Introduction to the CNS

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Introduction to the CNS

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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.

Nicotine
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Acetylcholine

• 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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Acetylcholine

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• See Patrick Chapter 19, pt. 1

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Alzheimers Disease

• Alzheimers Disease (AD) is characterized by an
  increasing impairment of cognitive abilities.
• AD is the most common cause of senile dementia
  (dementia decline in cognitive abilities beyond
  what is expected by normal aging)

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Stages of Alzheimers Disease

• Predementia Short term memory loss and inability
  to acquire new information
• Early dementia Shrinking vocabulary and
  increased problems with complex tasks
• Moderate dementia Extreme difficulty finding
  words. Long term memory is affected.
• Advanced Human behavior becomes automatic.
  Nearly all language is lost. Patients cannot
  perform even the most simple tasks, including
  feeding oneself. Death frequently results from
  pneumonia or infection (approx. 6-12 yrs after
  onset).

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Causes?

• Little is known about the causes of AD
• There has been some success in linking AD to
  certain genes.

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Cures?

• There is no cure for AD
• There are a few drugs available that can help
  moderate some of the symptoms
• There is no evidence that these drugs slow the
  progression of the disease

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Physiology of AD

• Amyloid plaques interfere with the normal
  transmission of nerve impulses within the brain
  and destroy other brain cells located in their
  same vicinity.
• Neurofibrillary tangles cause a collapse of the
  molecular skeletons that neurons rely on not just
  for structure but also for the transport of
  nutrients from the body of the cell to theaxons.
  This process not only disrupts the ability of
  neurons to communicate with one another but also
  eventually causes them to starve to death as
  vital nutrients cease to get distributed
  throughout the entire cell.

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• Amyloid precursor protein (APP) is a large
  nerve-protecting protein that is the source of
  beta amyloid. In Alzheimer's certain enzymes,
  particularly those called gamma-secretases, snip
  APP into beta amyloid pieces. This process is
  controlled by factors called presenilin proteins.
  (Genetic abnormalities that affect either APP or
  presenilin proteins occur in some inherited cases
  of early-onset Alzheimer's.)
• High levels of beta amyloid are associated with
  reduced levels of the neurotransmitter
  acetylcholine. (Neurotransmitters are chemical
  messengers in the brain.) Acetylcholine is part
  of the cholinergic system, which is essential for
  memory and learning and is progressively
  destroyed in Alzheimer's disease.

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Drugs to Treat ADInhibitors of
Acetylcholinesterase
Donezepril (Aricept)
Galantamine (Razadyne, Razadyne ER, Reminyl,
Nivalin)
Rivastigmine (Exelon)
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Drugs to Treat ADNMDA receptor antagonist
Memantine (Axura and Akatinol Namenda Ebixa
and Abixa Memox)
NMDA N-methyl-D-aspartate This drug interferes
with the action of the neurotransmitter glutamate
in the CNS
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N-Methyl-D-aspartate (NMDA)
Memantine
L-Glutamic Acid

• Memantine is a low affinity uncompetitive
  antagonist of the glutaminergic NMDA receptors.
• By binding and inhibiting these receptors,
  Memantine is believed to alleviate a process
  known as excitotoxicity, which is believed to be
  involved in 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).

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Norepinephrine

• Noradrenaline is classed as a monoamine
  neurotransmitter and noradrenergic neuron 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.

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Norepinephrine

• 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