The Nervous System

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The Nervous System

• The human nervous system can be divided into two
  parts the central nervous system (CNS) and the
  peripheral nervous system (PNS)
• http//pennhealth.com/health_info/animationplayer/
  nerve_conduction.html

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Central Nervous System

• Drugs that affect the CNS can
• Selectively relieve pain
• Reduce fever
• Suppress disordered movement
• Induce sleep or arousal
• Reduce appetite
• Allay the tendency to vomit
• Be used to treat anxiety, depression,
  schizophrenia, Parkinsons Disease, Alzheimers
  Disease, epilepsy, migraine, etc.

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How do drugs work in the CNS?

• A central underlying concept of
  neuropharmacology is that drugs that influence
  behavior and improve the functional status of
  patients with neurological or psychiatric
  diseases act by enhancing or blunting the
  effectiveness of specific combinations of
  synaptic transmitter actions.

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Blood Brain Barrier (BBB)

• A physiological mechanism that alters the
  permeability of brain capillaries, so that some
  substances, such as certain drugs, are prevented
  from entering brain tissue, while other
  substances are allowed to enter freely.
• The separation of the brain, which is bathed in a
  clear cerebrospinal fluid, from the bloodstream.
  The cells near the capillary beds external to the
  brain selectively filter the molecules that are
  allowed to enter the brain, creating a more
  stable, nearly pathogen-free environment.

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Diagram of a cerebral capillary enclosed in
astrocyte end-feet. Characteristics of the
blood-brain barrier are indicated (1) tight
junctions that seal the pathway between the
capillary (endothelial) cells (2) the lipid
nature of the cell membranes of the capillary
wall which makes it a barrier towater-soluble
molecules (3), (4), and (5) represent some of
the carriers and ion channels (6) the 'enzymatic
barrier'that removes molecules from the blood
(7) the efflux pumps which extrude fat-soluble
molecules that have crossed into the cells
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Blood-Brain-Barrier

• Oxygen, glucose, and white blood cells are
  molecules that are able to pass through this
  barrier. Red blood cells cannot.

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Blood Brain Barrier

• The blood-brain barrier (abbreviated BBB) is
  composed of endothelial cells packed tightly in
  brain capillaries that more greatly restrict
  passage of substances from the bloodstream than
  do endothelial cells in capillaries elsewhere in
  the body.
• Processes from astrocytes surround the epithelial
  cells of the BBB providing biochemical support to
  the epithelial cells.
• The BBB should not be confused with the
  blood-cerebrospinal fluid barrier (BCB), a
  function of the choroid plexus.

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History of the BBB

• The existence of such a barrier was first noticed
  in experiments by Paul Ehrlich in the late-19th
  century. Ehrlich was a bacteriologist who was
  studying staining, used for many studies to make
  fine structures visible. Some of these dyes,
  notably the aniline dyes that were then popular,
  would stain all of the organs of an animal except
  the brain when injected. At the time, Ehrlich
  attributed this to the brain simply not picking
  up as much of the dye.

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• However, in a later experiment in 1913, Edwin
  Goldmann (one of Ehrlich's students) injected the
  dye into the spinal fluid of the brain directly.
• He found that in this case the brain would become
  dyed, but the rest of the body remained dye-free.
  This clearly demonstrated the existence of some
  sort of barrier between the two sections of the
  body.

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History of the BBB

• At the time, it was thought that the blood
  vessels themselves were responsible for the
  barrier, as there was no obvious membrane that
  could be found.
• It was not until the introduction of the scanning
  electron microscope to the medical research
  fields in the 1960s that this could be
  demonstrated. The concept of the blood-brain
  (then termed hematoencephalic) barrier was
  proposed by Lina Stern in 1921.

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What is the purpose of the BBB?

• The blood-brain barrier protects the brain from
  the many chemicals flowing around the body.
• For example, many bodily functions are controlled
  by hormones, which are detected by receptors on
  the plasma membranes of targeted cells throughout
  the body.
• The secretion of many hormones are controlled by
  the brain, but these hormones generally do not
  penetrate the brain from the blood, so in order
  to control the rate of hormone secretion
  effectively, there are specialized sites where
  neurons can "sample" the composition of the
  circulating blood.

