GABA-A Receptors and Addiction Flashcards
Describe the GABAA receptor
Major inhibitory receptor in the mammalian brain
Both GABA-AR and glycine receptors are transmitter-gated anion (Cl-) conducting ion channels
What mediates fast inhibition within the spinal cord?
GABAARs and stychnine sensitive glycine receptors
What is the resultant action of inhibition of GABAAR?
Proconvulsant
Anxiogenic
Examples include bicuculline and picrotoxin
What is the resultant action of enhancement of GABAR?
Positive allosteric modulators (PAMs) such as diazepam Anticonvulsant Anxiolytic Sedative Analgesic
What subunits make up the GABAA receptors?
2 alpha
2 beta
1 gamma
What IV anaesthetics will modulate GABA activity?
Etomidate
Propofol
Barbiturates
What properties will drugs that enhance GABAAR function show?
Anxiolytic Anticonvulsant Analgesic Amnesic Sedative/ hypnotic: GA
Where do BZDs bind on GABAR?
Interface between the alpha and gamma subunit
What is the action of flumeazenil?
Antagonist at GABAR
Blocks effect of diazepam and beta-carboline
What is a “NAM”?
Negative allosteric modulator
Describe a “NAM”
Beta-carbolines e.g. DMCD
Do PAMs or NAMs have an effect in the absence of GABA?
No; GABA must be present
These drugs will either enhance GABA or inhibit GABA; have no action on the actual GABA receptor themselves
Do oocytes express GABAR?
No
In which direction does Cl- move through a GABAR?
Inward; hyperpolarization of the cell
What was the outcome of the first cloning of GABAr subunits alpha 1 and beta 1 in frog oocytes?
Alpha 1 and beta 1 GABAR subunits are activated by GABA. blocked by picrotoxin and bicuculline, and enhanced by barbiturates
No effect by BZD
This lead to the search for additional subunits e.g. the gamma 2 subunit
What is the basic composition of GABAR?
5 transmembrane crossing subunits
Majority contain 2 beta, 2 alpha and 1 gamma
How many subtypes are there for GABAR?
19; alpha 1-6 beta 1-3 gamma 1-3 delta pi
Are GABAR uniformly distributed in the brain and spinal cord
No;
For example;
alpha 1 is heavily expressed in the cortex, cerebellum and hippocampus
alpha 5 is heavily expressed in the hippocampus
delta subunit; granule cells of cerebellum and thalamus
What is the significance of GABAr receptor isoforms?
Distinct physiological and pharmacological patterns
Exhibit a heterogenous expression pattern in the CNS
Which GABAR isoform in particular is sensitive to BZD?
Alpha 1, beta 1, gamma 2
In terms of specific subunits of the GABAR; what confers BZD sensitivity?
Alpha 1, 2, 3 and 5 are sensitive
4 and 6 are not
Alpha 1,2,3 and 5 have a H (histidine) residue at position 101 of extracellular amino acid chain whereas 4 and 6 have an R (arginine; +ve charge) residue
Mutation of alpha 6 R101 to H produces a diazepam sensitive receptor
Mutation of alpha1H101 to R blocks diazepam sensitivity
What experiment was set up to determine if certain alpha receptors play a role in the multitude of side effects of BZD?
Alpha H-R “knock in” BZD insensitive mice
Alpha1 H101r
Alpha 2 H101R
Alpha 5 H101R
What was the results of the alpha 1H101R mutant mouse?
Autoradiography revealed that the alpha 1 mutation caused a loss of 3H-flumazenil binding in areas known to express the alpha 1 subunit
In the alpha1H101R mouse, diazepam was no longer sedative but retained its anxiolytic properties
What do the results of the alpha H101R suggest?
The sedative effects of BZD are mediated by alpha 1 subunits
How is anxiety tested in mouse?
Light/ dark box
What were the results of the alpha 2H101R mutant mouse?
Diazepam was no longer anxiolytic but sedative
What do the results of alpha 2H101R suggest?
The anxiolytic properties of BZD are mediated by alpha 2 subunits
What are BZD used to treat?
Sleep disorders
Anxiety disorders
Epilepsy
Muscle spasms
What are common side effects of BZDs?
Sedation
Amnesia
Dependence
Addiction
Through the use of the “knock in” mice; describe the role of GABAr subtypes in BZD properties
Sedation; alpha 1 Anxiolysis; alpha 2 Muscle relaxation; alpha2,3,5 Anticonvulsive; alpha 1 Amnesia; alpha 1, 5 Addiction; alpha 1 and 2
Can you develop tolerance to BZD?
Yes; this manifests as a withdrawal syndrome: sleep disturbances, irritability, anxiety, panic attacks
What is the action of flumazenil?
BZD antagonist
Helpful in overdose of diazepam
What can increase the risk of overdose of BZD?
Taken in conjunction with alcohol and opioids
What nT do the majority of neurons in the nucleus accumbens project?
GABAErgic