Serotonin Receptors and Serotonergic Drugscdn.neiglobal.com/content/encore/congress/2014/slides_at...Title The Neuroprotective Effects of Mood Stabilizers Author mgrady Created Date

Copyright © 2014 Neuroscience Education Institute. All rights reserved. Copyright © 2014 Neuroscience Education Institute. All rights reserved.

Serotonin Receptors and

Serotonergic Drugs

Handout for the Neuroscience Education Institute (NEI) online activity:

Copyright © 2014 Neuroscience Education Institute. All rights reserved.

Learning Objectives

• Describe the functions of various serotonin

receptors and their roles in mental illness

• Optimize treatment strategies by taking into

account the serotonin-modulating properties of

psychopharmacological agents


Pretest Question 1

Frank is a 38-year-old patient with major depressive disorder who began treatment with an SSRI nearly 1 week ago. So far, he has not shown any improvement in depressive symptoms. You explain to the patient how both 5HT1A and 5HT1B/D receptors are hypothesized to be responsible for the common delay in response to treatment with an SSRI. 5HT1A and 5HT1B/D receptors both:

1. Are located as autoreceptors on the axons of 5HT neurons

2. Inhibit the release of 5HT from serotonergic neurons

3. Both of the above


Pretest Question 2

Susanna is a 48-year-old morbidly obese patient. After numerous unsuccessful attempts by this patient to lose weight and improve her health through diet and exercise, you are considering a trial of lorcaserin. Lorcaserin is hypothesized to suppress appetite through its agonistic actions at which serotonergic receptor?

1. 5HT1A

2. 5HT2A

3. 5HT2C

4. 5HT6


Serotonin Circuits

PFC: prefrontal cortex; BF: basal forebrain; NA: nucleus accumbens; S: striatum; T: thalamus; HY: hypothalamus; A: amygdala;

H: hippocampus; C: cerebellum; NT: brainstem neurotransmitter centers; SC: spinal cord.

Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013.

PFC

BF

NA

S

HY

A

H

T

NT

SC

C


Serotonin Receptors

7 families and at least 14 subtypes

5HT1A

5HT1B

5HT1D

5HT2A

5HT2C

5HT3

5HT4

5HT6

5HT7

Ohno et al. Biol Pharm Bull 2013;36(9):1396-1400.

5HT1E

5HT1F

5HT2B

5HT5


Various Actions of 5HT Receptors

Shimizu et al. CNS Neurol Disord Drug Targets 2013;12:861-9.


5HT1A

• Located in:

– Hippocampus, septum, amygdala, corticolimbic areas

– Raphe nuclei (presynaptic autoreceptors)

• Actions include:

– Regulation of ACh release in the septum

– Regulation of Glu release in the prefrontal cortex (PFC)

– Regulation of DA release in the ventral tegmental area (VTA)

– Autoreceptors in the raphe nuclei inhibit 5HT

neurotransmission

Artigas F. Pharmacol Ther 2013;137:119-31; Carr, Lucki. Psychopharmacology 2011;213:265-87;

Ohno et al. Biol Pharm Bull 2013;36(9):1396-400; Shimizu et al. CNS Neurol Dis Drug Targets

2013;12:861-9.


5HT1A

• Associated with anxiety, depression,

temperature regulation, corticosterone

secretion, learning, and memory

• Postsynaptic heteroreceptors

– Unaltered or reduced in patients with depression

• Presynaptic autoreceptors

– Increased in patients with depression

– Located on soma and dendrites of 5HT neurons

Artigas F. Pharmacol Ther 2013;137:119-31.


5HT1A

somatodendritic

autoreceptor

5HT1A Somatodendritic Autoreceptors Regulate

Serotonergic Neurotransmission



5HT1A Somatodendritic Autoreceptors Regulate

Serotonergic Neurotransmission



5HT1A and EPS

• Stimulation of 5HT1A heteroreceptors increases

striatal DA activity by inhibiting glutamatergic

corticostriatal neurons

• Stimulation of 5HT1A autoreceptors also

increases striatal DA activity

Ohno et al. Biol Pharm Bull 2013;36(9):1396-400.


Increase in Dopamine Output in PFC by a Selective 5HT1A Agonist

Adapted from Arborelius L et al. Acta Physiol Scand 1993;148(4):465-6.

