Introduction to pharmacology of the CNS Flashcards
what type of receptors do acetylcholine, dopamine and noradrenaline used?
any exceptions?
what type of affect do they have?
they all use metabotropic receptors
only exception is the 5HT3 receptor which is ionotropic
they have mixed effects
what type of effects do the peptide neurotransmitters have?
opioid NT - inhibitory
NPY - excitatory
list some of the problems associated with drugs of the CNS
measurement and assessment of disorder
- not really applicable for epilepsy
multiple receptors
cellular tolerance
- most CNS conditions are chronic, so require prolonged drug use, but receptors can be dynamic
side effects:
- numerous and hinder compliance
drug delivery:
- problem with crossing the blood - brain barrier
particularly with peptide based drugs
neuronal circuitry
- e.g. inhibition leading to disinhibition
co-existence of peptides
how are peptides different from the normal neurotransmitters
they’re produced in precursor form, and processed en - route (they’ve slow axonal transport)
they’re not re-uptaken, but broken down by peptidases
in active neurones, if synthesis lags behind release - depletion occurs
peptide can be broken down by peptidases, and thereby diffuse into other cells further from cell that released them:
- thus they have important effects at distant sites
- volume transmission is very important
the type of peptides produced from the same gene, is very important on external factors
what are opioid receptors involved in? what can they cause?
receptors:
- anxiety
- pain
- dependance
indication in:
- chronic pain
- addiciton
what are tachykinin functions? what is their possible indication?
function:
- inflammation
- anxiolysis
indication:
- headache
- anxiety
what are CCK functions? what is their possible indication
function
- axiogenesis
- satiation
- dopamine function
- pain
indication:
- PD
- eating disorders
- physcosis
what are NPY function? what is their possible indication?
function:
obesity
mood
indication:
- eating disorder
- depression
- epilepsy
what is the function of vasopressin? what are the possible indication?
function:
- learning and memory
indication:
- amnesia
what is the function of somatostatin? what are the possible indications?
function:
- analgesia
indication:
pain
what are the functions of Galanin? what are the possible indications?
function
- sensory transmission
- feeding
indication:
- pain
- eating disorder
most neurotransmitters are amino acid derivatives, what are the exceptions?
acetylcholine
cannabinoids
adenosine
NO
what type of vesicles are involved in
- fast neuronal transmission
- slow peptide transmission
- slow synaptic transmission
small, synaptic vesicles
- large dense core synaptic vesicles
- small dense core synaptic vesicles
what are the GCPRs of the Gi type coupled to?
what toxin acts on this receptor
negatively coupled to AC
pertusis
what are the GCPRs of the Gs type coupled to
what toxin acts on this receptor
positively coupled to AC
cholera toxins
what are the GCPRs of the Gq type coupled to
positively coupled to PLCb
what are the roles of glutamate?
what receptors is it coupled to?
glutamate is coupled to post-synpatic receptors: NMDA AND AMPA
it is coupled to pre-synpatic receptors which are slow metabotropic
and kainaite receptors
involved in:
- LTP (memory)
- delayed hyperexciation
- neuronal development
- epilepsy
- neuronal death
- point - point transmission
- pain wind up in the spinal cord
- neuromodulation (through the GCPRs)
what are the metabotropic receptors of glutamate linked to?
so the metabotropic receptors can either be positively or negatively linked
Gi receptors: which are negatively coupled to AC
or Gq receptors: which are positively coupled to PLC
- the only one linked to this is mGLU R1/5 - this one is the positively linked one
what pathologies are the NDMA receptors involved in? and how?
recall they’re also involved in development of the visual system and LTP in hippocampus
pain transmission (wind up) - due to amplification and prolongation of impulses cell death - due to excessive calcium influx - alzheimer's - PD? - cerebral ischameia
epilepsy
explain how the NMDA receptor work?
both voltage and ligand gated
ligand required:
- glutamate and glycine
voltage gated:
- at physiological range, the gates are blocked from the inside by magnesium
- depolarisation, removes the magnesium
means:
- receptor not active at physiological range
- delayed in action, because required prior depolarisation
what two calcium channel types are involved in pre-synpatic transmission
N and P calcium channel types
explain wind up pain and LTP?
what nerve fibres are involved
LTP: long lasting enhancement of signal transmission between two neurones, even after neuronal firing is inactivated
it occurs when:
- high stimulation of C-nerve fibres occurs, causing a high rate of C fibre depolarisation
- this prior depolarisation activates NMDA receptors
- activation of NMDA receptor causes increase in the response to the same stimuli over a long period of time
this only occurs in C fibres
what are the two types of GABA receptors? how are they different?
how can the function of GABA receptors be modulated using two different classes of drugs?
