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PSYCH 478 > InInhibitory Neurotransmission: GABA and Glycine > Flashcards

InInhibitory Neurotransmission: GABA and Glycine Flashcards

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1
Q

What is the main inhibitory NT in the CNS and where can it be found?

A

GABA and 10-40% is found in the cortex, hippocampus and substantia nigra

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2
Q

What does GABA increase the conductance of?

A

Chloride ions across cell membranes

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3
Q

True or false: Glycine has comparable but limited functions as an inhibitory NT

A

true

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4
Q

What is the synthesis of GABA?

A

Glutamate————–> GABA
GAD
GAD- glutamic acid decarboxylase

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5
Q

True or false: GABA and glycine do not share a vesicular transporter

A

False; they do share transporters and they are VGAT or IAAT (inhibitory amino acid transporter)

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6
Q

What does VGAT identify

A

Both GABAergic and glycinergic neurons in the CNS

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7
Q

What is one antagonist of GAD that is used experimentally

A

Allyglycine

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8
Q

What does inhibition of GAD do and drugs that decrease GABAergic activity are limited to what?

A

Inhibition of GAD decreases GABA levels and leads to convulsive activity

GABAergic activity is limited in use to in vitro studies

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9
Q

Where are GABA transporters (GAT) located

A

GAT are found on astrocyte and neuronal membranes at the synapse

GAT-1 is located on neurons and astrocytes

GAT-2 and 3 are principally astrocytic

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10
Q

Review slide 7 for metabolism and neuronal synthesis

A

memorize that shit like your life depends on it

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11
Q

Drugs that increase GABA activity are

A

Anticonvulsants

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12
Q

Tiagabine is a selective antagonist of what

A

GAT-1 and elevates GABA levels in synapse, tiagabine is approved as an adjunctive AED for epilepsy

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13
Q

________ is an irreversible inhibitor of GABA-T and elevates GABA levels in the brain by blocking breakdown

A

Vigabatrin, also approved as an AED for epilepsy

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14
Q

True or false: GABA is widely used in inhibitory interneurons throughout the brain

A

true

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15
Q

What does chandelier cells synapse onto and the cells of the cortex are

A

Onto the axonal initial segments of pyramidal cells

cells of the cortex are GABAergic

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16
Q

in addition to axo-dentritic synapses GABA-ergic synapses are often what?

A

axo-somatic-> synapses that control excitability of cell body

axo-axonal-> synapses at the axon inital segment influence signal integration

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17
Q

what cells are large GABAergic projection neurons of the cerebellum and provides the sole output of motor coordination from the cerebellar cortex

A

purkinje cells

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18
Q

True or false: purkinje cells are under inhibitory control from GABAergic interneurons

A

true

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19
Q

what is the term for degeneration of purkinje neurons and what are the side effects

A

Holmes cerebellar degeneration-> impaired fine hand movements, speech deficits, tremors and ataxia while walking

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20
Q

What is the difference between the direct pathway and the indirect pathway that controls the initiation of motor activity in the basal ganglia

A

direct pathway-> excitatory input from cortex causes excitation of upper motor neurons in motor cortex

indirect pathway-> excitatory input from cortex causes inhibition of upper motor neurons in motor cortex

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21
Q

what kind of neurons comprises 90-95% in the striatum

A

medium spiny

input from neocortex (all except visual and auditory)

outputs to global pallidus and substantia nigra

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22
Q

Review slide 13 and 14 for reference on how the pathways carry out their functions

A

be able to draw the output of one another

everything starts with cortical input*

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23
Q

what are the disinhibit outputs of the direct pathway

A

VTh- excitatory projections to upper motor neurons of cortex

superior colliculus- controlling eye saccades

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24
Q

activation of what area of dopamine promote the direct pathway (d1- excitatory) over the indirect pathway (D2-inhibitory)