VTA

Rat Brain

DA

Ou

tpu

t

(% o

f b

ase

line

)

Effect of Systemic 5HT1A Agonist on Dopamine Output in PFC

Time (min)

(R)-8-OH-DPAT = (R)-8-

hydroxy-2(di-n-

propylamino)tetralin

(R)-8-OH-DPAT, 25 μg/kg s.c. 0

100

120

140

Baseline

0 40 80 120 200 160

PFC 5HT1A Agonist

VTA = ventral tegmental area


Cortical 5HT1A Receptors Increase Dopamine Release

5HT neurons

activated

glutamatergic

pyramidal

neuron

5HT1A

receptor glutamate

release

from glutamate

neuron

GABA release

from GABA

neuron

inhibited

DA neuron

5HT

inactive

glutamatergic

pyramidal

neuron

5HT neurons

increased

DA release

Stahl SM. Stahl's Essential

Psychopharmacology. 4th ed. 2013.


Psychotropic Agents With 5HT1A

Binding Affinity

Available

• Aripiprazole

• Clozapine

• Lurasidone

• Quetiapine

• Vilazodone

• Vortioxetine

In Development

• Agonists/Partial Agonists

– Cariprazine

– Brexpiprazole

– Adoprazine

– SSR181507

– F15063

– F15599

Artigas. Pharmacol Ther 2013;137:119-31; Carr, Lucki. Psychopharmacology 2011;213:265-87;

Ramirez et al. Drugs 2014;74:729-36; Shimizu et al. CNS Neurol Dis Drug Targets 2013;12:861-9;

http://pdsp.med.unc.edu.

http://pdsp.med.unc.edu/


5HT1B

• 5HT1B postsynaptic heteroreceptors

– Located on axons of non-serotonergic cells

• 5HT1B presynaptic autoreceptors

– Located in axons of serotonergic neurons

– Function similarly to 5HT1A receptors

• Reduce serotonergic output

• Must be desensitized for antidepressants to be fully effective

• May be more prominent than 5HT1D in median

raphe nuclei

Artigas F. Pharmacol Ther 2013;137:119-31; Carr, Lucki. Psychopharmacology 2013;213:266-87;

Olivier, van Oorschot. Eur J Pharmacol 2005;526:207-17; Shimizu et al. CNS Neurol Dis Drug Targets

2013;12:861-9; Hopwood, Stamford. Neuropharmacol 2001;40(4):508-19; Sari Y. Neurosci Biobehav Rev

2004;28:565-82 .


5HT1D

• 5HT1B and 1D have been historically difficult to

distinguish – Lack of selective agonists/antagonists, rodent vs. human,

nomenclature

• Presynaptc autoreceptors – Located in axons of 5HT neurons

• Function similarly to 5HT1A receptors – Reduce serotonergic output

– Must be desensitized for antidepressants to be fully

effective

• May be more prominent than 5HT1B in dorsal raphe

nuclei Artigas F. Pharmacol Ther 2013;137:119-31;

Carr, Lucki. Psychopharmacology 2013;213:266-87; Olivier, van Oorschot. Eur J Pharmacol 2005;526:207-17;

Shimizu et al. CNS Neurol Dis Drug Targets 2013;12:861-9; Hopwood, Stamford. Neuropharmacol

2001;40(4):508-19; Sari Y. Neurosci Biobehav Rev 2004;28:565-82 .


