Targets of Psychopharmacological Drug Action
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1 Targets of Psychopharmacological Drug Action (page 33 in syllabus) Stephen M. Stahl, MD, PhD Adjunct Professor, Department of Psychiatry University of California, San Diego School of Medicine Honorary Visiting Senior Fellow, Cambridge University, UK Sponsored by the Neuroscience Education Institute Additionally sponsored by the American Society for the Advancement of Pharmacotherapy This activity is supported solely by the sponsor, Neuroscience Education Institute.
2 Individual Disclosure Statement Faculty Editor / Presenter Stephen M. Stahl, MD, PhD, is an adjunct professor in the department of psychiatry at the University of California, San Diego School of Medicine, and an honorary visiting senior fellow at the University of Cambridge in the UK. Grant/Research: AstraZeneca, BioMarin, Dainippon Sumitomo, Dey, Forest, Genomind, Lilly, Merck, Pamlab, Pfizer, PGxHealth/Trovis, Schering-Plough, Sepracor/Sunovion, Servier, Shire, Torrent Consultant/Advisor: Advent, Alkermes, Arena, AstraZeneca, AVANIR, BioMarin, Biovail, Boehringer Ingelheim, Bristol-Myers Squibb, CeNeRx, Cypress, Dainippon Sumitomo, Dey, Forest, Genomind, Janssen, Jazz, Labopharm, Lilly, Lundbeck, Merck, Neuronetics, Novartis, Ono, Orexigen, Otsuka, Pamlab, Pfizer, PGxHealth/Trovis, Rexahn, Roche, Royalty, Schering-Plough, Servier, Shire, Solvay/Abbott, Sunovion/Sepracor, Valeant, VIVUS, Speakers Bureau: Dainippon Sumitomo, Forest, Lilly, Merck, Pamlab, Pfizer, Sepracor/Sunovion, Servier, Wyeth
3 Learning Objectives To explore transporters as drug targets To explore G protein-linked receptors as drug targets To explore ligand-gated ion channels as drug targets To explore voltage-sensitive ion channels as drug targets
4 Transporters and G Protein-Linked Receptors as Targets of Psychopharmacological Drug Action
5 Major Targets of Psychopharmacologic Drug Action transmembrane region transporter ~ 30% of psychotropic drugs 7 transmembrane region G protein linked ~ 30% of psychotropic drugs 4-1
6 Other Targets of Psychopharmacologic Drug Action 4 transmembrane region ligand-gated ion channel ~ 20% of psychotropic drugs 6 transmembrane region voltage-gated ion channel ~ 10% of psychotropic drugs enzyme ~ 10% of psychotropic drugs 4-2
7 Targets of Psychopharmacological Drug Action Transporters G protein-linked receptors Ligand-gated ion channels Voltage-sensitive ion channels Enzymes
8
9 Pretest Question 1 Presynaptic transporters are a primary mode of inactivation for which of the following? 1. Monoamines 2. Amino acid neurotransmitters such as GABA and glutamate 3. Neuropeptides 4. 1 and , 2, and 3
10 Pretest Question 2 The vesicular monoamine transporter 2 (VMAT2) is utilized by which neurotransmitter? 1. Serotonin 2. Norepinephrine 3. Dopamine 4. 2 and , 2, and 3
11 Monoamine Transporters presynaptic neurons VMAT 2 VMAT 2 VMAT 2 SERT NET DAT 5HT NE DA 4-4
12 vesicles proton pump VMAT 2 Na+ Cl- Na+ Cl-+ add fluoxetine ATPase serotonin (5HT) 4-8A K+ K+
13 Na+ Cl- Na+ Cl-+ fluoxetine (Prozac) 4-8B K+ K+
14 Acetylcholine and Choline Transporters presynaptic neuron VAChT choline transporter ACh choline ACh 4-9
15 GABA Transporters presynaptic neuron VIAAT GAT-1 GABA GAT-2 GAT-3 glial cell GAT
16 Glutamate Transporters presynaptic neuron VGluT 1 EAAT Glu EAAT EAAT glutamine glial cell postsynaptic neuron Glu 4-11
17 Targets of Psychopharmacological Drug Action Transporters G protein-linked receptors Ligand-gated ion channels Voltage-sensitive ion channels Enzymes
18
19 Pretest Question 3 An antagonist is the opposite of an agonist. 1. True 2. False
20 The Agonist Spectrum partial agonist antagonist agonist inverse agonist 4-21
21 No Agonist: Constitutive Activity
22 Full Agonist: Maximum Signal Transduction agonist 4-23
23 "Silent" Antagonist: Back to Baseline, Constitutive Activity Only, Same as No Agonist antagonist
24 Partial Agonist: Partially Enhanced Signal Transduction partial agonist 4-25
25
26 Pretest Question 4 A partial agonist can be a net agonist when neurotransmission is deficient but a net antagonist when neurotransmission is excessive. 1. True 2. False
27 FULL AGONIST light is at its brightest PARTIAL AGONIST light is dimmed but still shining NO AGONIST light is off 4-26
28 Inverse Agonist: Beyond Antagonism; Even the Constitutive Activity Is Blocked inverse agonist 4-27
29 Agonist Spectrum partial agonist no agonist or silent antagonist inverse agonist agonist 4-28
