CNS 1 - Anxiolytics and Hypnotics Flashcards
What are hypnotics used to treat?
Sleep disorders
What happens in the body during a fear response? (4)
- Autonomic nervous system activation
- Corticosteroid secretion (cortisol)
- Increased alertness
- Defensive behaviours
What is anxiety?
Anticipatory fear response which is often independent of external events
What are some types of anxiety observed in humans? (4)
- Panic disorder
- Social anxiety disorder
- PTSD
- Generalised anxiety
What animal models are used for studying anxiety? (3)
- Elevated Plus Maze/Cross Test
- Light/Dark Box
- Conflict Test
How does the Elevated Plus Maze/Cross Test work?
- Barrier on one side of the cross and open on the other side
- Rodent in the middle has the choice to walk in the open or enclosed region
- Usually rodents are afraid of the open side
- After treatment with anxiolytics, the rodent shows no preference between open/enclosed regions of the cross
How does the Light/Dark Box test work?
- Half the box is light, other half is dark
- Usually the rodent will prefer to hide in the dark side
- After treatment with anxiolytics, the rodent shows no preference between the light/dark side
How do Conflict tests work?
- Associate a treat with a sound and a mild electric shock
- Anxiolytics cause the rodents to ignore the sound and shock and go for the treat anyway
- Rodents still show the fear response when treated with analgesics/antidepressants which shows that the fear system is distinct from these
What were the first drugs used as anxiolytics?
Benzodiazepines
What is the target of benzodiazepines?
GABAa receptors
What kind of receptor is GABAa?
Ligand gated ion channel (ionotropic)
What is GABA?
Main inhibitory neurotransmitter in the CNS
Which drugs can bind to GABAa receptors and what is their effect? (3)
- Benzodiazepines
- Barbiturates
- Ethanol
All increase the activity of GABAa receptors therefore increasing inhibition in the CNS
What is the structure of GABAa receptors? (3)
- 5 subunits (pentameric)
- 2 alpha, 2 beta and a something else (different combinations of subunit determine the function)
- 2 GABA binding sites
How many GABA binding sites are there on GABAa receptors?
- 2
- Both need to be occupied for the channel to open
Where do benzodiazepines bind to GABAa receptors?
Benzodiazepine binding site is between the alpha and gamma subunit
Where does GABA bind to GABAa receptors?
GABA binding sites are between the alpha and beta subunits
Which ion are GABAa receptors selective for?
Chloride (i.e. inhibitory because the membrane potential becomes more negative)
What is an orthosteric binding site?
Active site where the normal agonist for a receptor binds
What binds to the orthosteric binding site on GABAa receptors? (4)
- GABA
- Muscimol (agonist)
- Bicuculline (competitive antagonist, blocks the binding site)
- Picrotoxin (non-competitive antagonist, blocks the pore)
What is an allosteric binding site?
- Where allosteric modulators bind
- Separate from the main orthosteric site
What symptoms do bicuculline and picrotoxin cause?
Seizures (main one) and anxiety
What is an allosteric modulator?
A substance that modifies the behaviour of the receptor when an agonist is bound to the orthosteric binding site
What does a competitive antagonist to the allosteric site do?
Binds to the allosteric site and prevents the allosteric agonist from modifying the receptors’ behaviour
What binds to the allosteric binding site on GABAa receptors? (2)
- Benzodiazepines e.g. diazepam (positive allosteric modulator)
- Flumazenil (competitive antagonist for the benzodiazepine allosteric site)
What is flumazenil used for?
Treating overdoses of benzodiazepines
Which alpha subunits are benzodiazepine sensitive? (4)
Alpha 1, 2, 3 and 5
What are the physiological effects of benzodiazepines? (5)
- Anxiolytic
- Hypnosis (sleepy)
- Anterograde amnesia (rohypnol)
- Anti-convulsant
- Reduction of muscle tone (relaxation)
Which alpha subunit is in GABAa receptors which are involved in anxiolysis?
Alpha 2
How do benzodiazepines work?
- Increases the frequency of opening of GABAa receptors in the presence of GABA binding (positive allosteric modulator)
- Binding of benzodiazepines to the allosteric site on GABAa increases the receptors’ affinity for GABA
What is a negative allosteric modulator for GABAa receptors? (2)
- Beta carbolines
- Convulsions as side effect (reduced activity of GABA)
Why does diazepam have such long lasting action?
Produces a metabolite when broken down in the body which has activity as a positive allosteric modulator so prolongs the activity of the drug
What is diazepam also known as?
Valium
What are the adverse side effects of benzodiazepines? (4)
- Misuse (taking too much)
- Tolerance
- Physical dependence with withdrawal symptoms
- Fatal in overdose when combined with other CNS depressants
Why are benzodiazepines safe when taken on their own?
- Benzodiazepines only increase the activity of GABAergic neurones that are already active (GABA needs to be bound in order for benzodiazepines to have an effect)
- This means that overdose of this alone is not fatal, just fall asleep
What are barbiturates used for and why?
- Euthanasia
- As you increase the concentration they start acting as an orthosteric agonist (unlike benzodiazepines) so increase all GABAergic activity in the CNS leading to coma and death
What happens when benzodiazepines are taken with alcohol?
The depressive effects are additive so overdose can be fatal
Which drugs are used now to treat anxiety? (5)
- Propranolol
- Antidepressants (SSRIs e.g. sertraline)
- Buspirone
- Antipsychotics
- Antiepileptics
What kind of drug is propranolol?
Beta blocker
What kind of drug is sertraline?
SSRI
What kind of drug is buspirone?
5HT1A partial agonist
Which drugs are used to treat insomnia? (4)
- Benzodiazepines e.g. lorazepam
- Melatonin receptor agonists
- Orexin receptor antagonists
- Anti-histamines
How do anti-histamines treat insomnia? (2)
- H1 receptors in the brain are involved in alertness
- H1 receptor antagonists help with sleep
What is an inverse agonist?
Binds to a receptor and stabilises it in a way which reduces constitutive activity
What is constitutive activity?
When a channel sometimes spontaneously opens in the absence of an agonist
