Neuroscience

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Neuroscience

• Neurotransmitters

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Neurotransmitter

• A neurotransmitter is defined as a chemical
  substance that is synthesized in a neuron,
  released at a synapse following depolarization of
  a nerve terminal, which binds to a postsynaptic
  terminal to elicit a specific response.
• Chemicals that relay and modulate messages
  between a neuron and an effector cell (neuron,
  muscle, gland).

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Neurotransmitters

• Chemicals that are stored in and released from
  the synaptic boutons of neurons.
• Antitransmitters destroy the neurotransmitters in
  the synaptic cleft. They break them down so that
  the postsynaptic neuron can repolarize in order
  to fire again.
• Neurotransmitters can also be reabsorbed by the
  presynaptic terminal bouton (reuptake).

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Neurochemical Basis for Human Behavior

• A large percentage of human behavior is modulated
  by the action of neurotransmitters in the brain.
• Behavioral pathology is largely due to imbalances
  in the neurotransmitter systems.
• Physical diseases can also be due to imbalances
  in neurotransmitter pathways (i.e. Parkinson
  disease).

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Criteria For Identification

• The substance must be synthesized in the neuron
  and the enzymes needed for synthesis must be
  present in the neuron.
• The substance must be released in sufficient
  quantity to elicit a response from the
  post-synaptic neuron or cell located in the
  effector organ.
• Mechanisms for removal or inactivation of the
  neurotransmitter must exist.
• It should mimic the action of the endogenously
  released neurotransmitter when administered
  exogenously at or near a synapse.

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Major Classes of Neurotransmitters

• Amino acids (eg Glutamate GLU, gamma
  aminobutyric acid GABA, aspartic acid,
  glycine).
• Peptides (eg, vasopressin, somatostatin).
• Monoamines (norepinephrine NE, dopamine,
  serotonin).
• Acetylcholine

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Mechanism of Neurotransmitter Release

• Exocytosis
• Recycling of Synaptic Vesicle Membranes

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Neurotransmitter Systems

• There are multiple neurotransmitter systems in
  the brain and the enteric nervous system.
• Only two neurotransmitters are used in the
  peripheral nervous system (Ach and
  noripinephrine).

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Function of Neurotransmitters

• http//www.youtube.com/watch?vhaNoq8UbSyc

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Excitatory and Inhibitory

• Neurotransmitters can be either excitatory or
  inhibitory depending upon which receptors sites
  to which they bind.
• They act as the brake and accelerator systems of
  the brain.
• The only direct effect of a neurotransmitter is
  to activate one or more receptor types on the
  post synaptic cell.
• The effect on the post synaptic cell depends
  entirely upon the types of receptors present upon
  it.

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Excitatory and Inhibitory continued

• For some neurotransmitters (i.e. glutamate) the
  most important receptors all have excitatory
  effects.
• For some neurotransmitters (i.e. GABA) the most
  important receptors all have inhibitory effects.
• Some neurotransmitters have both excitatory and
  inhibitory receptors (i.e. acetylcholine).
• Some neurotransmitters produce metabolic pathways
  in the post synaptic cell that cannot be
  considered either excitatory or inhibitory.
• It is an oversimplification to call a
  neurotransmitter excitatory or inhibitory
  however, it is sometimes convenient to do so.

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Degradation and Elimination

• A neurotransmitter must be broken down once it
  reaches the post synaptic cell to prevent further
  excitatory or inhibitory signal transduction.
• Several methods are utilized for removal of the
  neurotransmitter
• Diffusion
• Enzymatic degradation
• Uptake by cells
• Into the cells that released them (reuptake).
• Into neighboring glial cells (uptake).

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Acetylcholine (ACh)

• ACh was the first neurotransmitter to be
  discovered.
• In the peripheral nervous system. ACh is the
  major neurotransmitter that controls muscle
  action.
• There are relatively few ACh neurotransmitters in
  the central nervous system.
• This neurotransmitter most often has excitatory
  effects.
• It exerts its effects at the neuromuscular
  junction.