Serotonin 5HT1B/D Effects on Serotonin Release

5HT1B/D

axon terminal

autoreceptor



5HT1B/D

axon terminal

autoreceptor

5HT1B/D antagonists may increase

5HT release


Serotonin 5HT1B/D Effects on Serotonin Release


5HT 5HT

= GABA

Prefrontal cortex


5HT 5HT

= GABA

Prefrontal cortex

1B/D

1B/D

1B/D

1B/D

1B/D


Prefrontal cortex

5HT 5HT

Stimulate 5HT1B/D autoreceptors

1B/D

= GABA


Prefrontal cortex

5HT 5HT

Add 5HT1B/D antagonist

5HT 5HT

1B/D

5HT1B/D antagonist

= GABA


5HT 5HT

Prefrontal cortex

Basal forebrain

Tuberomammilary

nucleus

Ventral

tegmental area

Locus

coeruleus

Glu

ACh

HA

DA

NE

= GABA


5HT 5HT

Prefrontal cortex

Basal forebrain

Tuberomammilary

nucleus

Ventral

tegmental area

Locus

coeruleus

Glu

ACh

HA

DA

NE

1B

1B

1B

1B

= GABA 1B

Stimulate 5HT1B heteroreceptors


Prefrontal cortex

5HT 5HT

Basal forebrain

Tuberomammilary

nucleus

Ventral

tegmental area

Locus

coeruleus

ACh

HA

DA

Glu

NE

= GABA 1B

Stimulate 5HT1B heteroreceptors


Prefrontal cortex

5HT 5HT

Basal forebrain

Tuberomammilary

nucleus

Ventral

tegmental area

Locus

coeruleus

HA

DA

Glu

NE

= GABA 1B

5HT1B antagonist

Add 5HT1B antagonist

ACh

HA

DA

NE

ACh


Psychotropic Agents With 5HT1B/D

Binding Affinity

Available

• Aripiprazole

• Asenapine

• Clozapine

• Iloperidone

• Quetiapine

• Ziprasidone

• Vortioxetine

In Development

• Agonists

– Anpirtoline

– CP94253

• Antagonists

– GR127935

– SB 216641


Shimizu et al. CNS Neurol Dis Drug Targets 2013;12:861-9; http://pdsp.med.unc.edu.



5HT2A

• Located in:

– Cerebral, piriform, and entorhinal cortices, claustrum,

olfactory bulb, anterior olfactory nucleus, brainstem nuclei,

and limbic regions

• 5HT2A receptors are found on GABAergic

interneurons and glutamatergic neurons in cortex

• 5HT2A receptor density is increased in depressed

patients

• 5HT2A receptors have been implicated in

depression, anxiety, and negative symptoms of

schizophrenia Artigas. Pharmacol Ther 2013;137:119-31;

Carr, Lucki. Psychopharmacology 2011;213:265-87; Ohno et al. Biol Pharm Bull 2013;36(9):

1396-400; Shimizu et al. CNS Neurol Dis Drug Targets 2013;12:861-9.


5HT2A Antagonism

• Chronic administration of 5HT2A antagonists

results in:

– Down-regulation of 5HT2A receptors

– Antidepressant effects

– Improvement in EPS

• Via disinhibition of DA release in the striatum


Shimizu et al. CNS Neurol Dis Drug Targets 2013;12:861-9.


Cortical 5HT2A Receptors Decrease Dopamine Release

striatum

decreased

DA release

nucleus

accumbens

raphe

substantia

nigra



Cortical 5HT2A Receptors Decrease Dopamine Release

5HT neurons 5HT2A

receptor

activated

glutamatergic

pyramidal

neuron

5HT1A

receptor

5HT

5HT neurons

glutamate

release

from glutamate

neuron

GABA release

from GABA

neuron

inhibited

DA neuron




Blocking Cortical 5HT2A Receptors Increases Dopamine Release

5HT neurons 5HT2A

receptor

5HT1A

receptor

5HT neurons

glutamate

release

from glutamate

neuron

2A antagonist

inactive

glutamatergic

pyramidal

neuron

inactive GABA

neuron

activated

DA neuron

increased

DA release




Nigrostriatal Pathway

stimulate 5HT2A

receptor

DA neuron

5HT neuron

DA D2 receptor

5HT2A receptor

5HT

no DA release



Nigrostriatal Pathway:

Blocking D2 Receptors




SDA

block 5HT2A

receptor

Nigrostriatal Pathway: Blocking 5HT2A

Receptor Disinhibits DA Release and

Reduces D2 Blockade

EPS




Psychotropic Agents With 5HT2A

Binding Affinity

Available

• Aripiprazole

• Asenapine

• Clozapine

• Iloperidone

• Lurasidone

• Olanzapine

• Paliperidone

• Risperidone

• Quetiapine

• Ziprasidone

• Mirtazapine

• Trazodone

• Pimavanserin





Pimavanserin

• 5HT2A inverse agonist

– Blocks intrinsic activity when no

agonist is present and blocks the

agonist when present

• Recently received FDA

Breakthrough Therapy

Designation for Parkinson’s

disease psychosis

– Reduction in psychotic symptoms

– Unlike antipsychotics, pimavanserin

does not impair motor function or

reduce the efficacy of L-DOPA

Cummings et al. The Lancet 2014;383:533-40; Friedman JH. Expert Opin Pharmacother 2013;14(14):1969-75;

Goldman, Holden. Curr Treat Options Neurol 2014;16:281; McFarland et al. Beh Pharmacol 2011;22:681-92;

Meltzer HY et al. Neuropsychopharmacol 2010;35:881-92; Meltzer, Roth. J Clin Invest 2013;123(12):4986-91.

