BLOCK 3: MPP: (3.3) NEUROPHARMACOLOGY: GABA

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Questions and Answers

Which of the following statements accurately describes the function of GABA receptors?

They operate solely through the action of cyclic AMP.

They mediate their effects by binding to GABA and activating potassium ion channels.

They enhance excitatory neurotransmitter effects exclusively.

They bind GABA and open an intrinsic chloride ion channel. (correct)

What is a primary adverse effect associated with vigabatrin treatment?

Memory enhancement

Increased energy levels

Reduced appetite

Drowsiness (correct)

In the context of inhibitory postsynaptic currents (IPSCs), which effect do GABA receptors primarily mediate?

Reduction of chloride influx into the neuron

Increase in neuronal action potential frequency

Hyperpolarization of the postsynaptic membrane (correct)

Enhanced norepinephrine release

Which of the following components is characteristic of ionotropic GABA receptors?

They are multisubunit membrane proteins that bind GABA. Signup and view all the answers

What role does GABA uptake play in the nervous system?

It terminates the actions of GABA and helps regulate its levels. Signup and view all the answers

What effect does GABA have on neuronal excitability?

It diminishes neuronal excitability by hyperpolarizing the membrane. Signup and view all the answers

Which transporters are responsible for the uptake of GABA in the CNS?

GABA transporters (GATs) Signup and view all the answers

What is the primary role of GABA transaminase (GABA-T)?

To convert GABA into succinic semialdehyde. Signup and view all the answers

What mechanism does Tiagabine employ as a GABA reuptake inhibitor?

Increases both synaptic and extrasynaptic GABA concentrations. Signup and view all the answers

How does the activation of GABAA receptors generally affect the synaptic current?

It leads to hyperpolarization of the postsynaptic membrane. Signup and view all the answers

Which class of drugs is known to modulate GABAergic neurotransmission?

Benzodiazepines Signup and view all the answers

What common effect do benzodiazepines have on GABAA receptor activity?

They enhance the frequency of channel opening. Signup and view all the answers

What is the primary consequence of GABA-mediated hyperpolarization on action potential generation?

It increases the threshold for action potentials. Signup and view all the answers

Which statement about GABA metabolism is true regarding its synthesis?

GABA synthesis is dependent on GAD activity. Signup and view all the answers

What adverse effects may occur due to increased GABA activity from medications?

Sedation and dizziness. Signup and view all the answers

Which intracellular process is triggered by an elevation of calcium ions in GABAergic neurons?

Facilitation of GABA release into the synaptic cleft. Signup and view all the answers

What is a characteristic of vigabatrin in its action on GABA metabolism?

It acts as a 'suicide inhibitor' of GABA transaminase. Signup and view all the answers

What is the role of GABA receptors located on astrocytes?

To modulate neurotransmission through various mechanisms. Signup and view all the answers

What is the primary action of GABA binding to GABAA receptors?

It opens K+ or Cl− channels, inducing hyperpolarization. Signup and view all the answers

Which statement is true regarding the structure of GABAA receptors?

Most synaptic GABAA receptors have two α, two β, and one γ subunit. Signup and view all the answers

What is the role of modulatory sites on GABAA receptors?

To enhance or modify the effects of GABA on the receptor. Signup and view all the answers

What kind of currents result from fast inhibitory postsynaptic currents (IPSCs) in response to GABA?

Fast inhibitory postsynaptic currents (IPSCs). Signup and view all the answers

How quickly does GABA uptake occur in the synapse?

In less than 1 ms. Signup and view all the answers

What is a major consequence of prolonged GABA occupation on GABAA receptors?

Desensitization of GABAA receptors. Signup and view all the answers

What therapeutic effects are associated with agents activating GABAA receptors?

Control of epilepsy and neuroprotection. Signup and view all the answers

Which of the following drugs are considered modulators of GABAA receptors?

Benzodiazepines and barbiturates. Signup and view all the answers

How do benzodiazepines modify GABA's effects on GABAA receptors?

By enhancing the inhibitory response through increased frequency of channel openings. Signup and view all the answers

What effect do GABAA receptors have on neuronal action potentials?

They decrease the likelihood of action potentials. Signup and view all the answers

What is the primary ion movement induced by GABAA receptor activation?

Chloride influx or potassium efflux. Signup and view all the answers

Why are benzodiazepines considered safer than barbiturates for anxiety treatment?

Benzodiazepines do not cause respiratory depression like barbiturates. Signup and view all the answers

Which receptor is primarily responsible for the fast inhibitory effects in the central nervous system?

GABAA receptor. Signup and view all the answers

What is the primary role of GABA in the central nervous system?

To act as the main inhibitory neurotransmitter Signup and view all the answers

How does the signaling intensity of GABA affect the thalamus?

