1. (1)Graded potentials on the post-synaptic membrane: depolarization and hyperpolarization; ligand-gated mechanisms (2) What happens at a synapse? A.  Transmitter release  Recognition by receptors on post-synaptic membrane  Transmitter inactivation B. Graded potential changes across the post- synaptic membrane: EPSPs & IPSPs (3) Summing of EPSPs & IPSPs in TIME & SPACE (4) How neurotransmitters (ligands) produce voltage changes across the post-synaptic membrane: ionotropic and metabotropic (5) Types of neurotransmitters/neuromodulators (6) Drug actions: concepts SYNAPTIC POTENTIALS, TRANSMITTERS, & DRUG ACTIONS Class # 4: Synapses., p. 1

2. Graded membrane potentials Depolarization: voltage across the post-synaptic membrane becomes more positive than the resting membrane potential. EPSP: excitatory post- synaptic potential – a temporary depolarization Hyperpolarization: voltage across the post- synaptic membrane become more negative than the resting membrane potential. IPSP: inhibitory post- synaptic potential – a temporary hyperpolarization Class # 4: Synapses., p. 2 These graded deploarizations (EPSPs) and hyperpolarizations (IPSPs) are brought about by the movement of ions across channels of the membrane. The type of channel involved is the ligand-gated channel, which is activated by a neurotransmitter at a synapse.

3. What happens at a synapse? Class # 4: Synapses., p. 3

4. Class # 4: Synapses., p. 4 EPSPs (excitatory post-synaptic potentials) IPSPs (inhibitory post-synaptic potentials) EPSPs bring the membrane potential closer to its threshold for an action potential (i.e., depolarizes). IPSPs bring membrane further from threshold (i.e., hyperpolarizes).

5. SUMMATION OF EPSPs and IPSPs in time and space Class # 4: Synapses., p. 5

6. Class # 4: Synapses., p. 6 AN EXERCISE ON SUMMATION (to be done in class)

7. LIGAND-GATED ACTIONS on the post-synaptic membrane SOME MAY BE VOLTAGE- GATED AS WELL AS LIGAND- GATED; i.e., transmitter action will not occur unless the membrane voltage has also changed in the required way. Class # 4: Synapses., p. 7

8. EXAMPLES of different types of synaptic effects, and of the fact that neurotransmitters do not always have the same effect on the post-synaptic membrane. What happens depends on the receptor-ligand combination, the type of ion that crosses the membrane, and it’s direction of movement: IONOTROPIC: direct action on ion channels  Acetylcholine (ACh): acts on several types of nicotinic ionotropic receptors. At receptors in CNS and skeletal muscle, ACh opens Na + channels  EPSP; at nictotinic receptors in cardiac muscle, ACh opens K + receptors  IPSP  Glutamate: acts on at least 4 types of receptors (3 of which are ionotropic). For one major type (the “AMPA” receptor), glutamate opens Na + channels  EPSP  GABA: acts on many types of receptors. For the GABA A type, it opens CL - channels  IPSP METABOTROPIC: indirect action on ion channels via G-protein and sometimes also a second messenger.  Norepinephrine (NE): acts on at least 4 types of receptors (  1,  2,  1,  2 ), all metabotropic. For both beta types, it closes K + channel, extending the duration of EPSPs. (1) The binding of NE to the receptor activates a G-protein in the membrane. (2) The G- protein activates the enzyme adenylyl cyclase. (3) Adenylyl cyclase converts ATP into the second messenger cAMP. (4) cAMP activates a protein kinase. (5) the protein kinase causes a K + channel to close by attaching a phosphate group to it. Class # 4: Synapses., p. 8

9. TYPES OF NEUROTRANSMITTERS and NEUROMODULATORS Class # 4: Synapses., p. 9

10. SOME FACTORS THAT DETERMINE SYNAPTIC ACTION (drugs can influence all these factors except the first) Location of synapse relative to axon hillock. Nature/quantity of channels and receptors. What transmitter is released, (and how much). Which receptors are located on post-synaptic membrane (and how many). How the transmitter is stored and delivered to synaptic cleft. Transmitter recognition by the receptors (and the effect of recognition – direct vs indirect) If if indirect, which G-proteins and second messengers are involved. Transmitter inactivation: reuptake, enzyme degra- dation, diffusion, uptake into glia, uptake into post-synaptic cell. Synthesis of transmitters and inactivators. Class # 4: Synapses., p. 10

11. DRUGS and their ACTIONS (definitions) Ligand: A molecule that binds with the binding site of a receptor. Agonist: A ligand that binds with and activates a receptor (or that mimics or increases the effects of the typical ligand for that the receptor) Affinity: the strength by which the agonist binds to (attaches to) the receptor Efficacy: the intensity of the agonist- produced receptor activation. Antagonist: A drug that opposes or blocks the effects of a particular ligand on a receptor. Pharmacokinetics: How the body acts on the drug (processes by which it is absorbed, distributed, metabolized, and excreted). Pharmacodynamics: How the drug acts on the body (processes by which it exerts its actions). Class # 4: Synapses., p. 11

12. Addiction: a primary, chronic, neurobiologic disease, with genetic psychosocial, and enviornmental factors influenceing its development and manifestations. It is characterized by behaviors that include one or more of the following: imparied control over drug use, compulsive use, continued use despite harm, and craving. Physical Dependence: a state of adaptation that is manifested by a drug class-specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. Tolerance: a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. DRUGS and their ACTIONS (definitions: cont’d) CONSENSUS STATEMENT 2001 by the American Academy of Pain Medicine, American Pain Society, American Society of Addiction Medicine. Class # 4: Synapses., p. 12