Pharmacology Of The Brain (Lecture 16) Flashcards
Why is it hard to target output pathways for specific functions?
They only use ACh / noradrenaline - therefore have no FUNCTIONAL SPECIFICITY
Why do neurotransmitters have such a big modulatory effect?
NTs are synthesised and released from specific types of neurones (e.g. serotonergic neurones)
The neurones can project widely and release the same molecule in different areas
The same NT molecule can have different effects depending on the type of receptor-function specific pathway
Why are objective outcome measures difficult in neuropharmacology?
Subjective
E.g. with a drug aiming to change mood (e.g. antidepressants) the outcome is subjective
Why are neurotransmitter pathways effective targets for therapeutic modulation?
Disease states are typically caused by excessive / deficient signalling within a particular transmitter pathway (receptor sub-type is often important)
Therapeutic modulation targets this abnormal transmitter signalling
Why are neurotransmitter pathways better targets for therapeutic intervention than output pathways?
Information processing circuits within the brain (neurotransmitter pathways) offer more targets for modulation of function / behaviour with greater specificity than output targets
Which type of receptors produce slower & more sustained effects?
GPCRs
What type of receptor produces faster effects?
Ion channels
What is the use of nicotine and what transmitter pathway does it affect?
Recreational use
nicotinic ACh receptors
What is the use of heroin and what transmitter pathway does it affect?
Recreational / analgesic (pain relief)
Agonist of opioid peptides
What is the use of Fluoxetine and what transmitter pathway does it affect?
Antidepressant
Serotonin - acts as a selective serotonin re-uptake inhibitor
What is the use of Diazepam / Valium (type of benzodiazepine) and what transmitter pathway does it affect?
Anxiolytic (treats anxiety)
GABA - acts as a positive allosteric modulator of the GABA-a receptor
What is the use of cocaine and what transmitter pathway does it affect?
Recreational
Dopamine - inhibits dopamine re-uptake transporter
What type of receptor does LSD target, and what is the effect?
LSD is a 5-HT2A receptor agonist
Upregulates the function of 5-HT2A receptors, causing potent psychoactive effects
What type of receptor do antipsychotic drugs target?
Antipsychotic drugs are antagonists of the 5-HT2A receptor
*psychosis / schizophrenia are characterised by the hyperactive state of psychoactive functions
What is the motor output?
Signals to muscles to coordinate movement / behaviour
Signals via acetylcholine
What is the major challenge of neuropharmacology?
FUNCTIONAL SPECIFICITY
What is the function of the 5-HT2c serotonin receptor, and where is it mostly expressed?
Appetite
Mostly expressed in the brain stem
Describe the action of AUTORECEPTORS
Only respond to transmitters released from the cell of which they are embedded
Act as a regulatory mechanism - once NT reaches a certain level, it binds to autoreceptors which send an inhibitory signal and stop the release of NT
Usually terminate release - negative feedback mechanism
Describe the action of Heteroreceptors
Respond to NTs released from adjacent neurones
Usually increase release
What is the autonomic output and what does it signal via?
Signals unconscious, bodily, physiological processes (heart rate, blood pressure, digestion, etc.)
Signals via ACh & noradrenaline
What is interoception?
Reception of internal stimuli
What is exteroreception?
The reception of external stimuli
What is a good target in the brain which increases specificity?
Neurotransmitter pathways
What does the 5-HT2A serotonin receptor affect?
Cognitive function - cognition, perception, attention, memory
Highly expressed in the cortex
What does a mix of receptor subtypes allow for?
Mixed effects from the same neurotransmitter
They can be excitatory / inhibitory
They can be fast (i.e. msecs) / slow (secs / mins)
What determines the type of effect (excitatory / inhibitory) of NTs?
Their receptors
What are the 7 stages of synaptic transmission of NTs?
- NTs synthesised & stored in vesicles
- AP arrives at presynaptic terminal
- Causing voltage-gated Ca2+ ion channels to open
- Influx of Ca2+ stimulates secretory vesicles containing NT to move to and fuse with the presynaptic membrane
- NT released by exocytosis
- NT diffuses across synaptic cleft and binds to postsynaptic receptors (causing them to open / close)
- Excitatory / inhibitory postsynaptic potential is generated
- NT removed by re-uptake channels (into neurone / glia) or by enzymatic degradation
What are the 4 opportunities for pharmacological modulation of synaptic transmission?
- Synthesis - inc / inhibit
- Release - potentiate (inc / sustain) or inhibit
- Effects - target postsynaptic receptors
- Removal - block / inc re-uptake
What are the 4 neuro-modulatory transmitters?
- Adrenaline
- Noradrenaline
- Serotonin (5-HT)
- Dopamine
(all have mixed effects)
What are the 3 types of opioids?
- Endorphins
- Enkephalins
- Dynorphins
What are the 3 types of neuropeptides and their effects?
- Opioid - inhibitory
- GLP-1 - mixed effects
- Substance P - excitatory
What are the 2 types of receptor?
- Autoreceptors
- Heteroreceptors
What are the 2 types of receptor targeted by NTs?
- Ionotrophic - ligand-gated ion channels
- Metabotrophic - GCPRs
What are the 2 types of output?
Motor
Autonomic
What are the 2 types of NT used in outputs?
ACh & noradrenaline
What are the 2 major excitatory & inhibitory NTs?
Glutamate - excitatory
GABA - inhibitory
Work predominantly by ion channel receptors
Most neurones in the brain are glutamatergic / gabaergic
What are the (5) criteria for being a ‘true’ NT?
- Present in the presynaptic terminal
- Stored in vesicles
- Dependant on Ca2+ for release
- Target postsynaptic receptors - have a postsynaptic effect
- Mechanisms exist for the termination of their effect (negative feedback)
What are neuromodulators?
Messenger released from a neurone that affects the transmission of signals between neurones - modifies synaptic communication
They may not be ‘true’ NTs
Their action is always slow
What are 3 other examples of NTs and their effects?
- Nitric oxide (gas) - mixed effects
- Adenosine - inhibitory effects
- Lipids (endocannabinoids, bile acids) - mixed effects (formed from the lipid membrane of neurones themselves)
Pharmacological modulation of the release of NTs targets what receptors?
Presynaptic
Pharmacological intervention of the effects of NTs targets what receptors?
Postsynaptic
How many neurones & connections are there in the human brain?
Approx…
100 billion neurones
1 quadrillion (1x10^15) connections
How can receptors be used to achieve some specificity for drugs (therapeutic intervention)?
Targeting a receptor allows us to pharmacologically modulate a NT pathway
How can the same NT have different effects (inhibitory / excitatory)?
Same NT can act on different receptors
Receptors determine excitatory / inhibitory effect
Are NTs agonists or antagonists?
Always agonists
What are the 2 types of output from the brain, and what do they signal via?
- Motor output - signals via ACh
- movement / behaviour - Autonomic output - signals via ACh & noradrenaline
- physiological processes (e.g. HR, BP, digestion)
What is the major EXCITATORY NT?
Glutamate
What is the major INHIBITORY NT?
GABA