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Acetylcholine (ACh) continued

• Excessive ACh results in dyskinesia. Dyskenesia
  is hyperkinetic motor activity characterized by
  involuntary motor contractions.
• Deficient ACh results in paralysis.
• In the CNS, ACh participates in the autonomic
  nervous system (i.e. regulation of heart rate).
• Two main classes of ACh
• Fast acting receptor (nicotinic)
• Slow acting receptor (muscarinic)

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Acetylcholine

• http//www.youtube.com/watch?vAyoySswpvsofeature
  related

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Acetylcholinesterase

• Acetylcholinesterase is the antitransmitter that
  degrades acetylcholine.
• Nerve agents such as sarin gas (used in
  bioterrorism) inhibit acetylcholinesterase
  resulting in painful, continuous stimulation of
  muscles and glands.
• Many insecticides inhibit acetylcholinesterase in
  insects.

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Nicotinic Blocking Agents

• Some snake venoms block nicotinic receptors and
  can cause paralysis.
• Curare is a nicotinic blocking agent extracted
  from plants.
• Curare has been used as a poison (placed on
  arrowheads).

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Botulinum Toxin

• Botulin is a poison that blocks ACh and causes
  paralysis.
• Botox, which is a botulin derivative, has been
  used as a cosmetic treatment to diminish wrinkles
  by temporarily paralyzing the muscles.
• In April 2009, the FDA updated its mandatory
  boxed warning cautioning that the effects of the
  botulinum toxin may spread from the area of
  injection to other areas of the body, causing
  symptoms similar to those of botulism.
• In January 2009, the Canadian government warned
  that Botox can have the adverse effect of
  spreading to other parts of the body, which could
  cause muscle weakness, swallowing difficulties,
  pneumonia, speech disorders and breathing
  problems.

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Botulinum Toxin
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Botox Side Effects

• Paralysis of an unintended muscle group can
  occur.
• Inappropriate facial expression.
• Drooping eyelid
• Double vision
• Uneven smile
• Loss of the ability to close the eyes
• Allergic reaction can occur.
• Bruising can occur (typically lasting 7 11
  days).
• Masseter muscle injection can result in reduction
  in power to chew foods.
• Headaches

• Dysphagia
• Flu-like symptoms
• Blurred vision
• Dry mouth
• Fatigue
• Swelling or redness at injection site.
• Botox can take away or dampen emotional feelings.
  
• Botox can hinder the ability to understand
  language (particularly language of emotions).

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Alzheimers Disease

• A shortage of ACh in the brain is considered to
  be a contributing factor to Alzheimers disease.
• Some medicines that inhibit acetylcholinesterase
  have shown some effectiveness in treating the
  disease.
• Alzheimers disease is the most common form of
  dementia.
• There is no known cure. It worsens as it
  progresses.
• Early symptoms include loss of short term memory.
• Advanced symptoms include confusion,
  irritability, mood swings, aggression, trouble
  with language, and long term memory loss.
• Gradually, body functions are lost leading to
  death.

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Alzheimers Disease

• http//www.youtube.com/user/jnjhealth?vq1BkfV2h09
  g
• http//www.youtube.com/watch?vIcuDz7tOL7Efeature
  watch_response_rev
• http//www.youtube.com/watch?v7-P9lbTJ9Hwfeature
  relmfu
• Late Stage Alzheimers Disease
• http//www.youtube.com/watch?voTEbq4h-kvQfeature
  fvwrel

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Myasthenia Gravis

• Myasthenia gravis is an autoimmune disease
  characterized by muscle weakness and fatigue.
• The body produces antibodies against ACh
  receptors.
• ACh transmission is impaired.
• Drugs that inhibit acetylcholinesterase are often
  effective in treating myasthenia gravis.
• The hallmark of myasthenia gravis is
  fatigability. Muscles become progressively
  weaker during periods of activity and improve
  with rest.
• Muscles that control the eye and eyelid are
  particularly susceptible.
• In myasthenic crisis a paralysis of the
  respiratory muscles occurs.
• The heart muscle is regulated by the autonomic
  nervous system so it is generally unaffected by
  MG.