Significant improvement on the

Scale for the Assessment of

Positive Symptoms –Parkinson’s

Disease (SAPS-PD)


Pimavanserin Mechanism of Action

• Primarily visual hallucinations in PD

• Loss of nigrostriatal DA neurons causes

compensatory increase in 5HT signaling

• 5HT2A receptors are increased in visual

processing and limbic circuits in PD patients with

psychosis

Cummings et al. The Lancet 2014;383:533-40; Friedman JH. Expert Opin Pharmacother 2013;14(14):1969-75;

Goldman, Holden. Curr Treat Options Neurol 2014;16:281; McFarland et al. Beh Pharmacol 2011;22:681-92;

Meltzer HY et al. Neuropsychopharmacol 2010;35:881-92; Meltzer, Roth. J Clin Invest 2013;123(12):4986-91.


5HT2C

• Located in:

– Hippocampus, amygdala, anterior olfactory and

endopiriform nuclei, cingulate and piriform cortices,

thalamic nuclei, and substantia nigra

• Preferentially located on GABAergic

interneurons

– Also on DA neurons in the mesolimbic pathway

Artigas. Pharmacol Ther 2013;137:119-31; Carr, Lucki. Psychopharmacology 2011;213:265-87.


5HT2C

• Both 5HT2C agonists and antagonists may have

antidepressant effects

– Increase release of DA and NE in terminal regions

• 5HT2C agonism

– Suppresses DA release more from the mesolimbic

pathway than from the nigrostriatal pathway

• An antipsychotic without EPS?

– May be useful for treating obesity




Serotonin 2C Agonist Lorcaserin Suppresses Appetite

5HT neurons

raphe

hypothalamus

appetite

suppression lorcaserin



Lorcaserin Actions: Enhance POMC

AgRP

NPY appetite

suppre

ssin

g

appetite

stim

ula

ting

NPY

AgRP MSH

MC4R appetite

5HT2C 5HT

lorcaserin

POMC

MSH: -melanocyte stimulating hormone

AgRP: agouti-related protein

MCR4: melanocortin 4 receptor

NYP: neuropeptide Y

POMC: proopiomelanocortin



Psychotropic Agents With 5HT2C

Binding Affinity

Available

• Asenapine

• Clozapine

• Olanzapine

• Quetiapine

• Agomelatine

• Fluoxetine

• Mirtazapine

• Mianserin

• Nefazodone

• Trazodone

• Lorcaserin





5HT3

• Located in:

– Spinal cord, brainstem, hippocampus, amygdala,

and entorhinal, frontal, and cingulate cortices

– Regulate DA, NE, 5HT, ACh, GABA, and histamine

release

• 5HT3 antagonists may

– Enhance cognition

– Be anxiolytic

– Reduce EPS



2013;12:861-9; Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013.


Serotonin 5HT3

5HT3 receptors are localized in:

The chemoreceptor trigger

zone of the brainstem

• Mediate nausea and vomiting

The gastrointestinal tract

• Mediate nausea, vomiting, and

diarrhea/bowel motility

Blocking 5HT3 may protect against the serotonin-induced gastrointestinal

side effects that often accompany agents that increase 5HT release



5HT3 Antagonist Tropisetron Increases

Cortical Acetylcholine

Adapted from Giovannini MG et al. J Pharmacol Exp Ther 1998;285(3):1219-25.

Ac

ety

lch

oli

ne

(r

atio

to

ba

se

line)

Systemic 5HT3 Antagonist Reverses 5HT-Induced

Decrease of Cortical Acetylcholine

PFC

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0

100 mM K+

5HT (local)

Tropisetron (s.c.)

10 μM

0.5 mg/kg

5HT (local)

5HT3

Antag.

0

0

10 μM

0


Serotonin 5HT3 Effects on Norepinephrine and Acetylcholine Release

GABA neuron

5HT

neuron

NE

neuron

ACh

neuron

5HT3R

5HT3R 5HT3R Baseline

NE release

Baseline

ACh release

5HT

release

Reduced

ACh release

Reduced

NE release

NE: norepinephrine

ACh: acetylcholine

Stahl SM. Stahl's

Essential

Psychopharmacology.

4th ed. 2013.


Increased

ACh release

Increased

NE release

GABA neuron

5HT

neuron

Reduced

ACh release

Reduced

NE release

5HT3

antagonist

NE

neuron

ACh

neuron

Serotonin 5HT3 Effects on Norepinephrine and Acetylcholine Release

Stahl SM. Stahl's

Essential

Psychopharmacology.

4th ed. 2013.

