Thursday Feb 15

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Thursday Feb 15 Recap then GABA
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• Glial cells
• many more glia than neurons
• Ratio is 9 glia1 neuron.
• Glial cells play many supportive roles for
  neurons and also influence neurotransmission as
  well as having gliotransmission.

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• II. Glial cells - 4 types and 5 functions
• Structural support for brain (mostly astrocytes)
• B. Nutritive role - as part of the blood-brain
  barrier, glial cells transport important blood
  contents into neurons (astrocytes)
• C. Role in neurotransmission via
  gliotransmission (astrocytes) and active reuptake
  and degradation
• D. Conduction speed and information transfer-
  as myelin, glial cells influence the speed at
  which neurons can send messages, and help
  distribute certain types of information
  
• (In CNS, oligodendrocytes form myelin In PNS,
  Schwann cells)
• E. Assist the growth, repair, and formation of
  neurons throughout life (microglia and
  astrocytes)

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Glia in red CNS neurons in blue
neuron
Axon wrapped in oligodendrocytes
----------------oligodendrocyte
axon
neuron
-------------------synapse
neuron
astrocytes
blood vessel
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• III. Astrocytes
• the most abundant type of glial cell
• 90 of brain mass is astrocytes
• Astrocytes regulate overall brain function re
  physiology and communication
• 1. Regulate levels of K in extracellular space
  helps neurons maintain ionic balance
• 2. Regulate neurotransmitters in synaptic space
  via uptake and degradation remove GLU,
  GABA, DA, NE, ACh and SE from synapse

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Astrocytes regulate overall brain function re
physiology and communication 3. Regulate and
produce growth factors important for migration
as well as growth of dendrites and formation of
synapses throughout life 4. Form and maintain
function of Blood-Brain Barrier 5. Store
glycogen and convert it to glucose upon
demand 6. Manufacture immune cells and
regulate entry of bodily immune cells into
brain when needed 7. Provide Apolipoprotein to
brain (ApoE) reduces excitotoxicity influences
immune function facilitates repair
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Astrocytic role in regulation of
neurotransmission 1. Neuronal transmitters
evoke Ca elevations in astrocytes 2.
Astrocytes release gliotransmitters ATP GLU,
and d- serine ATP is converted into adenosine
which leads to synaptic suppression (ex.
caffeine) Gliotransmitters act to synchronize
neural activity and modulate neurotransmission
3. Astrocytes modulate availability, release,
and clearance of GLU and GABA 4. Actions on
GLU are important in LTP, neuronal survival
after injury, and neurogenesis
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Part 2 - Recap I. Different actions that result
when a neurotransmitter binds with a receptor 1.
At receptors coupled with an ion channel a. Fast
excitatory action receptor is coupled with a
Na ion channel, and when bound opens it.
Positive ions rush in and change voltage toward
firing threshold. b. Fast Inhibitory action -
receptor is coupled with a Cl- ion channel, and
when bound opens it. Negative ions rush in and
change voltage away from firing threshold.
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2. At receptors that use second
messengers Second messenger a protein inside
the neuron that is activated when the nt binds
the receptor, then causing a change in neuronal
activities that ultimately effect the membrane
potential or some aspect of transmitter
release. The voltage change may result from
modulation of effectiveness of pumps on ion
channels, or changes in energy metabolism, nt
synthesis or release, etc. c. Slow excitatory
action when bound, the action of second
messengers leads to positive changes in voltage
moves toward firing threshold. d. Slow Inhibitory
action - when bound, the action of second
messengers leads to negative changes in voltage
moves away from firing threshold.
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II. Fate of chemical messages after binding 1.
Neural messages are short-lived 2.
Neurotransmitters are broken down or carried
back in (reuptake) as soon as they are
released Breakdown by enzymes in synaptic space
or inside neuron or glial cell after
reuptake. Reuptake occurs by attachment of the
neurotransmitter to a transport protein receptor
- may be carried into releasing neuron or glial
cells.
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• Summary Characteristics of neurotransmitters
• manufactured within the neuron
• stored within the neuron
• released when an action potential occurs
• have a specific binding site on a receptor
• deactivated by special mechanisms

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III. Actions of neurotransmitters at receptors A.
Excitatory action follows binding - causes
changes that move neuron toward the firing
threshold B. Inhibitory action follows binding -
causes changes that move neuron further away from
the firing threshold
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• C. Lock and key analogy
• The neurotransmitter fits into a receptor
  
  like a key into a lock.
• Only one neurotransmitter has the right shape to
  fit a particular receptor.
• More than 200 neurotransmitters
• Many more receptor types
• There are multiple receptor types for a single
  neurotransmitter a neurotransmitter may fit many
  subtypes of receptor for that transmitter drugs
  may selectively fit only one or fit all.

