Dopamine and Serotonin

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The dopamine system is associated with reward, attention, short-term memory tasks, planning, and motivation. Dopamine tends to limit and select sensory information arriving from the thalamus to the fore-brain. A report from the National Institute of Mental Health says a gene variant that reduces dopamine activity in the prefrontal cortex is related to poorer performance and inefficient functioning of that brain region during working memory tasks, and to slightly increased risk for schizophrenia.

(http://en.wikipedia.org/wiki/Frontal_lobe)

Dopamine

The five known types of dopamine receptors—D₁, D₂, D₃, D₄, and D₅—and their variants.

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Dopamine was first synthesized in 1910 by George Barger and James Ewens at Wellcome Laboratories in London, England.  It was named dopamine because it is a monoamine whose precursor in the Barger-Ewens synthesis is 3,4-dihydroxyphenylalanine (levodopamine or L-DOPA).

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Dopamine has many functions in the brain, including important roles in behavior and cognition, voluntary movement, motivation, punishment and reward, inhibition of prolactin production (involved in lactation and sexual gratification), sleep, mood, attention, working memory, and learning.

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The reward system in insects uses octopamine, which is the presumed arthropod homolog of norepinephrine,  rather than dopamine. In insects, dopamine acts instead as a punishment signal and is necessary to form aversive memories. 

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In the frontal lobes, dopamine controls the flow of information from other areas of the brain. Dopamine disorders in this region of the brain can cause a decline in neurocognitive functions, especially memory, attention, and problem-solving. Reduced dopamine concentrations in the prefrontal cortex are thought to contribute to attention deficit disorder. It has been found that D1 receptors  as well as D4 receptors are responsible for the cognitive-enhancing effects of dopamine, whereas D2 receptors are more specific for motor actions.

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In humans, drugs that reduce dopamine activity (neuroleptics, e.g. antipsychotics) have been shown to impair concentration, reduce motivation, cause anhedonia (inability to experience pleasure), and long-term use has been associated with tardive dyskinesia, an irreversible movement disorder. Antipsychotics have significant effects on gonadal hormones including significantly lower levels of estradiol and progesterone in women whereas men display significantly lower levels of testosterone and DHEA when undergoing antipsychotic drug treatment compared to controls. Antipsychotics are known to cause hyperprolactinaemia leading to amenorrhea, cessation of normal cyclic ovarian function, loss of libido, occasional hirsutism, false positive pregnancy tests, and long-term risk of osteoporosis in women. The effects of hyperprolactinemia in men are gynaecomastia, lactation, impotence, loss of libido, and hypospermatogenesis. Furthermore, antipsychotic drugs are associated with weight gain, diabetes, drooling, dysphoria (abnormal depression and discontent), fatigue, sexual dysfunction, heart rhythm problems, stroke and heart attack. Selective D2/D3 agonists pramipexole and ropinirole, used to treat restless legs syndrome (RLS), have limited anti-anhedonic properties as measured by the Snaith-Hamilton Pleasure Scale (SHAPS).

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Sociability is also closely tied to dopamine neurotransmission. Low D2 receptor-binding is found in people with social anxiety. Traits common to negative schizophrenia (social withdrawal, apathy, anhedonia) are thought to be related to a hypodopaminergic state in certain areas of the brain. In instances of bipolar disorder, manic subjects can become hypersocial, as well as hypersexual.^{[citation needed]} This is credited to an increase in dopamine, because mania can be reduced by dopamine-blocking antipsychotics.

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Abnormally high dopaminergic transmission has been linked to psychosis and schizophrenia. Increased dopaminergic functional activity, specifically in the mesolimbic pathway, is found in schizophrenic individuals. However, decreased activity in another dopaminergic pathway, the mesocortical pathway, may also be involved. The two pathways are thought to be responsible for differing sets of symptoms seen in schizophrenia.^{[citation needed]}Antipsychotic medications act largely as dopamine antagonists, inhibiting dopamine at the receptor level, and thereby blocking the effects of the neurochemical in a dose-dependant manner. The older, so-called typical antipsychotics most commonly act on D2 receptors, while the atypical drugs also act on D1, D3 and D4 receptors. The finding that drugs such as amphetamines, methamphetamine and cocaine, which can increase dopamine levels by more than tenfold, can temporarily cause psychosis, provides further evidence for this link.

