Week 9 - CNS (neurotransmitters and aa) Flashcards
three main NT(neurotransmitter) classes
- amino acid and derivatives
(glutamic acid, GABA, aspartic acid, glycine) - peptides: vasopressin,
somatostatin, neurotensin - monoamines: NA, DA, 5-HT
CNS complexity at every turn
- Multi-synaptic environment
- Neurotransmitters affect multiple receptor targets with varying subunit conformations;
- Glial cells: outnumber neuronal cells (10:1), have major roles, receptor expression, electrical coupling – these affect and
support neuronal function. - Secondary adaptive effects which may result with drug presence on receptors;
- Individual experiences of the drug effects vary considerably, and this is often the main criterion used for effectiveness.
changes ocurring with time as well … via neurotransmitter, neuromodulator, and neuotrophic compounds
Neuromodulators:
- Cause complex responses/ modulation
- Alter sensitivities of synapses
- Modify post synaptic responses;
- Change pre-synaptic handling of NT
- Changes occur over minutes, hours or days; associated with slower events, e.g. growth, learning, protein synthesis
The Blood Brain Barrier
you need to cross this to affect the cns
-a system of tight junctions between
the endothelial cells and surrounding
astrocytes (glia) of the capillaries.
-creates a challenge as it can prevent
many therapeutic drugs from reaching the brain.
-tightly regulates the CNS and protects it from toxins, bacteria, etc.
Agonistic drug effects
- bind to autoreceptors and blocks their inhibitory effect on neurotransmitter release
- binds to post-synaptic receptors and either activates them or increases the effect on them of neurotransmitter molecules
- blocks the deactivation of neurotransmitter molecules by blocking degradation of reuptake
Antagonistic drug effects
- activate autoreceptors and inhibits neurotransmitter release
- is a receptor blocker, it binds to the postsynaptic receptors and blocks the effect of neurotransmitter
Glutamate
Glu
common currency for aa
glutamate within the CNS usually comes from either glucose or glutamine; there is relatively little entering the CNS directly from the periphery after the first few weeks of life
Glutamine - glutamate cycle in the CNS
Glutamine is converted by glutaminase to form glutamate.
Glutamate is then, using a pump, concentrated into a synaptic vesicle. This will require energy because we’re increasing concentration. If an action potential comes along that neuron, that vesicle will move to the end and fuse with the presynaptic membrane and release into the synaptic cleft.
Released Glu is captured partly by neurons and partly by astrocytes, which convert most of it to Gln.
Gln is tranported out of the astrocyte and taken up by neurons which use it to synthesis glutamate.
EAAT
excitatory amino acid transporter
GlnT
Glutamine transporter
VGluT
Glutamate transporter
Glycine
is a positive allosteric modulator of NMDA receptor glutamate responses
(glycine is not an agonist but can bind to the NMDA receptor and when it does it might change the affinity of that receptor)
issues with glutamate receptors (?)
penetration of BBB is a challenge
difficult to selectively block function as glutamate is so generally used throughout CNS
only two drugs in current medicinal use and they are lipid soluble and can cross the BBB:
- ketamine (anaesthesia, depression)
- memantine (alzheimers)
PCP and ketamine
both are drugs which bind to the same site within the NDMA receptor pore, blocking ion movement down the concentration gradient
this is a different site than where glutamate binds, so they are non-competitive antagonists of the NMDA receptor
PCP used to be used as an anaesthetic but is now illegal
ketamine has an affect on opiod receptors
memantine
non-competitive antagonist of the NMDA receptor
clinically useful drug to treat alzheimers disease
Life cycle of GABA
Glutamine can be converted enzymatically to glutamate.
Glutamate can then be converted to GABA via glutamic acid decarboxylase.
GABA is then pumped and concentrated into a synaptic vesicle and then exocytosis upon an action potential, you release GABA into that synaptic gap.
If there happens to be an astrocyte sitting nearby you have the enzymes to take that GABA, convert it to glutamate, convert it to glutamine and shuttle it across and start the whole cycle again.
If you’re presynaptic, you might take that GABA up through that transporter to repackage and recycle.
Benzodiapines (BNZs)
positive allosteric modulators
when bnz binds it does not activate the receptor, it simply enables it to be more responsive when a GABA is present.
Barbiturates have another positive allosteric binding site, and so do neurosteroids and alcohol.
problems with mixing some drugs
if you mix BNZs and alcohol, they have different binding sites, and they are positive allosteric modulators so its not just a summative effect, the net hyperpolarisation possible is significantly greater. Mixing drugs that have a common action is potentially dangerous particularly if it’s inhibitory.
GABA b receptors and useful drugs
Baclofen is a derivative of GABA and is an agonist of GABA b receptors
like GABA it decreases neurotransmitter release in excitatory spinal pathways and increases inhibitory pathway activity by working presynaptically …
Glycine
manufactured premondinalty in spinal chord, packed into vesicles, released, have diversity of receptors post synaptically, chloride ion channel down central pore, no metabotropic forms (all ionotropic)
cleared again using transporters located on nearby astrocytes
Are glycine receptors pharmacological targets?
No therapeutic drugs currently being used on
these receptors, although there has been considerable interest in modulating NMDA-R function using glycine.
Strychnine
A competitive antagonist for glycine receptors, blocking access of glycine to its receptors.
When blocking inhibitory receptors, the result is a greater excitatory response - normal stimulation leads to severe muscle spasms.
