Transcript Psychopharmacology

Chapter 7: Glutamate and GABA
• Glutamate
– An amino acid
– Used throughout the body
• Building proteins
• Helps with energy metabolism
– Also serve as NTs
• excitatory
synthesis
• Glutamine can be
converted to
glutamate via the
enzyme glutaminase
Vesicular glutamate transporter
• VGLUT1, VGLUT2, and VGLUT3
– Package glutamate into vesicles
– Different parts of the brain use different VGLUTs
• Not really known why
Reuptake
• Excitatory amino acid transporter (EAAT1EAAT5)
– EAAT3 is main neuronal transporter
– EAAT1 and EAAT2 are actually found on
astrocytes
– This relationship may occur because
extracellular glutamate is dangerous
• Spreading ischemia
7.3 Cycling of glutamate and glutamine between glutamatergic neurons and astrocytes
• Astrocytes breakdown
glutamate
– Into glutamine
– via the enzyme glutamine
synthetase
• Then the astrocytes
release the glutamine so
it can be picked up by
neurons and converted
back to glutamate
• This complex system may
help prevent the toxicity
of extracellular glutamate
• Glutamate is the workhorse transmitter for
excitatory signaling in the nervous system
• Glutamate is found throughout the brain, so we
won’t have specific pathways for this
neurotransmitter
• Involved in many behavioral and physiological
functions, but perhaps the most important is
synaptic plasticity
– Changes in the strength of connections
– Learning and memory
Receptors
• Ionotropic glutamate receptors
– 3 subtypes
• AMPA
– Named for the drug AMPA (a selective agonist of this
receptor)
– Most fast excitatory responses to glutamate occur
through this receptor
• Kainate
– Named for the drug Kainic acid (a selective agonist)
• NMDA
– Named for N-methyl-D-aspartate (NMDA; selective
agonist)
• The AMPA and Kainate receptors mediate
the flow of Na+
– Excitatory post synaptic potentials
• NMDA receptors mediates Na+, but also
Ca++
– CA++ works as a second messenger
– Thus, NMDA receptors can directly activate a
second messenger system
7.4 All ionotropic glutamate receptor channels conduct Na+ ions into the cell
NMDA receptors
• NMDA receptors require two different
neurotransmitters to open the channel
– 1) Glutamate
– 2) Glycine or D-serine
• Glycine (or D-serine) has its own binding site.
– Thus glycine (or D-serine) is considered to be a coagonist.
• Usually the co-agonist binding site is occupied
though, so the presence or absence of
glutamate determines channel opening
NMDA receptor
• There are two other binding sites on
NMDA receptors that affect their function
– Both of these receptor locations are inside the
channel
• Magnesium receptor
– Mg++
• Phencyclidine receptor
– PCP
Mg++
• When the cell
membrane is at
resting potential (-60
or -70 mv).
– Mg++ binds to its
location within the
channel.
– Thus, even if
glutamate (and glycine
or D-serine) bind to
the receptor the ions
cannot flow.
• However, if the
membrane becomes
somewhat
depolarized the Mg++
will leave its binding
site and exit the
channel.
– Now the channel will
allow the flow of ions if
glutamate and the coagonist are present.
NMDA receptor (coincidence detector)
• Thus, the NMDA channel will open only if
other receptors are active simultaneously
– Two events must occur close together in time.
• So channel will only open if
– 1) glutamate is released onto NMDA receptor
– 2) the cell membrane is depolarized by a
different excitatory receptor.
PCP
• This receptor recognizes
– Phencyclidine (PCP)
– Ketamine (Special K)
– MK-801 (dizocilpine; a
research drug)
• Most of the behavioral
effects of PCP and
Ketamine are the result of
antagonizing the NMDA
receptor
NMDA receptors and learning and memory
• Classical conditioning is based on the close
timing of two events
– Bell  Food
• The NMDA receptor may be a biochemical
mechanism that allows for these kinds of
associations.
– NMDA antagonism impairs learning and memory
– The hippocampus has a high density of NMDA
receptors
– NMDA receptors are critically involved in synaptic
plasticity
• Long-term potentiation (LTP)
LTP
• LTP is a persistent (at least 1 hour)
increase in synaptic strength.
– Produced by a burst of activity from the
presynaptic neuron
LTP studies
• Get a slice from the rat
hippocampus and keep
alive in Petri dish.
– It is common to stimulate
CA3 region which
synapses with cells in CA1
• 100 stimulations in 1
second
– Tetanic stimulation
(tetanus)
– Measure response of CA1
neurons
– You can produce similar
effects in other parts of the
pathway, however.
Box 7.1 Role of Glutamate Receptors in Long-Term Potentiation (Part 4)
Synaptic activity at test pulse
• Test pulse elicits release
of a small amount
glutamate from CA3
axons onto CA1
– Glutamate binds to AMPA
receptors and NMDA
receptors
– Channel does not open
because membrane not
depolarized enough to
dislodge Mg++
Synaptic activity during tetanus
• More glutamate is
released
– Prolonged activation of
AMPA
• Depolarization
dissociates Mg++
• NMDA channel opens
– Na+ enters
– More importantly Ca++
enters
• Ca++ Works as a second
messenger
– Increases the sensitivity of
receptors to glutamate
– Inserts more AMPA receptors
into the membrane.
