What is a neurotransmitter?
A chemical substance released at the end of a nerve fibre by the arrival of a nerve impulse to another nerve fibre, muscle fibre or some other structure
What is an excitatory neurotransmitter?
Increases the probability that the target cell will fire an action potential
Give an example of an excitatory neurotransmitter:
What is an inhibitory neurotransmitter?
Decreases the probability that the target cell will fire and action potential
Give two examples of inhibitory neurotransmitters:
GABA (fast, found in virtually every part of the brain = short interneurones e.g. pain modulation)
Glycine (the inhibitory transmitter in the spinal cord)
Anxiety is a disorder of the...
Too few GABA = Anxiety
What was GABA first discovered as?
A product of microbial and plant metabolism
Which drug enhances the effects of GABA?
What causes epilepsy?
When GABA is lacking in certain parts of the brain
Where are there long GABAergic tracts to?
Which enzyme produces GABA?
Glutamic Acid Decarboxylase (GAD) -> found primarily in CNS
Co-enzyme = Vitamin B6
Which reaction produces GABA?
Glutamate -> GABA + CO2
How many isoforms of Glutamic Acid Decarboxylase are found in the brain?
(GAD1 & GAD2 -> evolved separately but do same job!)
What is a glial cell?
A helper axillary cell = mop up and release neurotransmitter
What breaks GABA down?
Co-factor = Vitamin B6= located in the mitochondria
What does GABA-T break GABA down into?
Which drug is the most potent inhibitor of GABA-T?
Gabaculine (used more in lab than clinically)
What happens inside the cell after Gabaculine is given?
- Lots of GABA in cleft
- Eventually it stops vesicles containing GABA (relies on action of GAD to package produce GABA from glutamate and package into vesicle) = action potential = no release of GABA = no inhibition = Anxiety
Which cells express GABA receptors?
- Most neurones in the CNS
- Glial cells (astrocytes) = ANS neurones
When GABA binds what happens to the neurone?
Shift in membrane permeability to Chloride ions
postsynaptic inhibition = hyperpolarisation
presynaptic inhibition = depolarisation
How many types of GABA receptor are there?
What are they called?
GABA-A & GABA-B
What type of receptor is GABA-A?
Ligand-gated ion (chloride) channel
What type of receptor is GABA-B?
Which drug does GABA enhance the binding of?
Why does GABA enhance binding of benzodiazepine?
GABA-A and Benzodiazepine (BDZ) receptor make up 2 separate parts of the same complex
Which is the most prevalent GABA receptor?
How many subunits does the GABA-A receptor have?
N.b. subunit composition varies between brain regions and neuronal subpopulations (how we get sensitivity to specific regions)
Between which two subunits on the GABA-A receptor do benzodiazepines bind?
Alpha & Gamma
Which subunit of the GABA-A receptor binds GABA?
Whats the birds eye view subunit arrangement for the GABA-A receptor?
What are the two types of allosteric modulators that act on GABA-A receptors?
Channel blockers (picrotoxin)
Channel modifiers (ethanol, volatile anaesthetics & neurosteroids)
What is the most common arrangement of subunits in GABA-A receptors?
1 X Alpha
2 X Beta
2 X Gamma
What are the different effects of benzodiazepine on GABA-A receptors with different subunits?
No effect = Alpha 4 & 6
Sedation and Amnesia = Alpha 1
Anxiolytic = Alpha 2 &3
For sensitivity to benzodiazepine = Gamma 2
Where are GABA-A receptors found?
Where are GABA-B receptors found?
(many sites in brain & periphery)
When GABA binds to GABA-B receptors what happens?
- inhibition of voltage sensitive Ca channels
- inhibition of transmitter release
What type of receptor is the Glycine receptor?
Ligand gated Cl channel
What is the role of Glycine in interneurones?
High in ventral horn
Low in ventral root fibres= associated with inhibitory interneurones
N.B. inhibitory effect of glycine is restricted to spinal cord, lower brain stem and retina
What is the role of Glycine in the CNS?
N.B. inhibitory effect of glycine is restricted to spinal cord, lower brain stem and retina
What type of neurotransmitter is Glycine?
Name 3 amino acids that activate the glycine receptor:
Name two competitive agonists of the Glycine receptor:
Strychnine (high affinity)
Caffiene= block the receptor
Which receptors mediate the excitatory responses facilitated by Glycine?
What effects do glycine/NMDA receptor antagonists have?
What 4 features characterise anxiety disorders?
- Excessive rumination
Which four aspects of experiences does "anxiety" cover?
- mental apprehension
- physical tension
- physical symptoms
- dissociative anxiety
What are the (5) somatic and autonomic clinical manifestations of anxiety?
- Restlessness and agitation
- Increased sweating
- GI disorders
Which three disorders can anxiety disorder be divided into?
- Generalised anxiety disorder
- Phobic disorder
- Panic disorder(characterised by own symptoms and have own treatment)
What are the 6 clinically recognised anxiety disorders?
generalised anxiety disorder = ongoing anxiety lacking any clear reason or focus
social anxiety disorder = fear of being with/interacting with other people
Panic disorder = sudden attacks of overwhelming fear
Phobias = song fears of specific objects/ situations
Post traumatic stress disorder = anxiety triggered by recall of past stressful experiences
Obsessive compulsive disorder = compulsive ritualistic behaviour driven by irrational anxiety
Which types of drugs are used to treat anxiety disorders?