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• At these sites, the blood-brain barrier is
  'leaky' these sites include three important
  'circumventricular organs', the subfornical
  organ, the area postrema and the organum
  vasculosum of the lamina terminalis (OVLT).
• The blood-brain barrier is also an effective way
  to protect the brain from common infections. Thus
  infections of the brain are very rare however,
  as antibodies are too large to cross the
  blood-brain barrier, when infections of the brain
  do occur they can be very serious and difficult
  to treat.

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How does the BBB affect the design of therapeutic
agents?

• Mechanisms for drug targeting in the brain
  involve going either "through" or "behind" the
  BBB.
• Modalities for drug delivery through the BBB
  entail disruption of the BBB by osmotic means,
  biochemically by the use of vasoactive substances
  such as bradykinin, or even by localized exposure
  to high intensity focused ultrasound (HIFU).
• The potential for using BBB opening to target
  specific agents to brain tumors has just begun to
  be explored.

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The Blood Brain Barrier

• http//www.clinicaloptions.com/HIV/Management20Se
  ries/NeuroAIDS/Animation/Blood20Brain20Barrier.a
  spx

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Introduction to the CNS

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  rons-and-how-they-work-animation
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  ml

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Neurotransmitters found in the CNS
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Its a balancing act!!

• Current models of CNS diseases often attribute
  the physiological cause of the disease to an
  imbalance of neurotransmitters.

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Acetylcholine

• All ACh receptors in the CNS are nicotinergic.
  The stimulating effect of nicotine is due to the
  influence of these receptors.
• Acetylcholine is transmitted within cholinergic
  pathways that are concentrated mainly in specific
  regions of the brainstem and are thought to be
  involved in cognitive functions, especially
  memory. Severe damage to these pathways is the
  probable cause of Alzheimers disease.

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Norepinephrine

• Most cell bodies of noradrenergic neurons are in
  the locus coeruleus, a center in the brain stem.
  These neurons send their axons to the limbic
  system (appetite inhibition), the subcortical
  centers and the cerebral cortex (arousal).
• Noradrenaline is classed as a monoamine
  neurotransmitter and noradrenergic neurons? are
  found in the locus coeruleus?, the pons and the
  reticular formation in the brain. These neurons
  provide projections to the cortex, hippocampus?,
  thalamus? and midbrain. The release of
  noradrenaline tends to increase the level of
  excitatory activity within the brain, and
  noradrenergic pathways are thought to be
  particularly involved in the control of functions
  such as attention and arousal.

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Locus ceruleus

• The Locus ceruleus, also spelled locus caeruleus
  or locus coeruleus (Latin for 'the blue spot'),
  is a nucleus in the brain stem responsible for
  physiological responses to stress and panic.The
  locus ceruleus (or "LC") is located within the
  dorsal wall of the upper pons, under the
  cerebellum in the caudal midbrain, surrounded by
  the fourth ventricle. This nucleus is one of the
  main sources of norepinephrine in the brain, and
  is composed of mostly medium-sized neurons.
  Melanin granules inside the LC contribute to its
  blue color it is thereby also known as the
  nucleus pigmentosus pontis, meaning "heavily
  pigmented nucleus of the pons".

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Locus ceruleus
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hippocampus
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Thalamus
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• Dopamine is also classed as a monoamine
  neurotransmitter and is concentrated in very
  specific groups of neurons collectively called
  the basal ganglia. Dopaminergic neurons are
  widely distributed throughout the brain in three
  important dopamine systems (pathways) the
  nigrostriatal, mesocorticolimbic, and the
  tuberohypophyseal pathways. A decreased brain
  dopamine concentration is a contributing factor
  in Parkinson?s disease, while an increase in
  dopamine concentration has a role in the
  development of schizophrenia.

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Biosynthesis of Epinephrine
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• Although dopamine is synthesized by only several
  hundred thousand cells, it fulfils an exceedingly
  important role in the higher parts of the CNS.
  These dopaminergic neurons can be divided into
  three subgroups with different functions. The
  first group regulates movements a deficit of
  dopamine in this (nigrostriatal) system causes
  Parkinson's disease which is characterized by
  trembling, stiffness and other motor disorders,
  while in the later phases dementia can also set
  in. ?The second group, the mesolimbic, has a
  function in regulating emotional behavior. The
  third group, the mesocortical, projects only to
  the prefrontal cortex. This area of cortex is
  involved with various cognitive functions,
  memory, behavioral planning and abstract
  thinking, as well as in emotional aspects,
  especially in relation to stress. The earlier
  mentioned reward system is part of this last
  system. ?The nucleus accumbens is an important
  intermediate station here. Disorders in the
  latter two systems are associated with
  schizophrenia.