Both B and C are correct Signup and view all the answers

What distinguishes glutamate from GABA?

Glutamate primarily functions as an excitatory neurotransmitter Signup and view all the answers

What effect does GABA-mediated hyperpolarization have on action potential generation?

It decreases the likelihood of action potential firing Signup and view all the answers

Which group of neurotransmitters does GABA belong to?

Amino acid neurotransmitters Signup and view all the answers

How does GABA interact with certain medications?

It modulates its own signaling through various drugs Signup and view all the answers

What mechanism may reduce GABA signaling in the basal ganglia circuitry?

Repression of GABA release from presynaptic terminals Signup and view all the answers

In relation to neurotransmitter signaling, how can GABA levels be compared to a dimmer switch?

Both fluctuate based on neural activity Signup and view all the answers

Which enzyme is responsible for synthesizing GABA from glutamate?

Glutamate-glutamic acid decarboxylase (GAD) Signup and view all the answers

What is the role of VGAT in GABA signaling?

Transporting GABA into synaptic vesicles Signup and view all the answers

How is GABA signaling terminated in the synapse?

Through reuptake via GAT transporters Signup and view all the answers

What occurs following an action potential in a GABAergic neuron?

Calcium ions flood in, promoting neurotransmitter release Signup and view all the answers

What is the general effect of GABA on neuronal excitability?

It results in neuronal hyperpolarization Signup and view all the answers

Which type of neurotransmitter is GABA classified as?

Amino acid neurotransmitter Signup and view all the answers

Which mechanism involves the recycling of GABA in the nervous system?

GAT transporters on astrocytes and nerve terminals Signup and view all the answers

What is the primary physiological function of astrocytes in relation to GABA?

Assist in GABA uptake and recycling Signup and view all the answers

What is the primary effect of GABA on the resting membrane potential of a neuron?

Hyperpolarization of the membrane potential Signup and view all the answers

Which neurotransmitter is involved in generating an excitatory postsynaptic potential (EPSP)?

Dopamine Signup and view all the answers

Which of the following best describes the action of benzodiazepines and barbiturates on GABA A signaling?

They modulate GABA A receptors to enhance inhibitory effects Signup and view all the answers

What are amino acid neurotransmitters classified based on?

Their molecular structure Signup and view all the answers

How does ion movement differ between GABA and glutamate signaling?

GABA promotes chloride influx whereas glutamate promotes sodium influx Signup and view all the answers

What is the primary consequence of hyperpolarization in neurons?

Inhibition of neuronal excitability Signup and view all the answers

Which characteristic distinguishes the action of GABA from that of glutamate?

GABA generates IPSPs while glutamate generates EPSPs Signup and view all the answers

Which of the following pairs of neurotransmitters belong to the amino acid group?

GABA and Glutamate Signup and view all the answers

Study Notes

GABAergic Neurotransmission

GABA is the primary inhibitory neurotransmitter in the central nervous system (CNS)
GABAergic neurotransmission is the process of GABA release and its effect on the postsynaptic neuron
Inhibitory neurotransmitters hyperpolarize the membrane
GABA opens K+ channels or Cl- channels to induce K+ efflux or Cl- influx
This results in membrane hyperpolarization by decreasing intracellular cations and increasing intracellular anions
GABAergic neurotransmission is affected by benzodiazepines and barbiturates, which are pharmacologic agents that modulate GABAergic neurotransmission

GABA Metabolism

The synthesis of GABA is mediated by glutamic acid decarboxylase (GAD)
GAD catalyzes the decarboxylation of glutamate to GABA
GABA is packaged into presynaptic vesicles by a transporter (VGAT)
Elevation of intracellular Ca2+ causes GABA to be released into the synaptic cleft
Termination of GABA involves:
- Neurons and glia take up GABA via specific GABA transporters (GATs)
- GABA-transaminase (GABA-T) catalyzes the conversion of GABA to succinic semialdehyde (SSA)
- GABA-T then regenerates glutamate from α-ketoglutarate

Inhibitors of GABA Metabolism

Tiagabine is a “GABA reuptake inhibitor”
Tiagabine increases both synaptic and extrasynaptic GABA concentrations
Tiagabine is an oral medication that is rapidly absorbed with 90% bioavailability and is highly bound to serum proteins
Vigabatrin is a “suicide inhibitor” of GABA-T
Vigabatrin blocks the conversion of GABA to succinic semialdehyde resulting in high intracellular GABA concentrations
Vigabatrin increases synaptic GABA release