Anxiolytics -> anxiety
Sedatives -> sedation (calming effect)
Hypnotics -> insomnia (induce sleep)
How does dose effect anti-anxiety drugs?
Effect can be dose dependent
= same drug can be classified as anxiolytic/sedative/hypnotic at different dose
Too much anti-anxiety drugs =
What are the two possible mechanisms for anxiety?
- over activation of brain neurotransmission and neuronal firing (too much excitation e.g. excess glutamate & calcium)
- under-inhibition of brain neurotransmission and neuronal firing (insufficient inhibition e.g. insufficient GABA, GABA-A receptor function or enhancement of GABA)
How do many sedative/tranquillising drugs work?
Enhance the effects of GABA:
- increased GABA = blocks repute & increased GABA release
- increased GABA signalling = Benzodiazepine agonist (partial/total) or blocking benzodiazepine inverse agonists
Name 4 groups of anxiolytic drugs:
- Phenobarbitone :
- Older Tricyclic antidepressants (TCAs)
- Monoamine Oxidase inhibitors (MAOIs)
- Selective serotonin reuptake inhibitors (SSRIs)
Which receptor do barbiturates bind to?
Beta subunit of GABA-A
(ligand gated Cl channel) = increased duration of Cl channel opening
What are the 4 actions of barbiturates?
- potentiate GABA (increased duration of Cl opening)
- block AMPA receptor (glutamate receptor subtype)
- inhibit Ca dependent release of neurotramsmitters
- Binds entire superfamily of ligand gated ion channels
What are the 2 side effects of Barbiturates?
Sedation and hypnotic (too much inhibition)
Risk of abuse and addiction is high (rarely used anymore)
When are Barbiturates used clinically?
Short-term treatment of severe insomnia
(when benzodiazepines or non-benzodiazepines have failed)
What are the 5 clinical uses of benzodiazepines?
- anti anxiety
- muscle relaxant
What are the 6 side effects of benzodiazepines?
- Impaired motor co-ordination
- Lack of depth perception
- Reduced REM (rapid eye movement) sleep
In which two treatments are benzodiazepines often used?
As a premedication for medical or dental procedures
What are the three different categories of benzodiazepines?
Which two categories of benzodiazepines are preferred for insomnia?
Short & intermediate-acting
Which category of benzodiazepines is preferred for anxiety?
What happens following longer term use of benzodiazepines?
Tolerance, dependence & withdrawal
Psychological & physical effects
Which receptor interactions with benzodiazepines may contribute to their addictive properties?
inhibits NMDA & nACh receptors
Overall which is less toxic... barbiturates or benzodiazepines?
BUT... combination with other CNS depressants (alcohol & opiates) = increased toxicity and potential of fatal overdose
Why do we rarely use the older tricyclic antidepressants (TCAs)?
Severe side effects
Name 4 different older tricyclic antidepressants (TCAs):
Name 2 different Monoamine oxidase inhibitors (MAOs):
very effective for anxiety but lots of drug dangers so rarely prescribed
What is the main problem with selective serotonin reuptake inhibitors (SSRIs)?
Early in treatment they can produce anxiety due to negative feedback through serotonergic auto receptors
(reduced by combined with a low dose of benzodiazepine)
Name a 5HT-1A receptor partial agonist used as an anxiolytic drug:
What are the 4 side effects for Buspirone?
(less than benzodiazepines)
What are the 3 key let downs for Buspirone?
- Takes days/weeks to develop action
- Ineffective against panic attacks
- Prolonged use = adaptive changes/ desensitisation
What are the 3 key benefits of Buspirone?
- No reports of tolerance and physical dependence
- Less sedation
- Less motor incoordination
Name two hypnotics used to treat insomnia:
- Zopiclone (non BDZ hypnotic)
- Zolpidem (non BDZ hypnotic imidazopyridine)
Name three antihistamines used for sedation:
n.b. Drowsiness = side effect due to H1 antagonism in CNS
What are the 2 benefits of antihistamines over other sedatives?
Fewer side effects
Name a beta adrenoreceptor antagonist used to remove the peripheral symptoms of anxiety:
Why are anxiolytics often used in general dental practice?
As a premedication
What are the 6 indications of using anxiolytics in general dental practice?
If individual is:
- longer appointments
- especially invasive procedures
- pronounced gag reflex
- may help achieve profound local anaesthesia
What are the 5 contraindications of using anxiolytics in general dental practice?
- medically unstable (angina/diabetes)
- medically complex (sever systemic disease)
- patients already presenting adverse reactions to medications
Which anxiolytics are often used in general dental practice?
Chloral hydrate (now replaced with Midazolam)
Barbituates = phentobarbital
Benzodiazepines = Diazepam (valium), Lorazepam (ativan) & Triazolam
Antihistamine H1 - hydroxyzine (vistoril)
Serotonin 5-HT-1A partial antagonists = Buspirone
What is the mechanism of action for Benzodiazepines?
Increase the PROBABILITY of channel opening
What is the mechanism of action for phenobarbitone (barbiturates)?
Low conc = PROLONG channel opening High conc = open channel in absence of GABA