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Dopamine and Parkinsons Disease

• In patients with Parkinsons disease, there is
  disease or degeneration of the so-called basal
  ganglia in the deeper grey matter of the brain,
  particularly of that part known as the substantia
  nigra.

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Parkinsons Disease

• The substantia nigra, which connects with the
  striatum (caudate nucleus and globus pallidus),
  contains black pigmented cells and, in normal
  individuals, produces a number of chemical
  transmitters, the most important of which is
  dopamine. Transmitters are chemicals that
  transmit, that is, pass on, a message from one
  cell to the next, either stimulating or
  inhibiting the function concerned it is like
  electricity being the transmitter of sound waves
  in the radio. Other transmitters include
  serotonin, somatostatin and noradrenaline. In
  Parkinson?s disease, the basal ganglia cells
  produce less dopamine, which is needed to
  transmit vital messages to other parts of the
  brain, and to the spinal cord, nerves and muscles.

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In Parkinsons disease, there is degeneration of
the substantia nigra which produces the chemical
dopamine deep inside the brain
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Parkinsons Disease

• The basal ganglia, through the action of
  dopamine, are responsible for planning and
  controlling automatic movements of the body, such
  as pointing with a finger, pulling on a sock,
  writing or walking. If the basal ganglia are not
  working properly, as in Parkinsons disease
  patients, all aspects of movement are impaired,
  resulting in the characteristic features of the
  disease ? slowness of movement, stiffness and
  effort required to move a limb and, often,
  tremor.
• Dopamine levels in the brains substantia nigra
  do normally fall with ageing. However, they have
  to fall to one-fifth of normal values for the
  symptoms and signs of parkinsonism to emerge.

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Parkinsons Disease

• http//www.parkinsonshealth.com/AboutPD/Section.as
  px?SectionId798d598e-2a1c-4747-ac81-cd92f475744b
• http//www.medindia.net/animation/parkinsons_disea
  se.asp

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History

• James Parkinson (1755-1824), while best
  remembered for the disease state named after him
  by Charcot, was a man of many talents and
  interests. Publishing on chemistry, paleontology
  and other diverse topics, he was, early in his
  career, a social activist championing the rights
  of the disenfranchised and poor. His efforts in
  this area were enough to result in his arrest and
  appearance before The Privy Council in London on
  at least one occasion. In collaboration with his
  son, who was a surgeon, he also offered the first
  description, in the English language, of a
  ruptured appendix.

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History of Parkinsons Disease

• His small but famous publication, "Essay on the
  Shaking Palsy", appeared in 1817, 7 years before
  his death in 1824. The clinical description of 6
  patients was a remarkable masterpiece testifying
  to his prodigious powers of observation for most
  of the 6 were never actually examined by
  Parkinson himself rather, they were simply
  observed walking on the streets of London.

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Treatment of Parkinsons Disease

• Since PD is related to a deficiency of dopamine,
  it would be appropriate to administer dopamine
• Problem Dopamine does not cross BBB, since it
  is too polar

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History of Treatment of PD

• Arvid Carlsson (b. January 25, 1923) is a Swedish
  scientist who is best known for his work with the
  neurotransmitter dopamine and its effects in
  Parkinson's disease. Carlsson won the Nobel Prize
  in Physiology or Medicine in 2000 along with
  co-recipients Eric Kandel and Paul
  Greengard.Carlsson was born in Uppsala, Sweden,
  son of Gottfrid Carlsson, historian and later
  professor of history at the Lund University,
  where he began his medical education in 1941.
  Although Sweden was neutral during World War II,
  Carlsson's education was interrupted by several
  years of service in the Swedish Armed Forces. In
  1951, he received his M.L. degree (the equivalent
  of the American M.D.) and his M.D. (the
  equivalent of the American Ph.D.). He then became
  a professor at the University of Lund. In 1959 he
  became a professor at the G?eborg University.In
  the 1950s, Carlsson demonstrated that dopamine
  was a neurotransmitter in the brain and not just
  a precursor for norepinephrine, as had been
  previously believed. He developed a method for
  measuring the amount of dopamine in brain tissues
  and found that dopamine levels in the basal
  ganglia, a brain area important for movement,
  were particularly high. Carlsson then showed that
  giving animals the drug reserpine caused a
  decrease in dopamine levels and a loss of
  movement control. These effects were similar to
  the symptoms of Parkinson's disease. By
  administering to these animals L-Dopa, a
  precursor to dopamine, he could alleviate the
  symptoms. These findings led other doctors try
  L-Dopa with human Parkinson's patients and found
  it to alleviate some of the symptoms in the early
  stages of Parkinson's. L-Dopa is still today the
  cornerstone of Parkinson therapy.