GABA Receptors

GABA mediates its neurophysiologic effects by binding to GABA receptors
There are two types of GABA receptors:
- Ionotropic GABA receptors (GABAA and GABAC): they are multisubunit membrane proteins that bind GABA and open an intrinsic chloride ion channel
- Metabotropic GABA receptors (GABAB): they are heterodimeric GPCR that affect neuronal ion currents through second messengers

Ionotropic GABA Receptor: GABAA

GABAA receptors are the most abundant GABA receptors in the CNS
They are members of the superfamily of fast neurotransmitter-gated ion channels
Each member of the GABAA receptor family has different subunit combinations leading to distinct distributions at the cellular and tissue levels
Most synaptic GABAA receptors consist of two α, two β, and one γ subunit
GABAA receptors bind to two sites located in extracellular portions of the receptor-channel complex at the interface between the α and β subunits
GABAA receptors contain multiple modulatory sites which affect the GABA-mediated response
GABAA receptors generate fast inhibitory postsynaptic currents (IPSCs) which are responses activated by very brief bursts of GABA release at synapses
Prolonged occupation of the agonist sites by GABA also leads to GABAA receptor desensitization

Pharmacologic Classes and Agents Affecting Gabaergic Neurotransmission

Therapeutic agents that activate GABAA receptors are used for:
- Sedation
- Antianxiety
- General anesthesia
- Neuroprotection following stroke or head trauma
- Control of epilepsy

GABAA Receptor Modulators

Benzodiazepines and barbiturates are modulators of GABAA receptors that act at allosteric binding sites to enhance GABAergic neurotransmission
Benzodiazepines have sedative, hypnotic, muscle relaxant, amnestic, and anxiolytic effects
Barbiturates are used for control of epilepsy, general anesthetic agents, and for control of intracranial hypertension

GABAA Receptor Modulators: Benzodiazepines

Benzodiazepines are widely used anxiolytic drugs that replaced barbiturates as treatment of anxiety and insomnia
Benzodiazepines are generally considered to be safer and more effective, particularly when compared to barbiturates
Benzodiazepines modulate GABA effects by binding to a distinct site from the GABA-binding site
Benzodiazepines increase the frequency of channel openings produced by GABA

GABAA Receptor Modulators: Benzodiazepines: Actions

Benzodiazepines reduce anxiety by selectively enhancing GABAergic signaling
Benzodiazepines have sedative and calming properties, at higher doses some can produce artificially sleep

GABA: Inhibitory Neurotransmitter

GABA is the main inhibitory neurotransmitter in the central nervous system.
GABA receptors are present in the central nervous system and are responsible for mediating GABAergic signaling.
GABA receptors are chloride channels that open when GABA binds, allowing chloride ions to enter the cell.
Chloride influx hyperpolarizes the cell, making it harder for the cell to fire an action potential.
GABA is synthesized from glutamate by glutamate decarboxylase (GAD).
GABA is packaged into synaptic vesicles by the vesicular GABA transporter (VGAT).
GABA is released into the synaptic cleft when an action potential arrives at the presynaptic terminal, triggering calcium influx and fusion of synaptic vesicles.
GABA signaling is terminated by reuptake into the presynaptic terminal or astrocytes via GABA transporters (GAT).
GABAergic signaling is modulated by various drugs, including benzodiazepines and barbiturates.
Benzodiazepines and barbiturates enhance GABAergic signaling, leading to increased chloride influx and hyperpolarization.
Drugs that enhance GABAergic signaling have depressant effects on the central nervous system.
GABAergic signaling is crucial for regulating neuronal excitability, motor control, anxiety, and sleep.

Other Neurotransmitters and their Function

Dopamine, glutamate, and serotonin are other important neurotransmitters in the central nervous system.
Dopamine is involved in reward, motivation, and movement.
Glutamate is the main excitatory neurotransmitter in the central nervous system.
Serotonin is involved in mood, sleep, and appetite.
Glutamate and GABA have opposing effects on neuronal activity.
Glutamate promotes excitation, while GABA promotes inhibition.

Neurotransmitter Systems

Neurotransmitter systems are organized networks of neurons that communicate using specific neurotransmitters.
Neurotransmitter systems are involved in regulating various physiological functions, including mood, behavior, and cognition.
Understanding neurotransmitter systems is crucial for developing treatments for neurological and psychiatric disorders.

Upcoming Lectures

Upcoming lectures will focus on the neurotransmitter systems for dopamine, serotonin, and glutamate.
Lectures will explore the functions and mechanisms of these neurotransmitters.
Lectures will discuss the drugs that modulate these neurotransmitter systems and their clinical applications.

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Description

Explore the intricate processes of GABAergic neurotransmission, the role of GABA as an inhibitory neurotransmitter in the CNS, and its metabolic synthesis. Learn how GABA release and receptor engagement affect neuronal activity and how certain drugs influence these mechanisms.