia. As a consequence L-dopa was developed as a drug against Parkinson's disease and today still is the most important treatment for the disease. During Parkinson's disease dopamine producing nerve cells in the basal ganglia degenerate, which causes tremor, rigidity and akinesia. L-dopa, which is converted to dopamine in the brain, compensates for the lack of dopamine and normalizes motor behavior.

Antipsychotic and antidepressive drugs
Apart from the successful treatment of Parkinson's disease Arvid Carlsson's research has increased our understanding of the mechanism of several other drugs. He showed that antipsychotic drugs, mostly used against schizophrenia, affect synaptic transmission by blocking dopamine receptors. The discoveries of Arvid Carlsson have had great importance for the treatment of depression, which is one of our most common diseases. He has contributed strongly to the development of selective serotonin uptake blockers, a new generation of antidepressive drugs.

Dopamine nerve pathways in the brain. Arvid Carlsson showed that there were particularly high levels of the chemical transmitter dopamine in the so called basal ganglia of the brain, which are of major importance for instance for the control of our muscle movements. In Parkinson's disease those dopamine producing nerve cells whose nerve fibers project to the basal ganglia die. This causes symptoms such as tremor, muscle rigidity and a decreased ability to move about.

A message from one nerve cell to another is transmitted with the help of different chemical transmitters. This occurs at specific points of contact, synapses, between the nerve cells. The chemical transmitter dopamine is formed from the precursors tyrosine and L-dopa and is stored in vesicles in the nerve endings. When a nerve impulse causes the vesicles to empty, dopamine receptors in the membrane of the receiving cell are influenced such that the message is carried further into the cell. In the treatment of Parkinson's disease, the drug L-dopa is given, and is converted to dopamine in the brain. This compensates for the patient's lack of dopamine.

Sedatives

Sedatives (SED-uh-tivz), sometimes called as tranquilizers (TRANK-will-LY-zerz) or sleeping pills, include barbiturates or "downers." They are drugs that produce a calming effect or sleepiness. Physicians prescribe them to relieve anxiety, promote sleep, and treat seizures. When they are abused or taken at high doses, however, many of these drugs can lead to loss of consciousness or even death. Combining sedatives with alcohol is particularly dangerous. Possible effects of sedative abuse include poor judgment, slurred speech, staggering, poor coordination, and slow reflexes.

Cocaine is a mood-altering drug that interferes with normal transport of the neurotransmitter dopamine, which carries messages from neuron to neuron. When cocaine molecules block dopamine receptors, too much dopamine remains active in the synaptic gaps between neurons, creating feelings of excitement and euphoria.

GABA - $\gamma$ -aminobutyric acid

The term GABA refers to the simple chemical substance $\gamma$ -aminobutyric acid (NH₂CH₂CH₂ CH₂COOH). It is the major inhibitory neurotransmitter in the central nervous system. Its presence in the brain first was reported in 1950 (Roberts and Frankel, 1950a).

For several years the presence of GABA in brain remained a biochemical curiosity and a physiological enigma. It was remarked in the first review written on GABA that “Perhaps the most difficult question to answer would be whether the presence in the gray matter of the central nervous system of uniquely high concentrations of $\gamma$ -aminobutyric acid and the enzyme which forms it from glutamic acid has a direct or indirect connection to conduction of the nerve impulse in this tissue” . However, later that year, the first suggestion that GABA might have an inhibitory function in the vertebrate nervous system came from studies in which it was found that topically applied solutions of GABA exerted inhibitory effects on electrical activity in the brain. In 1957, the suggestion was made that indigenously occurring GABA might have an inhibitory function in the central nervous system from studies with convulsant hydrazides.

Also in 1957, suggestive evidence for an inhibitory function for GABA came from studies that established GABA as the major factor in brain extracts responsible for the inhibitory action of these extracts on the crayfish stretch receptor system. Within a brief period the activity in this field increased greatly, so that the research being carried out ranged all the way from the study of the effects of GABA on ionic movements in single neurons to clinical evaluation of the role of the GABA system in epilepsy, schizophrenia, mental retardation, etc. This surge of interest warranted the convocation in 1959 of the first truly interdisciplinary neuroscience conference ever held, at which were present most of the individuals who had played a role in opening up this exciting field.

Schematic representation of the gamma-aminobutyric acid (GABAA) receptor

Schematic representation of the gamma-aminobutyric acid (GABA_A) receptor. The functional receptor consists of five proteins, or subunits--most likely two α subunits, one β subunit, and two γ subunits. (Question marks indicate that the identity of these subunits has not been confirmed.) The proposed binding sites for GABA (α and β subunits), benzodiazepines (adjacent α and γ subunits), barbituates (unidentified subunit), and alcohol α, β, and γ subunits) are indicated. P's represent phosphate groups attached to the receptor that regulate the receptor's activity and sensitivity to alcohol.