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Biosynthesis of Epinephrine
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Wait a minute!

• If dopamine is too polar to cross the BBB, how
  can L-DOPA cross it?

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Answer!

• L-DOPA is transported across the BBB by an amino
  acid transport system (same one used for tyrosine
  and phenylalanine)
• Once across, L-DOPA is decarboxylated to dopamine
  by Dopa Decarboxylase (DDC).

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• This is an example of a prodrug, that is, a
  molecule that is a precursor to the drug and is
  converted to the actual drug at an appropriate
  place in the body.

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• In actual practice, L-DOPA is almost always
  coadminstered together with an inhibitor of
  aromatic L-amino acid decarboxylase, so it
  doesnt get converted to dopamine before it
  crosses the BBB.
• The inhibitor commonly used is carbidopa, which
  does not cross the BBB itself.
• The inhibitor also prevents undesirable side
  effects of dopamine release into the PNS,
  including nausea.

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SINEMET(CARBIDOPA-LEVODOPA)DESCRIPTIONSINEMET
(Carbidopa-Levodopa) is a combination of
carbidopa and levodopa for the treatment of
Parkinson's disease and syndrome.

• http//www.learningcommons.umn.edu/neuro/mod6/carb
  .html

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Endorphin

• Endorphins (or more correctly Endomorphines) are
  endogenous opioid biochemical compounds. They are
  peptides produced by the pituitary gland and the
  hypothalamus in vertebrates, and they resemble
  the opiates in their abilities to produce
  analgesia and a sense of well-being. In other
  words, they might work as "natural pain killers."
  Using drugs may increase the effects of the
  endorphins.

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Serotonin

• Although the CNS contains less than 2 of the
  total serotonin in the body, serotonin plays a
  very important role in a range of brain
  functions. It is synthesised from the amino acid
  tryptophan.Within the brain, serotonin is
  localised mainly in nerve pathways emerging from
  the raphe nuclei, a group of nuclei at the centre
  of the reticular formation in the?Midbrain?,
  pons? and medulla. These serotonergic pathways
  spread extensively throughout the brainstem?, the
  cerebral cortex? and the spinal cord?. In
  addition to mood control, serotonin has been
  linked with a wide variety of functions,
  including the regulation of sleep, pain
  perception, body temperature, blood pressure and
  hormonal activity.Outside the brain, serotonin
  exerts a number of important effects,
  particularly involving the gastrointestinal and
  cardiovascular systems.

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What is serotonin?
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, namely clinical depression,
obsessive-compulsive disorder (OCD), migraine,
irritable bowel syndrome, tinnitus, fibromyalgia,
bipolar disorder, and anxiety disorders.citation
needed If neurons of the brainstem that make
serotoninserotonergic neuronsare abnormal,
there is a risk of sudden infant death syndrome
(SIDS) in an infant.1
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Understanding Serotonin

• 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.

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Understanding Serotonin

• Serotonergic action is terminated primarily via
  uptake of 5-HT from the synapse. This is through
  the specific monoamine transporter for 5-HT, 5-HT
  reuptake transporter, on the presynaptic neuron.
  Various agents can inhibit 5-HT reuptake
  including MDMA (ecstasy), cocaine, tricyclic
  antidepressants (TCAs) and selective serotonin
  reuptake inhibitors (SSRIs).Recent research
  suggests that serotonin plays an important role
  in liver regeneration and acts as a mitogen
  (induces cell division) throughout the body.

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Anatomy of the Brain(seizures)

• http//www.epilepsy.com/web/animation.php?swfwhat
  _is

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The action of drugs to treat mental illness

• Serotonin, noradrenaline and dopamine are
  involved in the control of many of our mental
  states, sometimes acting on their own and at
  other times acting together (illustrated in the
  following diagram). These and other
  neurotransmitters are likely to play a pivotal
  role in the pathological basis of mental illness
  and diseases of the brain. Much of the evidence
  for this stems from the fact that most of the
  effective antidepressant drugs are thought to
  work by changing either serotonin and/or
  noradrenaline metabolism, or receptor sensitivity
  to these neurotransmitters