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Myasthenia Gravis

• Strabismus and ptosis are notes in this
  individual with myasthenia gravis while trying to
  open the eyes.

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Myasthenia Gravis

• http//www.youtube.com/watch?vYtypsBCjuyQ
• http//www.youtube.com/watch?vfTrWasKmHxY

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Gamma Aminobutyric Acid (GABA)

• GABA is the major inhibitory neurotransmitter of
  the brain.
• It turns off the functions of the neurons.
• It acts as a brake for the excitatory
  neurotransmitters that can cause anxiety.
• Without GABA, brain cells would fire
  uncontrollably (as in epileptic seizures).
• GABA deficiency is implicated in anxiety
  disorders, insomnia, and epilepsy.
• GABA excess is implicated in memory loss and
  inability for new learning.
• Agents that can block GABA-B receptors may
  improve learning and memory.

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GABA and Anxiety Disorders

• People who experience anxiety and panic attacks
  may have an imbalance in the GABA system and a
  depletion of GABA.
• Benzodiapines are a class of drugs eg, Xanax,
  Valium, Ativan) used to treat anxiety disorders.
• They enhance the effect of GABA on GABA-A
  receptors.
• Prolonged use results in adaptation.
• Down regulation occurs making the drug less
  effective over time.
• Larger doses are needed to provide relief from
  anxiety making the drug less effective over time.
  This is referred to as tolerance.
• Stopping the use of these drugs results in
  diminished sensitivity of GABA receptors, causing
  heightened anxiety.

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GABA Supplementation

• Some dietary supplement companies are selling
  GABA as a sleep aid and anti-anxiety treatment.
• GABA does not penetrate the blood brain barrier.
  It is synthesized in the brain.
• Picamilon is a prodrug that is able to cross the
  blood-brain barrier. It is then hydrolized into
  GABA and niacin.
• The GABA will stimulate GABA receptors and
  potentially produce an anxiolytic response.
• Niacin is a potent vasodilator and may help with
  migraine headaches.

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Glutamate (Glutamic Acid or GLU)

• Glutamate is the most common neurotransmitter in
  the CNS.
• It may account for up to half of the
  neurotransmitters in the brain.
• It is a major excitatory neurotransmitter.
• It is believed to play a major role in learning
  and memory.
• Some research has been done involving the use of
  glutamate to enhance learning and memory in
  patients with Alzheimers disease.
• Glutamate is a precursor for the synthesis of
  GABA.
• It is present in many foods and is responsible
  for the taste sense of umami.
• Sodium salt of glutamic acid (monosodium
  glutamate MSG).

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Epileptic Seizures

• Overactivity of glutamate may produce epileptic
  seizures.
• Epilepsy is an imbalance in brain chemistry
  involving over excitation.
• There is a delicate balance between excitation
  and inhibition in the brain.

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Epileptic Seizure

• http//www.youtube.com/watch?vMRZY2a2jnuw

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Epilepsy

• http//www.youtube.com/watch?vMNQlq004FkEfeature
  relmfu
• http//www.youtube.com/watch?v6NcqQkKjqTI

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Types of Epilepsy

• http//www.youtube.com/watch?votuaPazecDofeature
  related

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Excitotoxicity

• Excess glutamate can cause excitotoxocity
  resulting in neuronal damage and cell death.
• Trauma to the brain (such as CVA and head injury)
  triggers an excessive release of glutamate. This
  can result in the death of many more neurons than
  occurred with the original trauma.
• In CVA, it is believed that not only hypoxia
  kills neurons, but also the release of too much
  glutamate.

