lecture 8 LOs Flashcards
what can high levels of glutamate do
lesion any brain nucleus
what is excitotoxicity
prolonged depolarization of neurons leading to eventual damage or death
what is necrosis
fast death characterized by lysis due to osmotic swelling
what is apoptosis or programmed necrosis
a slower death triggered by a series of biochemical events. lysis does not occur
how can apoptosis/programmed necrosis happen
by lower concentration and longer exposure time to glutamate, cell death takes several hours and depends on NMDA receptor activation
how can brain damage occur
brain ischemia (interruption of blood flow from stroke/heart attack etc)
when a brain ischemia occurs, how does it happen
massive glutamate release occurs in the affected area
abnormally high Ca2+ levels inside the neuron overloads the Ca2+ buffers so they cant compensate
extremely high Ca2+ levels activate certain enzymes that kill cells
what is GABA the primary transmitter for in the brain
inhibition
which neurons use GABA
all medium spiny neurons in the striatum and other nuclei in the basal ganglia
projection neurons intermixed with monoamine cell groups (DA and serotonin)
interneurons in the cerebral cortex, hippocampus, amygdala, and most other brain regions
what does GABA transmission do for brain function
filter for info coming into neurons
regulates different patterns of firing in cortex
reduced GABA activity promotes seizures
many brain circuits are set up as a series of inhibitory GABAergic connections
how is GABA synthesized
from glutamate by glutamate decarboxylase (GAD)
where is GABA synthesized
in GABA neurons
where does the vesicular GABA transporter (VGAT) move GABA to
vesicles
how is GABA removed from the synpatic celft
reuptake transporters GAT1 to GAT3
where can GAT1 be located
on presynaptic terminals
how is GABA metabolized
it is metabolized to glutamate and succinate by GABA aminotransferase (GABA-T)
in astrocytes how is glutamate converted to glutamine
by glutamine synthesis
glutamine can be released by ___, taken up by ___, converted back to ___, and used to remake ___
astrocytes
neurons
glutamate
GABA
GABA-A GABA receptor subtype
ionotropic
allows Cl- to move from outside to inside the cell, aka hyperpolarization
each GABA receptor consist of ___ subunits
five
various combinations of the four types (alpha, beta, gamma, delta)
GABA binding site agonist and competitive antaonist
agonist: muscimol
competitve antagonist: bicuculline
inside GABA channel pore non competitive antagonist
picrotoxin
what do benzodiazepine (BDZ) and barbiturates do
bind to receptor sites distinct from GABA binding site
increase the potency of GABA to open receptor channel, does not open channel if GABA is not also bound
positive allosteric modulator
example of benzodiazepine (BDZ)
diazepam (vallium)
barbiturate example
phenobarbitol
what does benzodiazepine only bind to
the gamma subunit (which most receptors have)
neurosteroid binding site
some neurosteriods act like BDZ but bind to different part of the receptor
what do inverse agonist or negative allosteric moculators do at the BDZ site
no affect itself, but attenuates the ability of GABA to open channel, promoting anxiety, arousal, seizures
GABA-B receptors
metabotropic (G-proteins and second messenger)
require two different subuits to assemble in the membrane and work properly
what does activation of GABA-B receptor do
inhibitory effect on post synaptic cells by K+ channel opening and inhibiting CAMP formation
where else can GABA-B reside and serve as
can reside presynaptically and serve as autoreceptors or heteroreceptors
GABA-B agonist
baclofen, used as muscle relaxant, and experimental treatments for alcoholism
GABA-B antagonist
saclofen, convulsant primarily used for research
NTs that are catecholamines
dopamine, norepinephrine, and epinephrine
where are NE and EPI released from
adrenal medulla
what are the behavioural functions from DA and NE
motor (primarily DA)
learning and memory
attention
motivation and emotion
reward
what diseases are linked to catecholamine transmission
parkinsons, schizophrenia, depression, ADHD, drug addiction
what does catecholamine synthesis begin with
the amino acid tyrosine
where are tyrosine hydroxylase (TH) and dopamine decarboxylase found
in neurons that make DA
used as markers for DA neurons
what do NE-synthesizing neurons have
dopamine beta-hydroxylase (DBH)
what is activity of TH and catecholamine production regulated by
high catecholamine levels inhibit TH activity (neg feedback)
rate of cell firing (increased firing during stress stimulates TH to accelerate catecholamine synthesis)
what does L-Dopa do
terminals take up precursor and quickly transform it to DA/NE
increases transmitter levels
what does AMPT do
blocks TH, preventing synthesis
induces sedation, depression, reduced blood pressure (systemic effect)
effects can be reversed w L-Dopa
what happens to DA/NE after synthesis
packaged into vesicles via vesicular monoamine transporter (VMAT)
what does reserpine do
blocks VMAT, prevents DA/NE from being packaged (irreversible)
if DA/NE are not protected in vesicles, what happens and what is the effect of that
they are broken down by enzymes in terminal and levels drop
results in sedation and depression and systemic effects (reduced blood pressure and heart rate)
what have reversible VMAT inhibitors been developed for
reducing uncontrolled movements associated w huntingtons disease
what are catecholamines metabolized by
monoamine oxidase (MAO) and/or catechol-O-methyltransferase (COMT)
what is the primary mechanism of clearing catecholamines
reuptake
what is the main DA metabollite
HVA (homovanillic acid)
what are NE metabolites in the brain
MHPG
enter CSF and bloodstream, eliminated via urine
what can levels of HVA compounds in CSF provide
rough indication of catecholamine activity
MAO inhibitor
phenelzine, used to treat clinical depression
COMT inibitors
tolcapone, enhances the effecitveness of L-DOPA in treating parkinsons
