Thursday Oct 5

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Thursday Oct 5 GABA, Glutamate, Seizure
Disorders and Their Treatment
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• 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

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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
proportion (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/motility.
• 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 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)

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• Glutamate
• A. General functions in brain
  (non-neurotransmitter functions)
• - important metabolic role
• - detoxifies ammonia in brain
• - building block in synthesis of proteins and
  peptides
• - precursor for GABA

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B. Synthesis and metabolism - made in axon
terminals from glucose (coming from cell
metabolism) and from glutamine (coming from glial
cells) - glutaminase is the enzyme that converts
above to glutamate (Glutamic acid) - stored in
vesicles and released by Calcium dependent
exocytosis - action terminated by high affinity
reuptake transporter on presynaptic neuron and
glial cells (also helps to maintain extracellular
GLU below levels that may damage neurons) -
extracellular enzymes not relevant to termination
of action
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C. Receptors 5 types responsible for most
excitatory transmission in the CNS 1. NMDA
receptors ionotropic, but slow excitatory
longterm potentiation and memory formation,
developmental plasticity, epilepsy, neurotoxicity
related to brain damage 2. kainate receptors -
ionotropic, excitatory 3. AMPA receptors -
ionotropic, excitatory 4. AP4 receptors
(inhibitory autoreceptor) 5. ACPD receptors
slow, second messenger action that modifies
inositol phosphate metabolism Individual
synapses that use GLU appear to use combinations
of these receptors, rather than a distinct type.
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• Seizure Disorders
• Seizure abnormal neuronal activity resulting in
  excess activity
• 1 in 100 have Seizure Disorder
• Epilepsy 2 or more seizures (close together in
  time infrequent but severe)
• Causes
• brain architectural abnormality (wiring)
  neurons or glia - developmental
• neurochemical abnormality - transmitters or
  receptors (most attention to GABA and GLU)
• membrane abnormalities/channel abnormalities
• head injury stroke substance abuse disease
  toxicants

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• Types of Seizures
• Focal (partial)
• Restricted to one brain area
• 60 of people with seizure disorders have these
  alone or in combination with others
• Simple focal seizure remain conscious altered
  feelings, sensations (auras), thoughts
• Complex focal seizure loss or change in
  consciousness
• motor automatisms out-of-body experiences
  dreamlike state repetitive purposeful actions
  (continue activity they were engaged in at onset)
• Consistent symptoms within a person -
  stereotypies

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• 2. Generalized seizures
• Abnormal activity in both hemispheres
• May or may not lose consciousness
• May or may not have tonic-clonic seizure
• Absence seizures (petit mal) brief interruption
  in consciousness may seem to be staring off and
  lose train of thought
• Tonic seizures muscles contract (stiffen up)
  at max tone
• Clonic seizures repeated jerking of muscles on
  both sides of body
• Atonic loss of muscle tone may fall down or
  change posture
• Tonic-clonic seizures (grand mal) may cause
  loss of consciousness
• Types re often mixed in a single individual -
  gt50 have more than 1 type

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• Antiepileptic medications
• Marketed as efficacious for group that clinical
  trials were conducted on
• Some argued to be better for focal than
  generalized (CBZ for partial)
• In use, meds used across multiple types
• The med a person is on has as much or more to do
  with adverse reactions as efficacy.
• Trial and error required to find right med as
  well as right dose
• All have side effects on cognition and mood most
  on motor function (very dose and stage of
  treatment dependent)

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In general, 50 of patients achieve excellent
control on meds 30 improve 20 are
intractable. In general, side effects worse at
higher blood levels of med. In general, side
effects are worse with polydrug trt.
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• Mechanisms of Action of Antiepileptic Medications
• Barbiturates Phenobarbital (Luminal)
• Binds to GABAA receptor complex at barbiturate
  site enhances GABA action upon GABA binding
• Inc duration of Cl- channel opening
• 2. Benzodazepines Clonazepam (Klonopin)
  Chlorazepate (Tranxene)
• Binds to GABAA receptor complex at BZP site
  enhances GABA action upon GABA binding
• Some BZPs used to treat status epilepticus
  Diazepam (Valium) and Lorazepam (Ativan) rectal
  gel available

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Mechanisms of Action of Antiepileptic
Medications 3. Phenytoin (Dilantin) mephenytoin
(Mesantoin) Ethotoin (Perganome) Less CNS
depression than barbiturates Keeps Na channels
open longer and prolongs refractory period
following an action potential 4. Carbamazepine
(Tegretol) Slows rate of recovery of neuron after
firing by interfering with Na channels 5.
Ethosuximide (Zarontin) Reduces Ca entry into
neuron and interferes with neurotransmitter
release
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Mechanisms of Action of Antiepileptic
Medications 6. Valproic acid Depakote
Depakene Prolongs the recovery of Na channels
after action potential occurs Increases GABA
production and release stimulates synthesis and
breakdown 7. Trimethadione Tridione Inhibits
incoming Ca Give handout for newer ones
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Individual Differences in Response Several
relevant genes have been identified that alter
drug metabolism. For several medications, poor
metabolizers and ultrafast metabolizers have been
identified. Relevant to administered dose dosing
schedule drug interactions risks for adverse
effects immediate and long term Identifying
those at risk helpful to patient to drug
approval and marketing
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• Certain relevant genes
• CYP2D6
• Homozygous for particular allele poor
  metabolizers
• Some have gene amplification ultrarapid
  metabolizers
• This enzyme involved in metabolism of many
  psychoactive drugs anticonvulsants
  anxiolytics cardiac meds antipsychotics
• 1 of Japanese are poor metabolizers vs 5-10 of
  white North American or European as well as
  African
• Ultrametabolizers 1-2 Swedish and German vs
  20 saudi Arabia Ethiopia also high among those
  in Spain
• 2. CYP2C19
• Asian 13-23 poor metabolizers vs 2-5 whites