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Definitions

• Ergotropic Energy expending systems (sympathetic
  division of the PNS) Fight or flight
• Trophotropic Nutrient accumulating systems
  (parasympathetic division of the PNS) Rest and
  digest

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Schizophrenia

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  t.jsp?BV_UseBVCookieYeschannelNameSchizophrenia
  2fSch_Brain_Sch_Abilifyreferrernull

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Historical Drugs to treat schizophrenia

• http//www.pbs.org/wgbh/aso/databank/entries/dh52d
  r.html

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• Histamine is a biogenic amine chemical involved
  in local immune responses as well as regulating
  physiological function in the gut and acting as a
  neurotransmitter (Marieb, 2001, p.414). New
  evidence also indicates that histamine plays a
  role in chemotaxis of white blood cells.

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• Histamine is released as a neurotransmitter. The
  cell bodies of neurons which release histamine
  are found in the posterior hypothalamus, in
  various tuberomammillary nuclei. From here, these
  histaminergic neurons project throughout the
  brain, to the cortex through the medial forebrain
  bundle. Histaminergic action is known to modulate
  sleep. Classically, antihistamines (H1 histamine
  receptor antagonists) produce sleep. Likewise,
  destruction of histamine releasing neurons, or
  inhibition of histamine synthesis leads to an
  inability to maintain vigilance. Finally, H3
  receptor antagonists (which stimulate histamine
  release) increase wakefulness.It has been shown
  that histaminergic cells have the most
  wakefulness-related firing pattern of any
  neuronal type thus far recorded. They fire
  rapidly during waking, fire more slowly during
  periods of relaxation/tiredness and completely
  stop firing during REM and non-REM sleep.
  Histaminergic cells can be recorded firing just
  before an animal shows signs of waking.

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• Sexual response
• Research has shown that histamine is released as
  part of the human orgasm from mast cells in the
  genitals, and the histamine release has been
  connected to the sex flush among women. If this
  response is lacking while a woman also has
  trouble achieving orgasm, this may be a sign of
  histapenia. In such cases, a doctor may prescribe
  diet supplements with folic acid and niacin
  (which used in conjunction can increase blood
  histamine levels and histamine release), or
  L-histidine. Conversely, men with high histamine
  levels may suffer from premature ejaculations.

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Antibodies and the Immune Response

• Antibodies are manufactured by the lymph system.
  Antibodies are specialized proteins that the body
  produces in response to invasion by a foreign
  substance. The process of antibody formation
  begins when an antigen stimulates specialized
  lymphocytes, called B cells, into action.
  Antibodies then counteract invading antigens by
  combining with the antigen to render it harmless
  to the body.
• Production of white blood cells and antibodies in
  reaction to an invading disease organism is
  called an immune response. This response is one
  of the body's primary and most efficient lines of
  defense. In most cases, once antibodies have been
  produced to fight a certain organism, it no
  longer poses a great threat to the body. That is
  why one attack of a disease often prevents that
  same disease from infecting the body again -- the
  first attack causes production of antibodies that
  protect the body against subsequent attacks. With
  measles, for example, antibodies are produced as
  a result of having the disease or of being
  immunized with the measles vaccine. These
  antibodies are able to resist a second attack of
  the disease.

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Antibodies and the Immune Response

• Antibodies are not always beneficial. For
  example, when tissue from another body, such as a
  transplanted heart, is introduced, antibodies are
  produced to destroy the "invader." Transplants
  usually are made possible only by means of drugs
  that act against the body's natural immune
  response. Also, when blood is transfused from one
  person to another, it must be of a matching type
  otherwise, the recipient's immune system will
  manufacture antibodies to destroy the transfused
  blood.
• Sometimes, the immune system causes reactions
  that make the body unusually sensitive to foreign
  material. When the immune response is disruptive
  to the body in this way, it is called an allergic
  reaction. Let's look at this important mechanism,
  and the types of allergens, in the next section.

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Allergic Reaction

• An allergy is a state of special sensitivity to a
  particular environmental substance, or allergen.
  An allergic reaction is the body's response to
  exposure to an allergen.
• Although an allergy can be present almost
  immediately after exposure to an allergen, it
  usually develops over time, as the immune system
  forms antibodies against the foreign substance.
  Under normal conditions, such antibodies work to
  protect the body from further attack. In the case
  of an allergy, however, the antibodies and other
  specialized cells involved in this protective
  function trigger an unusual sensitivity, or
  overreaction, to the foreign substance.
• The antibodies stimulate specialized cells to
  produce histamine, a powerful chemical. Histamine
  causes the small blood vessels to enlarge and the
  smooth muscles (such as those in the airways and
  the digestive tract) to constrict. Histamine
  release can also cause other reactions, such as
  hives.

