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antagonist - one drug diminishes the effect of another ◦ Shifts the DRC to the right agonist – one drug is additive to the effect of another expected results – due to the principal actions of the drugs less expected – no drug is completely selective definition? types of tolerance ◦ metabolic tolerance – enzyme induction ◦ pharmacodynamic tolerance – chemical see-saw drug brain response The brain wants to rebalance the activity The Neuron, Synaptic Transmission, Neurotransmitters and the CNS a b c Need to think about this question 2 ways 1. within neurons – 2. between neurons- Neuron receiving info Information traveling down neuron within neurons – electrically between neurons – chemically ◦ Synapse – space between neurons the “resting” state the “active” state ◦ neuron is firing ◦ action potential the “refractory” state inside of the axon has a slightly negative charge relative to outside the axon ◦ called the membrane potential ◦ usually around -70mV inside of the axon has a slightly negative charge relative to outside the axon ◦ called the membrane potential why? action potential or spike see depolarization (change from negative inside neuron to more positive) action potential or spike see depolarization (change from negative inside neuron to more positive) ◦ “threshold” – if a great enough depolarization occurs, an action potential will occur see depolarization (change from negative inside neuron to more positive) ◦ “threshold” – if a great enough depolarization occurs, an action potential will occur ◦ action potential – very quick – milliseconds Other terms – spike, firing, generating an AP action potential or spike Hyperpolarization return to negative this is the refractory or recovery period action potential or spike All axons and cells have a membrane thin lipid (fat) bilayer The membranes have channels (to allow ions in or out) Ions – molecules with a charge These channels can be open or shut Ions flowing across the membrane causes the changes in the potential Ions are molecules that contain a positive or negative charge anion – negative charge cation – positive charge Na+ sodium ◦ HIGHER CONCENTRATION OUTSIDE THE AXON Cl- chloride ◦ HIGHER CONCENTRATION OUTSIDE AXON K+ potassium ◦ higher concentration inside the axon Aanions -large (-) molecules with a negative charge (stuck inside the axon) concentration gradient – ◦ ions diffuse from higher concentration to lower concentration example of concentration forces What would each ion do if the ion channel opened based on the concentration gradient? Na+ K+ Cl- What would each ion do if the ion channel opened based on the concentration gradient? Na+ K+ Cl- Na+ would enter axon Concentration Gradient Na+ Na+ would enter axon K+ K+ would leave axon Cl- Concentration Gradient Na+ Na+ would enter axon K+ K+ would leave axon Cl- Cl- would enter axon concentration gradient – ◦ ions diffuse from higher concentration to lower concentration electrical gradient ◦ opposite charges attract so ions are attracted to an environment that has a charge that is opposite of the charge they carry! example of electrostatic forces What would each ion do if the ion channel opened based on electrostatic forces ? Na+ K+ Cl- Electrical Gradient Na+ K+ Cl- go in Electrical Gradient Na+ go in K+ stay in Cl- Electrical Gradient Na+ go in K+ stay in Cl- stay out Concentration Gradient Electrical Gradient Na+ go in go in K+ go out stay in Cl- go in stay out opening of Na+ channels and influx of Na+ ions lidocaine, novocaine, cocaine TTX – tetrototoxin Sagitoxin◦ red tides Concentration Gradient Na+ go in K+ go out Cl- go in Electrical Gradient as cell is depolarized (+ intracellular) nodes of ranvier nodes of ranvier What about communication between neurons? presynaptic ending – ◦ portion of the axon conveying information to the next neuron presynaptic ending – ◦ the portion of the axon that is conveying information to the next neuron synapse or synaptic cleft ◦ the space between neurons where communication occurs presynaptic ending – ◦ the portion of the axon that is conveying information to the next neuron synapse or synaptic cleft ◦ the space between neurons where communication occurs postsynaptic membrane ◦ the portion of the neuron (usually dendrite) that receives information presynaptic