A

nigrostriatal

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25
true or false: cholinergic interneurons act directly on the indirect pathway
false; direct pathway
26
what antagonists and inhibitors are useful in therapeutics in early parkinson's as they compensate for decreased dopaminergic input
M4AChR antagonists and AChE inhibitors
27
what are the two classes of GABA receptors
ionotropic (GABA(A)) metabotropic (GABA(B))
28
what is ionotropic responsible for
classic ligand gated ion channel permeable to Cl- 5 subunits form the channel pore originally characterized by sensitivity to bicuccline (antagonist)
29
what is metabotropic responsible for
g-protein coupled receptors Gi- ihibits adenylate cyclase (decrease cAMP) Gby- opens G-protein coupled K+ channel originally characterized by sensitivity to baclofen (specific agonist)
30
True or false: GABA has 4 binding sites for endogenous and exogenous ligands
true
31
what are the four sites
GABA site-> binds two molecules of GABA at the interface between a and b subunits benzodiazepine site- binds benz (tranquilizers) as positive allosteric modulators barbiturate site-> binds barb (sedative and anxiolytic) as positive allosteric modulators neurosteroid site-> binds endogenous neurosteroids as positive allosteric modulators
32
what is picrotoxin
a non-competitive channel blocker
33
what binds in the pores at the same sites as picrotoxin in the non-competitive sites that was used as convulsants for depression therapy
pentylenetetrazol-> discontinued due to high risk of spontaneous seizures
34
what is the competitive antagonist in the GABA sites
bicucculine-> widely used in animals models of epilepsy
35
what is a classical agonist of GABA sites
muscimol
36
what does consumption of fly agaric lead to
serious side effects due to the muscarinic cholinergic effects at NMJ and parasympathomimetic effects
37
what is the synthetic version of muscimil with reduced psychotropic effects
gaboxidol investigated for insomnia treatment
38
true or false: barbiturates has a higher safety margin than benzodiazepines
false: benzodiazepines has a higher safety margin
39
what is a well known benzodiazepines
diazepam
40
binding of benzodiazepines causes ________ probability of pore opening
increased
41
high risk of drug interactions of benzodiazepines at the ___________ _____________
GABA(A) receptors
42
what is a best known barbiturates
phenobarbitol
43
what happens when barbiturates bind
prolongs open time of Cl- pore
44
where are barbiturates used
used in physician-assisted suicide and euthanasia
45
what is another term for sodium amytal
truth serum
46
what is a potent positive allosteric modulator of GABA(A) binding to a sie on the transmembrane surface
ethanol
47
what may ethanol exert
sedative, euphoric, and addictive effects through modulation of GABA(A)
48
True or false: ethanol binds GABA(A) with very low affinity- binding even at doeses that would be considered moderate
false: very high affinity
49
_______ is a potent anaesthetic that interacts with the transmembrane surface of the b-subunit of GABA(A)
propofol-> positive allosteric modulator that increases channel open time
50
how many subunits of GABA(A) channels
5- subunits: 6 α (GABARA1-6) 3 β (GABARB1-3) 3 γ (GABARG1-3) One each of δ (GABARD), ε (GABARE), θ (GABARQ), π (GABARP) 3 ρ (GABARR)*
51
what is the special case for GABA(A)
GABA(A)P which only forms homopentameric channels with itself
52
what is a normal channel form
atleast 1 each of a,b most common is a2b2y
53
What is an orphan receptor site? What are the proposed ligands?
- receptor site where endogenous ligand is not known - proposed ligands: inosine, diazepam binding inhibitor/acyl-CoA binding protein, endozepines
54
Which drug is associated with orphan receptor site?
benzodiazepines
55
GABAb receptors primarily affect _______ by coupling _________.
excitability; GIRK
56
Describe GIRK activation. Is it inhibitory or excitatory?
- inhibitory - K+ efflux --> hyperpolarize
57
While GABAa is repsonsible for _____, ___ IPSP, GABAb/GIRK is responsible for _____, ______ IPSP.
- GABAa = fast, weak - GABAb = slow, strong
58
What is the reversal potential of Cl- and K+? Which GABA receptors are these ions associated with?
- GABAa --> Cl- = -70mV - GABAb --> K+ = -90 mV
59
What is baclofen?
- specific agonist of GABAb - muscle relaxant - antispastic
60
What is γ-hydroxybutyric acid (GHB)? When is it excitatory/inhibitory?
- weak GABAb agonist - excite at GHB receptor at low dose --> recreational - inhibit at GABAb receptor at high does --> date rape drug
61
Describe GIRK signaling in detail.
- K+ channel activated during GPCR signalling - GIRK opens on binding of Gβγ - K+ exits the cell causing hyperpolarization of the cell membrane - GIRK signalling inhibits subsequent depolarizing stimuli
62
GABAa-rho receptor is insenstive to? more sensitive to? lack binding sites for?
- insensitive to: baclofen, bicucculine - more sensitive to: GABA - lack binding sites for: benzodiazepines, barbiturates, neurosteroids
63
Where are GABAa-rho receptors found? what kind of signals and from what cells does it receive?
- bipolar cells of retina - inhibitory signals from amacrine and horizontal cells
64
mutations in GABAa-rho are assocaited with hertiable cases of ______________.
retinites pigmentosa
65
GABA development in the ________ is a late developmental step and is associated with maturation of ____________, _____________, and _____________.
PFC; impulse control, working memory, and executive function
66
How is GABA related to anxiety? What are the possible models?
GABA agonists and positive allosteric modulators are ANXIOLYTIC 1. anxiety caused by secretion of endogenous INVERSE agonists of GABAR --> inhibitor of GABAR increase anxiety? 2. ligand activity at GABAR is shifted in anxiety --> subunit alteration? 3. secretion of endogenous agonists of BENZODIAZEPINE site during stress --> deficit in anxiety disorders?
67
How is development related to GABA?
- high levels of GABA and developmental chagnes (Excite/inhibit switch) in GABA activity - GABA --> cell proliferation, survival, motility - excitatory/inhibitory balance --> normal brain development
68
WHat is an example of E/I imbalance in conditions? these conditions have a higher risk for what disorder?
- down syndrome; autism - high risk of seizure disorder
69
How is epilepsy related to GABA? How do drugs that increase/decrease GABA relate?
- E/I balance in seizure disorders - drugs that decrease GABA/inhibit GABAR --> convulsant - drugs that increase GABA/increase GABAR fxn --> anticonvulsant
70
How are psychiatric disorders related to GABA?
contribute to hyperactivity through decreased inhibitory signaling

PSYCH 478 (28 decks)

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