GABA a - fast ionotropic - uses Cl- channels
GABA b - slow ionotropic - uses potassium and calcium channels
GABA receptors:
- allosteric modulation of GABAa receptors via benzodiazpenes, increasing the receptor affinity to GABA
- barbiturates: those hold open the Cl- channels of the receptors
what is glycine?
what antagonist is its sensitive to?
peripherial equivalent of GABA
sensitive to strychnine as an antagonist
what type of GCPRs are A1 receptors coupled to?
Gq/11 which are positively linked to PLC B
what type of GCRPs are A2 receptors coupled to?
Gi/o which are negatively coupled to AC
What type of GCRPs are B1 receptors coupled to?
Gs receptors which are positively coupled to AC
what type of GCRPs are dopamine receptors coupled to?
classes 1 - 5
1/5: G/s which is positively coupled to AC
2-4: G/i which are negatively coupled to AC
what are the precursors for:
- acetylcholine
- glutamine
- glycine
- GABA
- noradrenaline
- adrenaline
- 5HT
- dopamine
- histamine
precursors
- choline
- KG/ glutamate
- L serine
- L glutamine
- dopamine
- noradrenaline
- L tryptophan
- L tyrosine
- L histidine
give two examples of drugs that affect the availability of a neurotransmitter
LEVODOPA:
- increases the precursor for dopamine
- used in PD
metirosine:
- competitive antagonist for tyrosine hydroxylase
- prevents noradrenaline formation
- used in phaechromocytoma
how is the role of calcium in vesicle release different in peptide synapses and fast synapses?
in fast synapses:
- the calcium channels are released close to the active site
- form low affinity complex with vesicle and membrane
in peptide synapses:
- calcium not involved in fusion of vesicle to membrane
- but involved in moving vesicle to membrane
- requires fast depolarisation
- form high affinity complex with vesicle
what evidence is there to support the need for calcium for vesicle release?
removal of calcium blocks transmission
ions permeating calcium channels, aid transmission (Ba and SR)
ions that do not permeate the channels, block transmission (Co, Mn)
specific antagonists of the N and P type calcium channels block transmission
- conotoxin and agatoxin
how do Gi/o type GCPRs inhibit transmitter release?
- inhibit vescile fusion
- block calcium voltage gates
- increase potassium channel permeability
give two ways in receptor function can be modulated?
allosteric modulators:
- substances binding to a distinct binding site of receptor
- changing its shape, thereby its affinity for the NT
intracellular:
- phosphorylation of the receptor
- activates or inactivates the receptor
these are some potassium sites: - inwards rectifying potassium channels - two pore potassium channels, TASK - GIRK, G coupled inwards rectifying potassium channels how can they be modulated?
can you think of the slow potassium channels?
Kir - if inhibited causes depolarisation
TASK - if inhibited causes depolarsation
GIRK - e.g. GABAb
they cause hyper polarisation by opening
calcium activated calcium channel voltage gated M channels they remain open a long time after depolarisation closed by Ach on muscuraninc receptors glutamate on metabotropic receptors
list some drug types, and the uptake mechanisms they inhibit to increase NT concentration
tiagabine - GABA uptake blocker (epilepsy)
amitriptyline - noradrenaline and 5HT blocker (tricyclic anti-depressants)
fluoxetine: selective 5HT blocker (depression
give drug names, that inhibit enzyme that break down NT
Selegiline - MAO-B inhibitor - prevents dopamine metabolism - used in PD
valoproate GABA transaminase inhibitor -epilepsy
Vigabatin GABA transaminsae inhibitor - prevents GABA metabolism - Epilepsy
moclobemide MAO-A inhibitior - prevents noradrenaline metabolism - major depression
what type of receptors are cannabinoid receptors?
G coupled receptors (coupled with Gi/o)
CB1 in brain
CB2 in immune system
what are the effects of cannabinoids in the hippocampus?
CB1 receptors are coupled to glutamate and GABA releasing neurones, therefore because they inhibit calcium voltage gates - they will cause inhibition to BOTH excitatory and inhibitory signals
what are the effects of cannabis
depressant euphoria impaired learning and motor preformance analgesic and anti-emetic pyscomimetic
what are the clinical uses of cannaboid agonists?
glaucoma
anti-emetic in chemotherapy patients
prevent weight loss in cancer patients
neuropathtic pain
what are the clinical uses of cannabionoid antagonists?
obesity and drug addiction
how does cannabinoid neuromodulation work?
depolarisation induced cannabionoid production in post-synpatic cell
depolarisation activates DAG lipase, which breaks down DAG into 2DA
2DA is lipophillic and diffuses across the membrane to act on CB1 receptors
the CB1 receptors inhibit AP induced neurotransmitter release (by inhibiting calcium influx)
this causes short term suppression of excitatory and inhibitory signals
endocannibinoids and CB1 receptors are thought to play a role in long term suppression, involving long lasting decrease in neurotransmitter release
what type of activity do NO and adenosine have?
NO- excitatory
Adenosine - inhibitory