NE: norepinephrine

ACh: acetylcholine


2nd spike

5HT3 Modulates Cortical Pyramidal Neuron Activity

Zhou FM et al. J Neurophysiol 1999;82(6):2989-99; Siarey RJ et al. Neurosci Lett 1995;199(3):211-4.

5HT3 Agonist Inhibits Pyramidal Neurons in

Cortical Slices

PFC

Inh

ibit

ory

Po

sts

yn

ap

tic

Cu

rre

nt

Time 100μM mCPBG

mCPBG=1-(m-chlorophenyl)biguanide

5 sec

Greater

inhibition

Layer I neuron

Pyramidal neuron

50 pA

200 pA

5HT3 Antagonist Increases Excitability of

Pyramidal Neurons

10 ms

1 mV

100 μM Zacopride

Ort

ho

dro

mic

all

y-E

vo

ke

d

Fie

ld P

ote

nti

als

Control


Serotonin 5HT3 Effects on Glutamate Release

Baseline

5HT3

receptor PFC

Raphe

Baseline glutamate

release

5HT

neuron

Pyramidal

neuron

GABA

neuron

Overactivation

Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013; Ciranna L. Curr Neuropharmacol 2006;4(2):101-14.



5HT3

receptor PFC

Raphe

Stimulation of 5HT3

receptors in the

prefrontal cortex

reduces glutamate

release from

pyramidal neurons

Reduced glutamate

release

5HT

neuron

Pyramidal

neuron

GABA

neuron

Overactivation



5HT3

receptor PFC

Raphe

Increased glutamate

release

5HT

neuron

Pyramidal

neuron

GABA

neuron

Blockade of 5HT3

receptors in the

prefrontal cortex

enhances glutamate

release from

pyramidal neurons

5HT3

antagonist

Overactivation




Psychotropic Agents With 5HT3

Binding Affinity

Available

• Clozapine

• Fluoxetine

• Mirtazapine

• Vortioxetine

In Development for

Psychotropic Effects

• Tropisetron

• Ondansetron

• Granisetron





5HT4

• Located in:

– Putamen, caudate nucleus, hippocampus, nucleus

accumbens, globus pallidus, substantia nigra,

neocortex, raphe and pontine nuclei, and thalamus

• Involved in the expression of genes for synaptic

plasticity

– 5HT4 agonists may enhance cognition

– 5HT4 antagonists cause impairments in learning and

memory

• Increase release of ACh and reduce amyloid


Shimizu et al. CNS Neurol Dis Drug Targets 2013;12:861-9.


Psychotropic Agents With 5HT4 Binding

Affinity

In Development

• Tropisetron

• RS67333

• PRX-3140

• PF-04995274

• RQ-9


Ramirez et al. Drugs 2014;74:729-36; Shimizu et al. CNS Neurol Dis Drug Targets 2013;12:861-9;

http://pdsp.med.unc.edu.



5HT6

• Located in:

– Striatum, nucleus accumbens, olfactory tubercles,

cortex, hippocampus, amygdala, hypothalamus,

thalamus, and cerebellum

• Implicated in schizophrenia, depression, eating

disorders, and cognition

• Regulate release of ACh, NE, GABA, and DA

• Both 5HT6 agonists and antagonists may have

antidepressant and pro-cognitive effects



2013;12:861-9; Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013.


Psychotropic Agents With

5HT6 Binding Affinity

Available

• Asenapine

• Clozapine

• Olanzapine

• Quetiapine

• Clomipramine

• Amitriptyline

• Doxepin

• Mianserin

In Development

• Antagonists

– SB-399885

– SB-742457

– Lu-AE-58054

– P7C3

– SUVN-502

• Agonists

– LY-586713

– WAY-181187

– WAY-208466

Artigas. Pharmacol Ther 2013;137:119-31; Carr, Lucki. Psychopharmacology 2011;213:265-87; Ramirez et al.

Drugs 2014;74:729-36; Shimizu et al. CNS Neurol Dis Drug Targets 2013;12:861-9; http://pdsp.med.unc.edu.



5HT7

• Located in:

– Thalamus, hypothalamus, hippocampus, and cortex

• Implicated in thermoregulation, circadian

rhythms, sleep, and mood disorders

• 5HT7 antagonism has antidepressant effects

Artigas. Pharmacol Ther 2013;137:119-31; Carr, Lucki. Psychopharmacology 2011;213:265-8; Stahl

SM. Stahl's Essential Psychopharmacology. 4th ed. 2013; Shimizu et al. CNS Neurol Dis Drug

Targets 2013;12:861-9.


