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Chapter 4 Electrical to Chemical Signal to Electrical/Psychopharmacology The players: a) Ion channels: 1) Signals that __transduce__ (change from one signal type to another) a) Ligand Gated a. Ligand = a chemical that attaches to a binding site on a receptor b. Found in dendrites, cell body and axon terminal b) Mechanically Gated a. Found in sensory systems (example: skin) 2) Signals that ___propogate___ c) Voltage Gated a. Found all throughout neuron membrane b. Propagate post-synaptic potentials and action potentials b) Receptors: NT receptor Directly/indirectly Speed of location? opens channel? action? On channel Directly Fast Ionotropic (ligand - via NT receptor) Coupled to GIndirectly Slow Metabotropic (g protein protein - via alpha subunit coupled receptor) Length of action? Short Long c) Neurotransmitters; their lifecycle: 1. Biosynthesis a. Differs for each neurotransmitter but each begins with precursor + enzyme = NT 2. Storage a. Vesicles are created in the golgi apparatus b. Precursors, enzymes, and vesicles are transported down the axon to the terminal (microtubules) c. Once in the terminal, NT are synthesized and packaged into vesicles 3. Release (See below) 4. Receptors [See above (iono vs. metabotropic) ] 5. Inactivation a. Destruction (enzymes break NT down) b. Diffusion (the process by which molecules spread from areas of high concentration, to areas of low concentration) c. Reuptake (by presynaptic receptors). For a picture: pg. 61 c.2) For specific neurotransmitters, see chart below d) Regulation of axon terminal activity (how does a neuron know its fired too much or too little) 1. Autoreceptor: a. Definition: Metabotropic receptors on the presynaptic neuron that respond to the neurotransmitter that they themselves release b. Purpose: to regulate the synthesis and release of the neurotransmitter; mostly inhibitory effects that is the presence of that NT causes a decrease in the rate of synthesis or release of the NT c. Picture: pg. 113, more information in chapter 2 pg. 63 2. Heteroreceptor: a. Definition: Activation of neuron 1’s terminal button causes presynaptic inhibition OR facilitation of the neuron 2’s terminal button. The second neuron contains heteroreceptors that are sensitive to the NT released by neuron 1. b. Purpose: also to regulate synthesis and release of neurotransmitter possibly through regulating Ca++ c. Example: Endorphins, Picture: pg. 113 3. Retrograde signaling a. Definition: Post-synaptic cell sends messengers back to the presynaptic cell b. Example: If a post-synaptic neuron is receiving too much input, they may snip off a NT like 2-AG which resides in the cell membrane of the post-synaptic neuron. The 2-AG NT will float back to the pre-synaptic cell and bind to CB1. CB1 will slow down the entry of Ca++ to the cell. The Game Plan WHAT? 1. Action potential 2. Na+ influx 3. Ca++ influx 4. 5. 6. 7. 8. 9. 10. 11. 12. Vesicles NT Receptors Ion channels Ions Membrane potential EPSP and IPSP Membrane potential Action potential ACTION? arrives at the ___terminal button_____ causes opening of voltage-dependent/gated __Ca++__ channels severs __anchoring proteins__ and causes vesicles to fuse with presynaptic membrane release NT via __exocytosis__ diffuses across synaptic cleft bind NT open move changes (__EPSP__ if depolarized, __IPSP__ if hyperpolarized) summate reaches threshold propagates Psychopharmacology (routes of administration of drugs and their fate in the body) [i.e. Big picture] - Psychotropics: drugs affecting perception, mood and behavior - Pharmacokinetics: the process by which drugs are absorbed, distributed, metabolized, and excreted within the body o Administration: Injection (in muscles, underneath the skin, veins and more) Oral (sublingual, inhalation) Topical (directly into the skin, steroids) o Measurement: Blood plasma Microdialysis o Distribution: Properties that affect absorption Lipid solubility: molecules that are lipid soluble pass through cells easily & quickly pH Impediments to drugs MAO in gut (will break down monoamines and inactivate certain NT) Depot binding o Blood albumin: if the molecule is bound to a depot (like albumin) they cannot reach their sites of action o Fat cells: another example, most slowly, and