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Excitotoxicity continued

• When the brain experiences a series of crises,
  glutamate is released 1000 times more than its
  normal level.
• This may be a method for the organism to
  facilitate a painless death after severe CNS
  damage occurs.
• Glutamate release is often responsible for the
  greatest amount of damage from TBIs and CVAs.
• Researchers are attempting to develop drugs that
  can prevent the release of glutamate after a
  severe brain injury.
• These drugs would have to be administered in the
  first few hours after the injury.

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Dopamine (DA)

• Dopamine exerts effects in the areas of the motor
  system, cognition, and motivation / reward.
• There is no antitransmitter for dopamine. It is
  removed from the receptor site by reuptake into
  the presynaptic neuron, enzymatic breakdown, and
  diffusion out of the synaptic cleft. These
  processes take longer than the antitransmitter
  therefore, dopamine exerts its effects for longer
  periods of time than other neurotransmitters.
• Dopamine is produced in the substantia nigra and
  the tegmentum of the midbrain.

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Parkinsons Disease

• Dopamine affects the basal ganglia and thus
  influences movement.
• Loss of dopamine from the substantia nigra is
  believed to be the primary cause of Parkinsons
  disease.
• Parkinsons disease causes paucity of movement,
  festinating gait, and masked face.
• Precursors to dopamine, such as L-dopa, can
  alleviate some of the symptoms of Parkinsons
  disease.

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Parkinsons Disease
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Parkinsons Disease

• http//www.youtube.com/watch?vjyBakRkzswUfeature
  fvwrel
• http//www.youtube.com/watch?vYVEv9ulfqd4feature
  related
• http//www.youtube.com/watch?vol_pXf-FYJwfeature
  related

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Schizophrenia

• Too much dopamine has been implicated in
  Schizophrenia.
• Schizophrenia is characterized by hallucinations,
  delusions, disorganized thinking, and paucity of
  thought.
• Phenothiazines are antipsychotic drugs that block
  D2 dopamine receptors.
• Older classes of drugs used to treat
  Schizophrenia would often cause Parkinsonian-like
  symptoms. Called tardive dyskinesia (involuntary
  muscle contractions - lip smacking, repetitive
  tongue protrusion, blepharospasm).

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Eugen Bleuler

• The term szhizophrenia was coined by Eugen
  Bleuler.

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Schizophrenia

• http//www.youtube.com/watch?vn_Zv59e68mUfeature
  fvwrel
• http//www.youtube.com/watch?v5I4yw2FyOHE

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Reward System and Addiction

• Dopamine plays a significant role in the brains
  reward system.
• Dopamine is commonly released in response to
  highly pleasurable experiences such as eating and
  sexual activity.
• Drugs such as heroine, amphetamines, and cocaine
  increase dopamine levels to unnaturally high
  states. This is responsible for the high
  experienced from these addictive substances.
• The brain then decreases its natural production
  of dopamine, which causes a severe craving for
  the drugs.

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Cognitive Function and Dopamine

• Dopamine disorders of the frontal lobes may be
  responsible for a decline in cognitive functions
  such as memory, attention, and problem solving.
• Diminished dopamine concentrations may be a
  contributing factor to attention deficit disorder
  (ADD).
• Diminished dopamine levels may also contribute to
  the negative symptoms of depression and
  schizophrenia.

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Serotonin (5-HT)

• Serotonin is synthesized in the serotenergic
  neurons of the CNS and in the gastrointestinal
  tract.
• It is synthesized from the amino acid tryptophan.
• In the CNS neurons of the raphe nuclei in the
  medulla are the principle site of serotonin
  release.

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Serotonin Functions

• Serotonin helps to regulate many body activities
• Sleep
• Emotional control and equanimity
• Pain regulation
• Emesis (vomiting)
• Carbohydrate feeding behaviors (binging
  behaviors)

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Serotonin and Circadian Rhythms

• Serotonin is more abundant in the pineal gland
  than anywhere else in the body.
• The pineal gland does not use serotonin as a
  neurotransmitter though.
• The pineal gland uses serotonin to synthesize
  melatonin.
• Melatonin helps to regulate circadian rhythms,
  diurnal patterns, and sleep-wake cycles.
• Low serotonin levels can disrupt circadian
  rhythms as seen in seasonal affective disorder.