ending – ◦ the portion of the axon that is conveying information to the next neuron synapse or synaptic cleft ◦ the space between neurons where communication occurs postsynaptic membrane ◦ the portion of the neuron (usually dendrite) that receives information pre and postsynaptic receptors ◦ proteins in both the presynaptic and postsynaptic ending that allow for information to be transferred synaptic vesicles --small enclosed membranes that contain neurotransmitter found in presynaptic ending neurotransmitter – substance in vesicles that are released in synapse and convey info to the next neuron synapse AP reaches presynaptic endingCa+2 channels in presynaptic ending open and Ca+2 enters Why are Ca+2 ions important? Ca+2 entry into the presynaptic ending critical for neurotransmitter release Figure 3.5 A. Photomicrograph of a synapse in action, taken with the electron microscope. B. Schematic of the process Julien: A Primer of Drug Action, Eleventh Edition Copyright © 2008 by Worth Publishers protein embedded in membrane mechanism for neurotransmitter to influence postsynaptic activity by binding to receptor NT binds to postsynaptic receptors and causes small local changes in electrical potential (depolarizations or hyperpolarizations)◦ Called graded potentials Graded Potentials- ◦ increase or decrease the likelihood of the neuron receiving info to generate an action potential graded potentials that increase the likelihood of an action potential are called EPSPs (excitatory postsynaptic potentials) graded potentials that increase the likelihood of an action potential are called EPSPs (excitatory postsynaptic potentials) graded potentials that decrease the likelihood of an action potential are called IPSPs (inhibitory postsynaptic potentials) NT binding to postsynaptic receptors cause local ion channels to open – chemically dependent ion channels in contrast with electrically dependent ion channels postsynaptic receptors open ion channels – ◦ ion channels in postsynaptic membrane (that we need to worry about) include Na+, Cl- and K+ EPSPs – excitatory postsynaptic potentials - increase the likelihood of an AP - opening of EPSPs – excitatory postsynaptic potentials opening of local Na+ channels IPSPs – inhibitory postsynaptic potentials ◦ IPSPs – inhibitory postsynaptic potentials • decreases the liklihood of an action potential opening of ◦ graded potentials are summed at axon hillock Axon hillock ◦ EPSPs and IPSPs are summed a axon hillock……..AND Graded potentials are localized – has impact in limited region; AP travels down the axon General Principles Synthesis 1. Formation of transmitters 2. Precursors are the main ingredient. Brought to the neuron by the bloodstream. Taken up by cell body and/or terminal. Often come from substances in the diet. 3. Enzymes put the ingredients Transmitters Stored in Vesicles 1. Concentration 2. Protection Release = exocytosis ◦ Vesicles fuse with presynaptic membrane and release transmitters into the synapse. Binding = attachment of transmitter to receptor There are different varieties of receptors. ◦ Some respond fast ◦ Called Ionotropic ◦ Direct reaction to the transmitter Neurotransmitters and Receptors Different varieties of receptors: ◦ Other types of receptors respond more slowly. ◦ Indirectly ◦ Called Metabotropic, or G protein-coupled ◦ Initiates a second signal (messenger) inside the neuron. Inactivation: Termination of Synaptic Transmission 1. Metabolism 2. Re-uptake 3. Re-uptake by glial cell (glutamate only) Acetylcholine Catecholamines ◦ norepinephrine ◦ dopamine Indoleamines ◦ serotonin amino acids ◦ gaba ◦ glutamate peptides ◦ opiates biogenic amines ◦ histamine Acetylcholine—first to be recognized, because of peripheral actions • Synthesis – Acetyl-CoA (in mitochondria) + choline (from diet) Published in 1939 Inactivation: ◦ Acetylcholinesterase (AChE) ◦ After action in postsynaptic cleft, AChE degrades ACh to choline and acetate, which are taken back up into the neuron. Where is ACh produced? Septal nucleus and nucleus basalis Ach ◦ Projects to forebrain. Midbrain ◦ Projects to reticular formation, pons, cerebellum, and cranial nerve nuclei. Ach NE Ach Ach Receptors ◦ Nicotinic ◦ Muscarinic AChE Inhibitors ◦ Irreversible Often toxic Include pesticides and nerves gases ◦ Reversible Cognitive enhancers Treating Alzheimer’s