Advanced Receptor

Psychopharmacology

Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC.

© 2017 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD February 2017 MRC2.CORP.D.00208

The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice
1 or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
 This program was developed with the support of
Otsuka Pharmaceutical Development &
Commercialization, Inc. and Lundbeck, LLC.
The speakers are either employees or
paid contractors of Otsuka Pharmaceutical
Development & Commercialization, Inc.

The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice
2 or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
 Table of Contents

• Receptor Types and Subtypes

– Ionotropic vs Metabotropic
– Autoreceptor vs Heteroreceptor

• Intrinsic Activity and Functional Selectivity

• Neurotrophic Factors
• Synaptic Plasticity

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 Receptor Types:
Ionotropic vs Metabotropic
• Ionotropic receptor
– Fast and direct action1,2
– Examples include some
glutamate receptors
(AMPA, NMDA,
Kainate) and nicotinic
acetylcholine
receptors3,4

AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-D-aspartate.

1. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience.

3rd edition. Sinauer Associates; 2004.
2. Turk E, et al. Hum Brain Mapp. 2016;37(5):1856-65.
3. Vignes M, et al. Nature. 1997;388(6638):179-82.
4. Sargent PB. Annu Rev Neurosci. 1993;16:403-43. Image from: Purves D, et al; 20041

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4 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
 Receptor Types:
Ionotropic vs Metabotropic (continued)

• Metabotropic receptor
– Comparatively slow and
indirect action1
– Examples include some
Glutamate receptors
(mGluR) and muscarinic
acetylcholine receptors2

mGluRs, metabotropic glutamate receptors.

1. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004. Image from: Purves D, et al. 20041
2. Sherman SM. Trends Neurosci. 2001;24(2):122-6.

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5 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
 Receptor Types: Auto vs Hetero

Autoreceptor Heteroreceptor
• Receptor is only sensitive to the • Receptor is only sensitive to
neurotransmitter of the cell type neurotransmitters of cell types
it’s located on1 other than the type it’s located
• Example: on4
– A serotonin (5-HT) receptor can be • Example:
located on a presynaptic 5-HT – A 5-HT receptor can be located on
neuron2
a dopamine (DA) neuron5,6
• Result: • Result:
– 5-HT binding to an autoreceptor on
its own neuron can influence the – 5-HT binding to a heteroreceptor
activity or concentration of 5-HT on a DA neuron can influence the
release3 activity or concentration of DA
release6

1. Starke K, et al. Physiol Rev. 1989;69(3):864-989. 4. Gilsbach R, et al. Br J Pharmacol. 2012;165(1):90-102.

2. Barnes NM, et al. Neuropharmacology. 1999;38(8):1083-152. 5. Esposito E, et al. Prog Brain Res. 2008;172:3-6.
3. Sharp T, et al. Trends Pharmacol Sci. 2007;28(12):629-36. 6. Bostwick JM, et al. J Clin Psychiatry. 1999;60(12):857-60.

The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or
6 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
 Intrinsic Activity
• Intrinsic activity of drug at a receptor
– The physiologic effect a ligand elicits once bound to its receptor1,2
– Ligand can partially or fully stimulate (agonism) or inhibit (antagonism, inverse agonism)
receptor activity1,3,4
Agonist Partial agonist Antagonist Inverse agonist

Full activation Partial activation No activation Reduced likelihood of

activation
1. Brunton LL, Lazo, JS, Parker KL (eds). Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th edition. McGraw-Hill; 2005.
2. Jackson CM, et al. Accred Qual Assur. 2007; 2:283–294.
3. Kore PP, et al. Open Journal of Medicinal Chemistry. 2012;2:139-148.
4. Lieberman JA. CNS Drugs. 2004;18(4):251-67.

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7 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
 Spectrum of Intrinsic Activity

Image from: Szkudlinski MW; 2015

Szkudlinski MW. Front Endocrinol (Lausanne). 2015;6:155.

The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or
8 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
 Neurotrophic Factors

• Greek “trophé,” meaning “nourishment”

• Regulate neuronal differentiation and growth
• Signaling via neurotrophic factors can activate:
– cell survival/death
– synapse stabilization/elimination
– process growth/retraction
• Types:
– Nerve growth factor (NGF)
– Brain-derived neurotrophic factor (BDNF)
– Neurotrophin 3 (NT-3)
– Neurotrophin 4/5 (NT-4/5)

Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004.

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10 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
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 Neurotrophin Signaling Pathway
(A) NGF BDNF NT-4/5 NT-3 (B) NGF NT-4/5
BDNF NT-3

Outside

Inside

TrkA receptor TrkB receptor TrkC receptor

p75 receptor

PI 3 kinase ras PLC

SC1 NADE RhoA

IP3 DAG
NGF, nerve growth factor; BDNF, brain-derived Kinases
neurotrophic factor; NT, neurotrophin; Trk, tyrosine PKB
receptor kinase; PI 3, phosphoinositide 3; ras, rat Akt kinase
sarcoma; PLC, phospholipase C; PKB, protein kinase MAP Kinase Ca2+
B; Akt, AKT serine/threonine kinase 1; MAP, mitogen- release PKC Cell Cell Neurite
activated protein; IP3, inositol trisphosphate; DAG, cycle death growth
diacylglycerol, Ca2+, calcium; PKC, protein kinase C; Neurite arrest
SC1, Schwann cell 1; NADE, neurotrophin-associated
cell death executor; RhoA, Ras homolog gene family
outgrowth Activity–
member A. Cell and neuronal dependent
survival differentiation plasticity
Purves D, Augustine GJ, Fitzpatrick D, et al (eds).
Neuroscience. 3rd edition. Sinauer Associates; 2004.

The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or
11 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
Synaptic Plasticity and Long-term Potentiation

 Synaptic plasticity: complex, ongoing, structural/functional alterations in the nervous

system1,2
• Long-term potentiation (LTP): robust and long-lasting form of synaptic plasticity2
– Leading candidate for a cellular mechanism contributing to learning and memory2
– Glutamate receptors are required for the induction and expression of this form of plasticity, and GABA receptors
are involved in their modulation3

AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; PSD, postsynaptic density Image from: Vitureira N, et al; 20133
1. Collingridge GL, et al. Nat Rev Neurosci. 2004;5(12):952-62.
2. Sweatt JD. J Neurochem. 2001;76(1):1-10.
3. Vitureira N, et al. J Cell Biol. 2013;203(2):175-86.

The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or
12 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
 Summary
• Specific subtypes of neurotransmitters can have different
signaling pathways (eg, ionotropic vs. metabotropic) or
functions (eg, autoreceptor vs heteroreceptor), depending
on their neuroanatomical location1,2,3
• Receptor activation via ligand binding can variably
influence a receptor’s intrinsic activity and functional
selectivity2–5
• Neurotrophic factor signaling can regulate activities such as
neuronal differentiation, growth, survival, and plasticity2,6
1. Starke K, et al. Physiol Rev. 1989;69(3):864-989.
2. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004.
3. Gilsbach R, et al. Br J Pharmacol. 2012;165(1):90-102.
4. Jackson CM, et al. Accred Qual Assur. 2007; 2:283–294.
5. Gilchrist A. Trends Pharmacol Sci 2007;28(8):431-437.
6. Lo DC. Neuron. 1995;15(5):979-81.

The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or
13 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
 Advanced Receptor
Psychopharmacology

Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC.

© 2017 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD February 2017 MRC2.CORP.D.00208

The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice
14 or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.