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Serotonin Depression, Anger, OCD

• Low levels of serotonin are associated with
  depression and suicidal behavior.
• Serotonin Specific Reuptake Inhibitors (SSRIs)
  increase the brains level of serotonin by
  blocking the reuptake of serotonin by the
  presynaptic neuron.
• Low levels of serotonin are also linked to
  aggression, anger and violence.
• Too little serotonin has also been linked to
  obsessive-compulsive disorder (OCD).
• SSRIs have shown some success in treated all of
  these conditions.

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Norepinephrine (NE)

• Also called noradrenaline.
• Norepinephrine and acetylcholine are the only two
  neurotransmitters used in the PNS.
• NE is released from the medulla of the adrenal
  glands as a hormone into the bloodstream.
• Norepinephrine does not have an antitransmitter
  and therefore its effects last longer than other
  neurotransmitters.

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Norepinephrine and Alertness

• Norepinephrine plays a role in wakefulness /
  arousal.
• Norepinephrine is important in the active
  surveillance of ones surroundings. It increases
  attention to sensory information from the
  environment.
• It is an agent in treatment of people with ADHD
  because it appears to enhance concentration and
  cognitive function.
• Psychostimulant medications such as Ritalin
  increase norepinephrine and dopamine levels in
  people with ADD / ADHD..

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Norepinephrine as a Stress Hormone

• Norepinephrine activates the sympathetic nervous
  system to produce the fight / flight response,
  increase the heart rate, release energy from fat
  storage, and increase muscle preparedness.
• Over activity of norepinephrine produces fear,
  anxiety, and panic.
• Beta blocking agents prevent norepinephrine from
  binding to beta receptors. This prevents
  sweating, tachycardia and other sympathetic signs
  that occur in stressful situations.
• Musicians, actors, and public speakers often use
  beta blockers to reduce sympathetic NS signs and
  enhance calmness.

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Norepinephrine and Depression

• Low levels of norepinephrine have been linked to
  depression.
• Serotonin-norepinephrine reuptake inhibitors
  (SNRIs) are a class of antidepressants that
  increase the amount of serotonin and
  norepinephrine in the brain.

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Substance P

• Substance P is a neuropeptide that functions as
  both a neurotransmitter and a neuromodulator.
• Substance P is associated with mood regulation,
  anxiety, stress, neurogenesis, respiratory
  rhythm, neurotoxicity, vasodilation, nausea,
  emesis, and pain perception.
• Substance P is a neurotransmitter in the
  nociceptive pathway. It is involved in the
  transmission of pain.
• Substance P may play a role in fibromyalgia.
• The pain reliever capsaicin (active ingredient in
  peppers) has been shown to reduce Substance P
  levels.

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Opioid Peptides

• Opioid peptides include endorphins, enkephalins,
  and dynorphins.
• These neurotransmitters are produced in the
  pituitary gland and hypothalamus.
• They also participate in the brains reward
  system as they have a major role in the
  perception of pleasure.

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Opioids and Pain

• The primary action of opioids is the inhibition
  of nociceptive or pain information.
• The opioids resemble opiates (opium, morphine,
  heroin). They can produce analgesia and feelings
  of well-being.
• They are the bodys natural pain killers.
• The analgesic capsaicin stimulates the release of
  endorphins.
• Studies show that acupuncture stimulates the
  release of endorphins as well.

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Opioid Peptides Other Functions

• Opioid peptides also play a role in cardiac,
  gastric, and vascular functions.
• Low levels of opioids are associated with anxiety
  and panic.
• Opioids play a role in satiety and appetite
  control.