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Allergic Reaction

• No one knows why allergies develop, but it is
  known that an allergy can appear, disappear, or
  reappear at any time and at any age. Allergic
  reactions rarely occur during the first encounter
  with the troublesome allergen because the body
  needs time to accumulate the antibodies. Also, an
  individual's sensitivity to certain allergens
  seems to be related to a family history of
  allergies. People who have a tendency to develop
  allergies are referred to as atopic.
• An allergic reaction can be so mild that it is
  barely noticeable or so severe that it is
  life-threatening. An extremely severe allergic
  reaction, called anaphylactic shock, is marked by
  breathing difficulties (from swelling of the
  throat and larynx and narrowing of the bronchial
  tubes), itching skin, hives, and collapse of the
  blood vessels, as well as by vomiting, diarrhea,
  and cramps. This condition can be fatal if not
  treated immediately.

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Allergic reaction Histamine and Antihistamines

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  ml
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  allergies.html

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Antihistamines to Antipsychotics?

• In the late 1930s, such dicyclic antihistamines
  as phenbenzamine, diphenhydramine, and mepyramine
  were in wide clinical use. The antihistamines'
  most striking clinical side-effect was CNS
  depression -- drowsiness.

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Antihistamines to Antipsychotics?

• In common use, the term antihistamine refers only
  to H1-receptor antagonists, also known as
  H1-antihistamines. It has been discovered that
  these H1-antihistamines are actually inverse
  agonists at the histamine H1-receptor, rather
  than antagonists per se.

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Antihistamines to Antipsychotics?

• In the late 1930s, Paul Charpentier had
  synthesized the first tricyclic antihistamine,
  promethazine, which had a strong sedative effect.
  He then synthesized a variety of promethazine
  analogues, including chiorpromazine.

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Antihistamines to Antipsychotics?

• http//ajp.psychiatryonline.org/cgi/content/full/1
  60/10/1895?etoc

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Antihistamines to Antipsychotics?

• Chlorpromazine was the first antipsychotic drug,
  used during the 1950s and 1960s. Used as
  chlorpromazine hydrochloride and sold under the
  tradenames Largactil? and Thorazine?, it has
  sedative, hypotensive and antiemetic properties
  as well as anticholinergic and antidopaminergic
  effects. It also has anxiolytic (alleviation of
  anxiety) properties. Today, chlorpromazine is
  considered a typical antipsychotic.

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Antihistamines to Antipsychotics?

• The drug had been developed by Laboratoires
  Rh?e-Poulenc in 1950 but they sold the rights in
  1952 to Smith-Kline French (today's
  GlaxoSmithKline). The drug was being sold as an
  antiemetic when its other use was noted.
  Smith-Kline was quick to encourage clinical
  trials and in 1954 the drug was approved in the
  US for psychiatric treatment. The effect of this
  drug in emptying psychiatric hospitals has been
  compared to that of penicillin and infectious
  diseases.1 Over 100 million people were treated
  but the popularity of the drug fell from the late
  1960s as the severe extrapyramidal side effects
  and tardive dyskinesia became more of a concern.
  From chlorpromazine a number of other similar
  neuroleptics were developed (e.g.
  triflupromazine, trifluoperazine).

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Antihistamines to Antipsychotics?

• Previously used as an antihistamine and
  antiemetic its effects on mental state were first
  reported by the French doctor Henri Laborit in
  1951 or 1952 (different sources) as sedation
  without narcosis. It became possible to cause
  'artificial hibernation' in patients, if used as
  a cocktail together with pethidine and hydergine.
  Patients with shock, severe trauma or burns,
  become, if treated so, sedated, without anxiety
  and unresponsive/indifferent to painful external
  stimuli like minor surgical interventions. The
  first published clinical trial was that of Jean
  Delay and Pierre Deniker at Ste. Anne H?pital in
  Paris in 1952, in which they treated 38 psychotic
  patients with daily injections of
  chlorpromazine.1 Drug treatment with
  chlorpromazine went beyond simple sedation with
  patients showing improvements in thinking and
  emotional behaviour. Ironically, the
  antipsychotic properties of chlorpromazine appear
  to be unrelated to its sedative properties.
  During long term therapy some tolerance to the
  sedative effect develops.
• Chlorpromazine substituted and eclipsed the old
  therapies of electro and insulin shocks and other
  methods such as psychosurgical means (lobotomy)
  causing permanent brain injury. Before the era of
  neuroleptics, starting with chlorpromazine,
  positive long-term results for psychotic patients
  were only 20.