– May also produce presynaptic
changes that increase
glutamate release from
terminal button
• Retrograde messenger
• Nitric oxide?
• These effects increase the
strength of the synapse
Doogie mouse
• Genetically engineered to
have a more efficient
NMDA receptor.
– Also may have more
NMDA receptors than
normal mice
• Show enhanced LTP
• Show improved learning
and memory
– Enhanced fear conditioning
– Learn Morris water maze
more quickly
Object recognition
• Novel-object-recognition
– Explore 2 objects for 5
minutes
– Wait 1hour, 1 day, 3 days,
or 1 week
– Present 2 objects 1 novel
and 1 familiar
• Animals tend to prefer to
examine the novel object
• Can only have this
preference if they
remember
7.8 Enhanced memory shown by Doogie mice in the novel-object-recognition task
Metabotropic glutamate receptors
• mGluR1-mGluR8
– Some serve as
autoreceptors
• mGluR1 has been
implicated in movement
– Knockout mice
• No mGluR1 – inactivity
• MGluR1 only in
cerebellum
– Normal movement
– Implies mGluR1 in
cerebellum is required for
normal movement
High levels of glutamate can be toxic
• Injection of monosodium
glutamate (MSG) caused
retinal damage in mice
– Lucas and Newhouse
(1957)
• Olney (1969) showed
MSG causes brain
damage in young mice
• Now known that
glutamate causes lesions
in any brain area when
injected directly into that
area. Young or old
Excitotoxicity hypothesis
• Excitotoxicity hypothesis
– The damage produced by exposure to glutamate is
caused by a prolonged depolarization of receptive
neurons
• Studied in cultured nerve cells
– Strong activation of NMDA receptors most readily
causes cell death
• Though AMPA and Kainate activation can also cause cell
death
• If both NMDA and non NMDA receptors are
activated by substantial amounts of glutamate
there is a large percentage of cell death in a few
hours.
Necrosis vs Apoptosis
• When many cells die in a
few hours this is called
necrosis
– Cells burst (called lysis)
due to swelling
• However, there can also
be delayed responses
that can continue for
hours after initial
exposure
– Apoptosis (programmed
cell death).
– No lysis
• Do not spill contents into
extracellular space.
• Apoptosis occurs normally during development
– Selective pruning
• Can also be elicited by ingesting toxins
– Domoic acid
• Excitatory amino acid contained in marine algae.
• When marine animals eat this algae they concentrate the toxin
• If consumed by humans can lead to neurological problems
–
–
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–
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Headache
Dizziness
Muscle weakness
Mental confusion
Loss of short-term memory
– Regulated for humans, but can affect other wild life
• Dolphins
• Sea birds
Ischemia
• Ischemia occurs whent there is disruption of
blood flow to brain (or part of the brain).
– Massive release of glutamate in affected area
– Prolonged NMDA receptor activation
• In animal studies treatment with NMDA
antagonists reduces damage
– Clinical studies with humans not so successful
• Some researchers are considering drugs that
block the co-agonist location
– Glycine blockers
– Fewer side effects (than drugs like PCP)
y-aminobutyric acid (GABA) = gamma-aminobutyric acid
• Synthesis
– Precursor
• Glutamate
– Enzyme
• Glutamic acid
decarboxylase (GAD)
• Drugs that block GABA synthesis
– Reduce GABA levels
– Cause convulsions
• Provides evidence that inhibitory effects of
GABA are important in controlling brain
excitability
Transporters
• Vesicular GABA transporter
(VGAT)
– Puts GABA into synaptic
vesicles
• GABA transporters
– GAT-1, GAT-2, and GAT-3
– GAT-1 primary neuronal
GABA transporter
• Drugs that block GABA
transporters
– Prevent seizures
– GAT-1 blocker is most studied
• tiagabine (Gabatril)
• Used as a treatment for
epilepsy
Breakdown of GABA
• GABA aminotransferase
(GABA-T)
– Converts GABA into
• Glutamate
• Succinate
– In astrocytes
• Glutamate is converted to
glutamine
– By glutamine synthetase
• Then released to be
recycled by cells just like
for Glutamate cells
• Drugs that block GABA-T
– Used as anticonvulsants
GABA receptors
• Only two
– GABAA (ionotropic)
– GABAB (metabotropic)
• GABAA is the receptor that is relevant to us
GABAA
• GABAA controls a
chloride channel
• Notice that there are
additional binding sites
– Picrotoxin (antagonist)
• Blocks the channel if
occupied
• Causes convulsions
– Synthetic versions
used to be used to
induce convulsions to
treat depression
GABAA
• Benzodiazepines
– valium
• Barbiturates
• These drugs enhance the
effectiveness of GABA.
– Open the Cl- channel more
effectively.
• Alcohol works similarly at
the GABA channel
• These drugs tend to
reduce anxiety
– anxiolytic