(http://en.wikipedia.org/wiki/Dopamine)

Serotonin

Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal (GI) tract, platelets, and in the central nervous system (CNS) of animals including humans. It is popularly thought to be a contributor to feelings of well-being and happiness.

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Approximately 90% of the human body’s total serotonin is located in the enterochromaffin cells in the gut, where it is used to regulate intestinal movements.^[6][7] The remainder is synthesized in serotonergic neurons in the CNS where it has various functions. These include the regulation of mood, appetite, and sleep. Serotonin also has some cognitive functions, including in memory and learning. Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants.

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Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it. When the platelets bind to a clot, they disgorge serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting. Serotonin also is a growth factor for some types of cells, which may give it a role in wound healing.

Serotonin is mainly metabolized to 5-HIAA, chiefly by the liver. Metabolism involves first oxidation by monoamine oxidase ( MAO ) to the corresponding aldehyde…One type of tumor, called carcinoid, sometimes secretes large amounts of serotonin into the blood, which causes various forms of the carcinoid syndrome of flushing, diarrhea, and heart problems. Because of serotonin’s growth promoting effect on cardiac myocytes, persons with serotonin-secreting carcinoid may suffer a right heart (tricuspid) valve disease syndrome, caused by proliferation of myocytes onto the valve.

In addition to animals, serotonin is also found in fungi and plants. Serotonin’s presence in insect venoms and plant spines serves to cause pain, which is a side effect of serotonin injection. Serotonin is produced by pathogenic amoebas, and its effect on the gut causes diarrhea. Its widespread presence in many seeds and fruits may serve to stimulate the digestive tract into expelling the seeds.

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For example, in the roundworm C. elegans, which feeds on bacteria, serotonin is released as a signal in response to positive events, e.g., finding a new source of food or in male animals finding a female with which to mate. When a well-fed worm feels bacteria on its cuticle, dopamine is released, which slows it down; if it is starved, serotonin also is released, which slows the animal down further. This mechanism increases the amount of time animals spend in the presence of food. The released serotonin activates the muscles used for feeding, while octopamine suppresses them. Serotonin diffuses to serotonin-sensitive neurons, which control the animal’s perception of nutrient availability. This system has been partially conserved during the 700 million years of evolution which separate C. elegans from humans. When humans smell food, dopamine is released to increase the appetite. But unlike in worms, serotonin does not increase anticipatory behaviour in humans; instead, the serotonin released while consuming activates 5-HT2C receptors on dopamine-producing cells. This halts their dopamine release, and thereby serotonin decreases appetite. Drugs which block 5-HT_2C receptors make the body unable to shut off appetite, and are associated with increased weight gain, especially in people who have a low number of receptors. The expression of 5-HT_2C receptors in the hippocampus follows a diurnal rhythm, just as the serotonin release in the ventromedial nucleus, which is characterised by a peak at morning when the motivation to eat is strongest.

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The gut is surrounded by enterochromaffin cells, which release serotonin in response to food in the lumen. This makes the gut contract around the food. Platelets in the veins draining the gut collect excess serotonin.

If irritants are present in the food, the enterochromaffin cells release more serotonin to make the gut move faster, i.e., to cause diarrhea, so that the gut is emptied of the noxious substance. If serotonin is released in the blood faster than the platelets can absorb it, the level of free serotonin in the blood is increased. This activates 5HT3 receptors in the chemoreceptor trigger zone that stimulate vomiting. The enterochromaffin cells not only react to bad food, they are also very sensitive to irradiation and cancer chemotherapy. Drugs that block 5HT3 are very effective in controlling the nausea and vomiting produced by cancer treatment, and are considered the gold standard for this purpose.

