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Section 10 (PT1) - Drugs and Toxins Affecting the CNS
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Second level
Third level
Fourth level
Fifth level
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Second level
Third level
Fourth level
Fifth level
Principles of Pharmacology and Toxicology (BIOL3020)
Section 10 Drugs Affecting the Central Nervous System
Rang et al 2007 (Chapters 32-34)
Stine and Brown (2006) Principles of Toxicology
The action of drugs at the CNS (Brain and Spinal Cord)
Understanding the action of drugs on the CNS is challenging
The effects of drug on the brain far less direct than in the heart or kidney
This is because of the complex neuron connections
However, there are things we do understand
Neurotransmitters
y
Action Potential
Na
Excitatory
neurotransmitter
Presynaptic neuron
Postsynaptic neuron
Excitatory cation channel
Depolarization and possible
Action Potential
Action Potential
Cl-
Inhibitory
neurotransmitter
Presyntaptic neuron
Postsyntaptic neuron
Inhibitory anion channel
hyperpolarization reduces
likelihood of an Action Potential
Neurotransmitter action in the CNS
Drug action in the brain can be complex
Drug action in the CNS
Drugs that effect the CNS do so by affecting, for example
Receptors
Transmitter release
Transmitter reuptake
Amino acid neurotransmitters in the CNS
The two main amino acid neurotransmitters in the CNS are L-glutamate and gamma-aminobutyric acid (GABA)
L-Glutamate is the principal and ubiquitous excitatory transmitter (aspartate to a lesser extent)
GABA is the main inhibitory transmitter
L-Glutamate
L-Glutamate Receptors
Glutamate receptors are named for their selective binding to certain agonists
L-Glutamate Receptors
A closer look at the NMDA receptor
Potentiation of NMDA receptors by glycine
Below are voltage clamp recordings from mouse brain neurons in culture
The traces measure the degree on ion flow into cells
Both NMDA and
glutamate responses
are dependent on
glycine
Excess glutamate can be damaging to the brain
Enhanced glutamate-receptor activity (NMDA mostly) can result in brain damage
In other words, glutamate can be toxic to the brain
The mechanism of cell damage in the brain by glutamate
Depolarization caused by
interruption of blood flow
Glutamate
Presynaptic neuron
Postsynaptic neuron
AMPA Receptors
Ca2
Depolarization
NMDA Receptor
Na
I
Metabotropic Receptor
Mechanism of
Excitotoxicity
Ca2
Mg2
Some environmental toxins also cause excitotoxicity
Several examples of neurodegenerative conditions caused by toxins
Domoic acid is a glutamate analogue found in mussels
Caused neurodegeneration in some people in Newfoundland in 1987 who consumed these mussels
Glutamate can cause long-term changes in brain (associated with learning)
Evidence of the role of glutamate receptors in learning
Association with leaning and memory is controversial
SOME EVIDENCE
NMDA receptor antagonists applied to hippocampus impair learning in rats
Long-term changes in the brain is detected after learning has taken place
Benefits of Drugs affecting L-Glutamate Receptors
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