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• IV. How drugs work
• alter synthesis of nt
• alter transport of nt to axon terminal
• alter storage of nt
• alter release of nt
• mimic neurotransmitter and activate or block the
  receptor
• alter enzymatic breakdown within neurons or glia
• alter reuptake of nt by neurons or glia

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• Part 3
• I. The neurotransmitter, GABA
• Gamma amino butyric acid GABA
• major inhibitory neurotransmitter - keeps
  cortical excitation under control helps
  relaxation of mind and body
• Most neurons in brain have GABA receptors
• 75 of synapses in brain are GABAergic
• Esp. in basal ganglia, hippocampus, brainstem,
  and throughout cortex spinal cord

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• B. GABA synthesis
• formed from metabolites of oxidative metabolism
  of carbohydrates
• Neurons that make GABA contain Glutamic acid
  decarboxylase enzyme that converts L glutamic
  acid (the metabolite) to GABA.
• L Glutamic acid plus GAD (plus coenzyme) ?GABA

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• B. GABA synthesis
• formed from metabolites of oxidative metabolism
  of carbohydrates
• Neurons that make GABA contain Glutamic acid
  decarboxylase GAD
• Localization of GAD correlates well with GABA
  content in brain
• GAD requires a second enzyme to work, pyridoxal
  phosphate, a form of Vitamin B6
• Pyridoxine deficiency seizures.
• Availability of pyridoxal phosphate important in
  regulation of GABA synthesis (and breakdown) so
  B6 very important

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C. GABA breakdown - broken down, mostly in glial
cells, by GABA-transaminase (GABA-T) - also
requires B6
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• D. GABA Receptors
• Most neurons in CNS have GABA receptors
• GABAA receptor family
• GABAB receptor family
• GABAC receptor family

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• D. GABA Receptors
• GABAA receptor family most relevant to drugs
  under study most prevalent, best understood
• When bound, GABAA opens a Cl- ion channel fast
  inhibitory action.
• Found on postsynaptic and presynaptic sites.
• Multiunit receptor complex specific binding
  site for GABA, benzodiazepines, barbiturates,
  steroid hormones, alcohol, etc.
• 15 subunits known composition varies across
  brain areas.

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• D. GABA Receptors
• 2. GABAB receptor family
• not directly coupled with ion channel
• Slow inhibitory action second messenger G
  proteins alter Ca and K influx
• Found largely at presynaptic sites
• When bound, reduces release of GABA, as well as
  Glutamate, certain amine transmitters,
  neuropeptides, and certain hormones
• Not critical to most drug actions

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D. GABA Receptors 3. GABAC receptor
family Involved in pain modulation
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E. Coexistence in neurons GABA coexists in
neurons that also make certain steroid
hormones serotonin dopamine glycine histamine
acetylcholine Same neuron makes 2 or more
neurotransmitters more elegant control based on
ratios at work (motor mood)
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• F. Primary actions in CNS
• inhibitory actions mostly on interneurons with
  short axons within brain areas
• influences anxiety, stress, aggression
• affects memory storage and access
• without GABA inhibition, seizures occur
• Some projections from cerebellum to brainstem and
  from substantia nigra to other basal ganglia
  structures important in balance, motor
  learning, and in control of body movement (limbs
  eyes posture)
• Decreases general activity
• Effects balance and postural control.

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F. Primary actions in CNS 3. Control of certain
hypothalamic and pituitary hormone secretions
Influences release of prolactin, gonadotropin
releasing hormone, corticotropin releasing
hormone, opioid peptides, growth hormone,
thyrotropin releasing hormone
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• modulates ovarian and androgen secretions
• modulates sexual receptivity of females
• impairs male sexual activity
• modulates adrenal gland secretions
• modulates food intake

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• GABA
• GABA acts in peripheral nervous system in gut -
  oviduct, ovary, male reproductive tract,
  pancreatic islet cells, kidney
• modulates intestinal motility
• modulates food intake
• 5. In spinal cord and CNS role in pain control

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• G. Relevant illnesses
• Epilepsy - uncontrolled neural activity that
  causes seizures
• motor disorders Huntingtons Chorea
  (Huntingtons Chorea involuntary jerks of limbs
  and eyes progressive disease also involves
  intellectual deterioration single dominant gene
  inheritance death of GABA neurons 1st in basal
  ganglia)
• anxiety - nervousness agitation
• possibly involved in depression, mania,
  schizophrenia

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• H. Relevant drugs
• (Cannot increase GABA action by giving GABA
  does not cross the BBB) must manipulate
  production breakdown response or act on
  receptor complex
• CNS depressants - dose-related effects from calm
  to relaxation to disinhibition to drowsiness to
  sleep to anesthesia.
• Alcohol
• certain inhalants
• anticonvulsant medications
• barbiturates sedatives anesthetics
• Benzodiazepines - antianxiety drugs
• certain date rape drugs (GHB)