less likely to interfere with the initial effects of the drug Blood brain barrier: only lets fat soluble molecules pass; the faster a drug can get pass this the better the “high” - Psychodynamics: effect the drug exerts Drug Effectiveness -How to measure? Dose Response Curve: Therapeutic Index: ratio of a lethal dose to effective dose: High therapeutic index ratio = drug relatively safe (because you need a lot of the drug for it to be lethal) Low therapeutic index ratio: BE CAREFUL. Sites of Action: What are the many ways drugs can affect you? Agonist -chemical that facilitates post-synaptic effects -example: AChE (acetylcholinesterase) breaks down ACh. In a patient with ACh deficit, can block enzyme so that ACh can continually stimulate a post-synaptic cell. So a chemical that blocks AChE is a ACh agonist. Antagonist -chemical that block or inhibit postsynaptic effects -example: a choline reuptake blocker would prevent choline from reentering the cell thereby preventing the re-synthesis of ACh Drugs can be either: Indirect -chemical that binds to a receptor site other than the primary receptor site or indirectly affects the effectiveness of a drug -example: benzodiazepines promote the activity of the GABAa receptor and therefore is an indirect agonist Non-competitive binding -a receptor has a separate neuromodulator binding site. The molecule does not compete with molecules of -example: GABAa has a separate receptor for specific drugs (benzodiazepine) Inverse Agonist -chemical that binds to the receptor site of an agonist but reverses the activity of the receptor -example: if a zinc ion binds with the zinc binding site on an NMDA receptor, the activity of that receptor is decreased Direct -chemical that binds directly to the primary binding site and directly affects the effectiveness of a drug -example: muscimol binds to the GABA binding site and serves as a direct agonist. Competitive binding -drug binds at the exact same receptor site as a neurotransmitter -example: direct agonist NT E/I Amino acids Glutamate + GABA - Precursor Glutamine Byproduct of Krebs Glutamate Receptor type I: NMDA, AMPA, kainate M: metabotropic glu receptor [NMDA: 6 binding sites: (glu, gly, polyamine, zinc, mg, PCP), also known as an AND gate= will only open if there is depolarization and glu binds] I: GABAa (controls Cl-) M: GABAb (controls K+) Inactivation Reuptake Reuptake Function Sensory motor Direct excitatory effects in brain and spinal cord raise or lower the threshold of excitation affecting the rate of action potentials Brain pathway Everywhere Cortex cortex Direct inhibitory effects throughout brain and spinal cord Cortex cortex Modulatory -Primary NT secreted by efferent axons in CNS and 1st discovered -Help learning (basal) -Form memories (medial) -REM sleep (pons) -Arousal -Attention -Increases vigilance Midbrain Cortex -Basal forebrain -Medial septum -Pons -Movement -Nigrostriatal pathway: Substantia nigra striatum (BG) -Mesocortical: VTA Cortex -Mesolimbic: VTA Limbic [GABAa, at least 5 binding sites: (GABA, benzodiazepine, steroid, picrotoxin, barbiturate) Biogenic amines Acetylcholine + (ACh) Choline & Acetyl CoA Norepinephrine + (NE) (ge Catecholamine ner al) Dopamine (DA) Catecholamine + - Tryosine L-DOPA Dopamine NE Tyrosine (AA) L-DOPA Serotonin + (5-HT) Indolamine Neuropeptides/ Opioids (ex. Endorphins) - I: nicotinic; in skeletal muscles -agonized by: nicotine -antagonized by: curare M: muscarinic; in smooth muscle -agonized by: muscarine -antagonized by: atropine M: α1 & β1-2 (post-syn, excitatory) α1 (autoreceptor, inhibitory) M: D1 (post-synaptic) D2 (pre & post-synaptic) -AChE (acetylcholin esterase), eventual reuptake of choline Reuptake, MAO (monoamine oxidase) Reuptake, MAO -Working mem/planning Tryptophan 9 types All metabotropic but 1 Reuptake, MAO Amino acids 3 all Metabotropic: mu: most analgesic effects delta: some analgesic effects kappa: negative side effects Enzymes (no reuptake) -Reinforcement/addiction -Mood, social cognition -Suppresses certain categories of speciestypical behavior -Act as both NT and NM -Modulation of effects of other NT Locus coeruleus (dorsal pons) EVERYWHERE! Raphe nucleus (in pons, midbrain, medulla) cortex, basal ganglia, hippocampus -Used in combination with other NTs -Everywhere, esp. limbic