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Definitions

• Neuroleptic A term that refers to the effects of
  antipsychotic drugs on a patient, especially on
  his or her cognition and behavior.
• Neuroleptic drugs may produce a state of apathy,
  lack of initiative and limited range of emotion.
  In psychotic patients, neuroleptic drugs cause a
  reduction in confusion and agitation and tend to
  normalize psychomotor activity.The term comes
  from the Greek "lepsis" meaning a taking hold.

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Definitions

• Extrapyramidal side effects Physical symptoms,
  including tremor, slurred speech, akathesia,
  dystonia, anxiety, distress, paranoia, and
  bradyphrenia, that are primarily associated with
  improper dosing of or unusual reactions to
  neuroleptic (anti-psychotic) medications.

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Reward pathways in the CNS

• The most important reward pathway in brain is the
  mesolimbic dopamine system. This circuit
  (VTA-NAc) is a key detector of a rewarding
  stimulus. Under normal conditions, the circuit
  controls an individual?s responses to natural
  rewards, such as food, sex, and social
  interactions, and is therefore an important
  determinant of motivation and incentive drive. In
  simplistic terms, activation of the pathway tells
  the individual to repeat what it just did to get
  that reward. It also tells the memory centers in
  the brain to pay particular attention to all
  features of that rewarding experience, so it can
  be repeated in the future. Not surprisingly, it
  is a very old pathway from an evolutionary point
  of view. The use of dopamine neurons to mediate
  behavioral responses to natural rewards is seen
  in worms and flies, which evolved 1-2 billion
  years ago.
• http//www3.utsouthwestern.edu/molpsych/paths_b02.
  htm

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Norepinephrine Reuptake Inhibitors as
Antidepressants

• Norepinephrine reuptake inhibitors (NRIs), also
  known as noradrenaline reuptake inhibitors
  (NARIs), are compounds that elevate the
  extracellular level of the neurotransmitter
  norepinephrine in the central nervous system by
  inhibiting its reuptake from the synaptic cleft
  into the presynaptic neuronal terminal. The drugs
  inhibit the class of neurotransmitter
  transporters known as norepinephrine
  transporters. They have virtually no action at
  other monoamine transporters.

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Depression

• http//www.healthcentral.com/depression/introducti
  on-5003-109.html
• http//www.healthcentral.com/depression/introducti
  on-5003-109.html
• http//www.healthscout.com/animation/68/10/main.ht
  ml
• http//www.insidecymbalta.com/patient_resources/ne
  uro_animation.jsp

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Norepinephrin Reuptake Inhibitors for Depression

• Atomoxetine is classified as a norepinephrine
  reuptake inhibitor, and is approved for use in
  children, adolescents, and adults.
• Atomoxetine is the first non-stimulant drug
  approved for the treatment of attention-deficit
  hyperactivity disorder (ADHD). It is sold in the
  form of the hydrochloride salt of atomoxetine. It
  is manufactured and marketed under the brand name
  Strattera? by Eli Lilly and Company as a generic
  Attentin by Torrent Pharmaceuticals. There is
  currently no generic available within the United
  States due to patent restrictions.

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Atomoxetine

• Strattera was originally intended to be a new
  antidepressant drug however, in clinical trials,
  no such benefits could be proven. Since
  norepinephrine is believed to play a role in
  ADHD, Strattera was tested and subsequently
  approved as an ADHD treatment.

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• Reboxetine is an antidepressant drug used in the
  treatment of clinical depression, panic disorder
  and ADD/ADHD. Its mesilate (i.e.
  methanesulfonate) salt is sold under tradenames
  including Edronax?, Norebox?, Prolift?, Solvex?
  or Vestra?.
• Unlike most antidepressants on the market,
  reboxetine is a noradrenaline reuptake inhibitor
  (NARI) it does not inhibit the reuptake of
  serotonin, therefore it can be safely combined
  with an SSRI.