30 Ion Channels and Enzymes as Targets of Psychopharmacological Drug Action
31 Targets of Psychopharmacological Drug Action Transporters G protein-linked receptors Ligand-gated ion channels Voltage-sensitive ion channels Enzymes
32 The Agonist Spectrum partial agonist antagonist agonist inverse agonist 5-9
33
34 Pretest Question 5 A receptor will stop responding to an agonist: 1. When the agonist stops binding to it 2. When the receptor becomes desensitized 3. When the receptor becomes inactivated 4. 1 and , 2, and 3
35 Channel in resting state Channel open Channel closed Channel desensitized Channel inactivated 5-19
36 Opening, Desensitizing, and Inactivating of Ligand-Gated Ion Channels by Agonists Resting state Open state activated by acute agonist order of hours Desensitized state activated by prolonged agonist 5-20 order of hours Inactivated state not immediately reversed by removal of agonist
37 Cl - GABA benzodiazepine agonist positive allosteric modulation GABA A receptors resting open open further 5-23
38 Benzodiazepines: Indirect Effect on GABA Neurotransmission
39 Targets of Psychopharmacological Drug Action Transporters G protein-linked receptors Ligand-gated ion channels Voltage-sensitive ion channels Enzymes
40
41 Pretest Question 6 When voltage-sensitive sodium channels are open and activated, the flow of sodium is: 1. Into the neuron 2. Out of the neuron
42 The Pore of a Voltage-Sensitive Ion Channel Has 6 Transmembrane Regions outside the cell inside the cell 5-27
43 The Loop Between Regions 5 and 6 is an Ionic Filter Voltage-sensitive sodium channel (VSSC) Voltage-sensitive calcium channel (VSCC) outside the cell inside the cell Na+ Ca
44 Four Subunits Combine to Form the Alpha Pore Subunit, or Channel, for Sodium of a VSSC (Voltage-Sensitive Sodium Channel) outside the cell Na+ outside the cell I II III IV inside the cell pore inactivation = pore inactivation inside the cell 5-29
45 Structure of Voltage-Sensitive Sodium Channels (VSSCs)
46
47 Pretest Question 7 Which of the following has evidence that it binds the alpha subunit of voltage-sensitive sodium channels? 1. Gabapentin 2. Pregabalin 3. Lamotrigine 4. 1 and , 2, and 3
48 Possible Binding Sites for Certain Mood Stabilizers on VSSCs inside the cell lamotrigine carbamazepine oxcarbazepine 5-32 outside the cell
49
50 Pretest Question 8 The alpha-2 delta subunit of voltagesensitive calcium channels is believed to help regulate opening and closing of the voltage-sensitive calcium channel. 1. True 2. False
51 VSCCs (Voltage-Sensitive Calcium Channels) Have Multiple Associated Regulatory Proteins inside the cell 1 2 Ca outside the cell
52 Opening a Presynaptic Voltage-Sensitive N or P/Q Calcium Channel Triggers Neurotransmitter Release glutamate snare vesicle N P,Q N P,Q 2 Ca
53 Structure of Voltage-Sensitive Calcium Channels (VSCCs)
54 Site of Action of Alpha-2 Delta Ligands as Selective Inhibitors of Presynaptic Voltage-Sensitive N and P/Q Calcium Channels N P,Q N P,Q N P,Q open = alpha-2 delta ligand open closed 5-37
55 Molecular Action of Alpha-2 Delta Ligands
56
57 Pretest Question 9 Which of the following are involved in regulating neurotransmission via excitation-secretion coupling? 1. Voltage-sensitive sodium channels 2. Voltage-sensitive calcium channels 3. Both 1 and 2 4. Neither 1 nor 2
58 Nerve Impulse Propagation in Presynaptic Neuron: Serial Opening of VSSCs (Voltage-Sensitive Sodium Channels) reception integration chemical encoding electrical encoding A signal propagation signal transduction B 5-39
59 Presynaptic Release of Neurotransmitter by Excitation-Secretion Coupling: VSSCs, VSCCs, and Synaptic Vesicles reception integration chemical encoding electrical encoding A signal propagation signal transduction B 5-40
60 action potential neurotransmitter vesicle VSSC VSCC 5-41
61 Na+ VSSC VSCC 5-41
62 VSSC VSCC 5-41
63 VSSC VSCC 5-41
64 Ca++ VSSC VSCC 5-41
65 Ca++ VSSC VSCC 5-41
66 Ca++ VSSC VSCC 5-41
67 Synaptic Neurotransmission With Vesicular Release
68 Range of Synaptic Neurotransmission
69 Summary The major targets of psychopharmacologic drug action are transporters and G protein-linked receptors Ion channels, both ligand gated and voltage sensitive, are also important targets of psychopharmacologic drug action Enzymes also are the targets of some important psychopharmacological drugs
Sponsored by the Neuroscience Education Institute Additionally sponsored by the American Society for the Advancement of Pharmacotherapy
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