Objectives
- Describe neurotransmitters and their functions in the CNS
- Be able to describe how common neurotransmitters are involved in disease and treatment
- Describe how drug manipulation of neurotransmitters and their receptors may lead to clinical effects, useful in the treatment and disorders of the CNS
- Explain how one drug affects glutamate and GABA signalling
Communication of neurons
Neurons communicate through synapses which are where an axon terminal comes close to the post synaptic neuron. It is at the synapse that the presynaptic neuron releases neurotransmitters which will in the end hyperpolarise or depolarise the post synaptic neuron.
Neurotransmitters
A neurotransmitter is a chemical which acts to carry the change from presynaptic neuron to postsynaptic neuron.
It must be released from synaptic depolarisation and artificial application of the chemical to the postsynaptic neuron must trigger the same effect.
The most common neurotransmitters are
- Glutamate (Present in 90% of excitatory synapes)
- GABA (30% of inhibitory synapses)
- Acetylcholine (present in 5% of neurons)
- Dopamine, serotonin, noradrenaline (less common but still essential)
Neurotransmission
Excitatory neurotransmission
This is where the neurotransmitter leads to depolarisation. In the case of glutamate it occurs as thus.
Glutamate activates AMPA and NMDA receptors leading to depolarisation.l
AMPA
These are simple and when glutamate binds, as it is a ligand gated ion channel, it will let in sodium ions, leading to depolarisation.
NMDA
This is slower to activate as there are more steps needed for activation. There is a Mg2+ ion lodged in the channel which blocks anything flowing into the cell. The Mg2+ is held in place by the attraction to the negative intracell environment and is released upon depolarisation the mg2+ is no longer attracted and held in the channel and will thus leave allowing Na+ and Ca2+ to enter.
Inhibitory neurotransmission
This is where the neurotransmitter leads to hyperpolarisation in the PoSN.
In the case of GABA it occurs via directly opening GABAa Cl- channels leading to chloride ion influx and a hyperpolarisation of the cell.
It also activates GABAb channels which are GPCRs which lead to slower but longer inhibition.
Excitatory Neurotransmission and Long term potentiation.
Long term potentiation is a process which allows neurons to fire with a lower stimulus threshold. Essentially a stronger connection and better connection.
Tetanus is a very strong potentiate for LTP. NMDA is long term depolariser and can easily lead to tetanus.
The mechanism for LTP is the calcium ions from the NMDA leads to more AMPA receptors released to the synaptic gap, leading to easier reaching of threshold.
This is theorised to be the main molecular basis of learning.
We think this because NMDA antagonists can cause amnesia and are often used as aesthetic agents.
Examples of Neuropharmacology
Ketamine
Ketamine is a NMDA antagonist. It causes amnesia at very high doses. In high doses it can cause deficits in working memory and learning
in moderate doses it works as a antidepressant. a current theory is that it inhibits the inhibitory neurons leading to net excitation and increases LTP and BDNF production. This is called disinhibition.
in moderate doses it also can cause analgenia.
Reuptake inhibitors
these are good as they boost existing connections. It slows clearing of certain NTs
for example SSRIs selectively inhibits the clearing of serotonin. SNRIS are serotonin and norepinphrine uptake inhibitors NDRISa for adhd (ritalin) norepinephrine and dopamine
Releasing agents
These work by reversing uptake transporters and vesicle release causing higher concentrations at the synaptic cleft.
Enzyme inhibitors
These disable enzymes which disable neurotransmitter effects in the cleft
These have very broad effects and can inhibit a range of things.
Positive allosteric modulators
These increase receptor activity when the endogenous agonist binds at the same time as the PAM ( the PAM binds to a different site on the same protein.)
Basically a signal boost for certain neurotransmitters.
Pams inlcuse alcohol and benzodiazapines
Propofol
common anesthetic
pam for gabaa
Drugs which block ion channels
lidocaine gets stuck in ion chennals
Summary
This explains neurotransmission, proteins involved, LTP and lists a number of examples of drugs and drug classes for treating psychiatric illnesses