Section 10 (PT1) - Drugs and Toxins Affecting the CNS

Click to edit Master title style Click to edit Master text styles Second level Third level Fourth level Fifth level Click to edit Master title style Click to edit Master text styles 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