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• Viloxazine (Emovit, Vivalan, Vivarint, Vicilan)
  is a bicyclic antidepressant morpholine
  derivative that inhibits the reuptake of
  norepinephrine.
• In 1976, Lippman and Pugsley reported that
  viloxazine, like imipramine, inhibited
  norepinephrine reuptake in the hearts of rats and
  mice unlike imipramine, (or desipramine or
  amitriptyline, for that matter) it did not block
  reuptake of norepinephrine in neither the
  medullae nor the hypothalami of rats.

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Further tinkering with the structure of the
antipsychotic drugs led to a drug which was
useful in treating depression
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Historical

• Imipramine was, in the late 1950s, the first
  tricyclic antidepressant to be developed (by
  Ciba-Geigy). Initially, it was tried against
  psychotic disorders (e.g. schizophrenia), but
  proved insufficient.
• During the clinical studies its antidepressant
  qualities, unsurpassed until the advent of SSRIs,
  became evident. Subsequently it was extensively
  used as standard antidepressant and later served
  as a prototypical drug for the development of the
  later released tricyclics.
• It is not as commonly used today but sometimes
  used to treat major depression as a second-line
  treatment.

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Tricyclic Antidepressants

• The tricyclic antidepressants share the common
  structural feature of fused 6-7-6 membered rings,
  as shown below.

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Tricyclic Antidepressants
91
Tricyclic antidepressants

• Tricyclic antidepressants are a class of
  antidepressant drugs first used in the 1950s.
  They are named after the drugs' molecular
  structure, which contains three rings of atoms
  (compare tetracyclic antidepressant). The term
  'tricyclic antidepressant' is sometimes
  abbreviated to TCA.
• The exact mechanism of action is not well
  understood, however it is generally thought that
  tricylic antidepressants work by inhibiting the
  re-uptake of the neurotransmitters
  norepinephrine, dopamine, or serotonin by nerve
  cells. Tricyclics may also possess an affinity
  for muscarinic and histamine H1 receptors to
  varying degrees. Although the pharmacologic
  effect occurs immediately, often the patient's
  symptoms do not respond for 2 to 4 weeks.1
• Tricyclic antidepressants are used in numerous
  applications mainly indicated for the treatment
  of clinical depression, pain, nocturnal enuresis,
  and ADHD, but they have also been used
  successfully for headache, bulimia nervosa,
  interstitial cystitis, irritable bowel syndrome,
  narcolepsy, persistent hiccups, pathological
  crying or laughing, smoking cessation, as an
  adjunct in schizophrenia, and in ciguatera
  poisoning.1

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Definitions

• Narcolepsy is a neurological condition most
  characterized by Excessive Daytime Sleepiness
  (EDS). A narcoleptic will most likely experience
  disturbed nocturnal sleep, confused with
  insomnia, and disorder of REM or rapid eye
  movement sleep. It is a type of dyssomnia. A
  person with narcolepsy is likely to become drowsy
  or to fall asleep, often at inappropriate times
  and places.
• While the cause of narcolepsy has not yet been
  determined, scientists have discovered conditions
  that may increase an individual's risk of having
  the disorder. Specifically, there appears to be a
  strong link between narcoleptic individuals and
  certain genetic conditions. One factor that may
  predispose an individual to narcolepsy involves
  an area of Chromosome 6 known as the HLA (human
  leukocyte antigen) complex.
• Certain variations in the HLA complex are thought
  to increase the risk of an auto-immune response
  to protein producing neurons in the brain. The
  protein produced, called hypocretin or orexin, is
  responsible for controlling appetite and sleep
  patterns. Individuals with narcolepsy often have
  reduced numbers of these protein-producing
  neurons in their brains.

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Attention Deficit Hyperactivity Disorder (ADHD)

• Attention-Deficit/Hyperactivity Disorder (ADHD)
  (sometimes referred to as ADD when only
  inattentiveness and distractibility are
  problematic) is a neurological disorder initially
  appearing in childhood which manifests itself
  with symptoms such as hyperactivity,
  forgetfulness, poor impulse control, and
  distractibility.
• Research suggests that ADHD arises from a
  combination of various genes, many of which
  affect dopamine transporters.27 Suspect genes
  include the 10-repeat allele of the DAT1
  gene,28 the 7-repeat allele of the DRD4
  gene,28 and the dopamine beta hydroxylase gene
  (DBH TaqI).29 Additionally, SPECT scans found
  people with ADHD to have reduced blood
  circulation,30 and a significantly higher
  concentration of dopamine transporters in the
  striatum which is in charge of planning ahead.

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