5HT7 Antagonist SB-269970 Increases

Cortical 5HT

Adapted from Bonaventure P et al. J Pharmacol Exp Ther 2007;321(2):690-8.

5HT7 Antagonist Augments SSRI-

Induced Cortical 5HT Release

Rat Brain

PFC

DR

Vehicle

(n=3)

Citalopram, 3 mg/kg

(n=3)

SB-269970, 10 mg/kg +

Citalopram, 3 mg/kg

(n=4)

Ex

tra

ce

llu

lar

5H

T in

Fro

nta

l C

ort

ex

(% o

f b

as

al le

ve

l)

800

700

600

500

400

300

200

100

0

−120 −60 0 60 120 180 240 300

Subcutaneous injection

Time (min) DR = dorsal raphe


5HT7: Serotonin Release in the Prefrontal Cortex

Overactivation

Baseline

5HT

neuron GABA

neuron

5HT7

receptor

Baseline 5HT

release

PFC

Raphe



Baseline 5HT

release

PFC

Raphe

Stimulation of

5HT7 receptors in

the raphe reduces

serotonin release in

the PFC

Reduced

5HT release

Overactivation

GABA




PFC

Raphe

Blockade of 5HT7

receptors in the

raphe increases

serotonin release

5HT7 antagonist

Increased

5HT release

Overactivation




Psychotropic Agents With

5HT7 Binding Affinity

Available

• Aripiprazole

• Asenapine

• Clozapine

• Lurasidone

• Paliperidone

• Risperidone

• Quetiapine

• Ziprasidone

• Amisulpride

• Amoxapine

• Desipramine

• Imipramine

• Mianserin

• Fluoxetine

• Vortioxetine

Artigas. Pharmacol Ther 2013;137:119-31; Carr, Lucki. Psychopharmacology 2011;213:265-87; Ramirez et al.

Drugs 2014;74:729-36; Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013; Shimizu et al. CNS Neurol

Dis Drug Targets 2013;12:861-9; http://pdsp.med.unc.edu.



Multimodal Agents

• Combine multiple modes of monoaminergic action

• Example: vortioxetine (LuAA21004)

– Transporter mode: SERT inhibitor

– Ion channel mode: 5HT3 antagonist

– G protein receptor mode:

• 5HT1A agonist

• 5HT1B partial agonist

• 5HT1D antagonist

• 5HT7 antagonist

– Raises neurotransmitters in preclinical models

• 5HT, NE, DA

• Plus histamine, acetylcholine, and glutamate

Stahl SM. CNS Spectrums 2013;18:113-7.


Vortioxetine: 3 Modes, 6 Pharmacological

Actions

SERT inhibition 5HT1A

agonism

5HT7

antagonism

5HT3

antagonism

transporter

ion channel-linked

receptors G protein-linked receptor

5HT1B

partial agonism

5HT, NE, DA, ACh, HA, GABA, Glu


5HT1D

antagonism

1D


Vortioxetine

Antidepressant

Reduce sexual

dysfunction?

Antidepressant Antidepressant? Antidepressant

Pro-cognitive

Antidepressant

Pro-cognitive?


SERT inhibition 5HT1A

agonism

5HT7

antagonism

5HT3

antagonism

transporter

ion channel-linked

receptors G protein-linked receptor

5HT1B

partial agonism

5HT1D

antagonism

1D


Summary

• Neurotransmission through the various serotonin receptors may have a wide range of molecular and behavioral effects

• Antidepressant effects may be mediated by agonism of 5HT1A, 5HT2C, 5HT4, and 5HT6 receptors or by antagonism at 5HT1B/D, 5HT2A, 5HT2C, 5HT3, 5HT6, and 5HT7 receptors

• Pro-cognitive effects may be mediated by agonism of 5HT2C, 5HT4, and 5HT6 receptors or by antagonism at 5HT1A, 5HT1B/D, 5HT3, and 5HT6 receptors

• Anti-drug-induced EPS may be mediated by agonism of 5HT1A receptors or antagonism at 5HT2A, 5HT2C, 5HT3, and 5HT6 receptors

• Employing treatment strategies that target a variety of serotonin receptors as well as increasing 5HT levels through the inhibition of SERT may provide for optimal clinical outcomes

Documents

Serotonin Receptors and Serotonergic Drugscdn.neiglobal.com/content/encore/congress/2014/slides_at...Title The Neuroprotective Effects of Mood Stabilizers Author mgrady Created Date