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How much food an animal gets not only depends on the abundance of food, but also on the animal’s ability to compete with others. This is especially true for social animals, where the stronger individuals might steal food from the weaker. Thus, serotonin is not only involved in the perception of food availability, but also of social rank. If a lobster is injected with serotonin, it behaves like a dominant animal, while octopamine causes subordinate behavior. A frightened crayfish flips its tail to flee, and the effect of serotonin on this behavior depends on the animal’s social status. Serotonin inhibits the fleeing reaction in subordinates, but enhances it in socially dominant or isolated individuals. The reason for this is social experience alters the proportion between serotonin receptors (5-HT receptors) that have opposing effects on the fight-or-flight response. The effect of 5-HT₁ receptors predominates in subordinate animals, while 5-HT₂ receptors predominates in dominants. In humans, levels of 5-HT_1A receptor activation in the brain show negative correlation with aggression, and a mutation in the gene that codes for the 5-HT_2A receptor may double the risk of suicide for those with that genotype. Most of the brain serotonin is not degraded after use, but is collected by serotonergic neurons by serotonin transporters on their cell surfaces. Studies have revealed nearly 10% of total variance in anxiety-related personality depends on variations in the description of where, when and how many serotonin transporters the neurons should deploy, and the effect of this variation was found to interact with the environment in depression.

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Serotonin has also been identified as the trigger for swarm behavior in locusts.

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Serotonin in mammals is made by two different tryptophan hydroxylases: TPH1 produces serotonin in the pineal gland^{[citation needed]} and the enterochromaffin cells, while TPH2 produces it in the raphe nuclei and in the myenteric plexus. Genetically altered mice lacking TPH1 develop progressive loss of heart strength early on. They have pale skin and breathing difficulties, are easily tired, and eventually die of heart failure. Genetically altered mice that lack TPH2 are normal when they are born. However, after three days they appear to be smaller and weaker, and have softer skin than their siblings. In a purebred strain, 50% of the mutants died during the first four weeks, but in a mixed strain, 90% survived. Normally, the mother weans the litter after three weeks, but the mutant animals needed five weeks. After that, they caught up in growth and had normal mortality rates. Subtle changes in the autonomic nervous system are present, but the most obvious difference from normal mice is the increased aggressiveness and impairment in maternal care of young.

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n humans, defective signaling of serotonin in the brain may be the root cause of sudden infant death syndrome (SIDS). Scientists from the European Molecular Biology Laboratory in Monterotondo, Italy genetically modified lab mice to produce low levels of the neurotransmitter serotonin. The results showed the mice suffered drops in heart rate and other symptoms of SIDS, and many of the animals died at an early age. Researchers now believe low levels of serotonin in the animals’ brainstems, which control heartbeat and breathing, may have caused sudden death, they said in the July 4, 2008 issue of Science. If neurons that make serotonin — serotonergic neurons — are abnormal in infants, there is a risk of sudden infant death syndrome (SIDS).

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Recent research conducted at Rockefeller University shows, in both patients who suffer from depression and mice that model the disorder, levels of the p11 protein are decreased. This protein is related to serotonin transmission within the brain.

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The 5-HT receptors are the receptors for serotonin. They are located on the cell membrane of nerve cells and other cell types in animals, and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and hallucinogenic drugs.

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In 1935, Italian Vittorio Erspamer showed that an extract from enterochromaffin cells made intestines contract. Some believed it contained adrenaline, but two years later Erspamer was able to show that it was a previously unknown amine, which he named enteramine. In 1948, Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic discovered a vasoconstrictor substance in blood serum, and since it was a serum agent affecting vascular tone, they named it serotonin. In 1952 it was shown that enteramine was the same substance as serotonin, and as the broad range of physiological roles were elucidated, the abbreviation 5HT of the proper chemical name 5-hydroxytryptamine became the preferred name in the pharmacological field.

(http://en.wikipedia.org/wiki/Serotonin)