Subanesthetic S-ketamine does not acutely alter striatal dopamine transporter binding in healthy Sprague Dawley female rats

Simone Larsen Bærentzen; Jakob Borup Thomsen; Majken Borup Thomsen; Steen Jakobsen; Mette Theilgaard Simonsen; Gregers Wegener; David J Brooks; Anne M Landau

doi:10.1002/syn.22294

Subanesthetic S-ketamine does not acutely alter striatal dopamine transporter binding in healthy Sprague Dawley female rats

Simone Larsen Bærentzen, Jakob Borup Thomsen, Majken Borup Thomsen, Steen Jakobsen, Mette Theilgaard Simonsen, Gregers Wegener, David J Brooks, Anne M Landau^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Major depressive disorder is one of the most prevalent mental health disorders, posing a global socioeconomic burden. Conventional antidepressant treatments have a slow onset of action, and 30% of patients show no clinically significant treatment response. The recently approved fast-acting antidepressant S-ketamine, an N-methyl-D-aspartate receptor antagonist, provides a new approach for treatment-resistant patients. However, knowledge of S-ketamine's mechanism of action is still being established. Depressed human subjects have lower striatal dopamine transporter (DAT) availability compared to healthy controls. Rodent studies report increased striatal dopamine concentration in response to acute ketamine administration. In vivo [ 18F]FE-PE2I ([ 18F]-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4'-methyl-phenyl) nortropane) positron emission tomography (PET) imaging of the DAT has not previously been applied to assess the effect of acute subanesthetic S-ketamine administration on DAT availability. We applied translational in vivo [ 18F]FE-PE2I PET imaging of the DAT in healthy female rats to evaluate whether an acute subanesthetic intraperitoneal dose of 15 mg/kg S-ketamine alters DAT availability. We also performed [ 3H]GBR-12935 autoradiography on postmortem brain sections. We found no effect of acute S-ketamine administration on striatal DAT binding using [ 18F]FE-PE2I PET or [ 3H]GBR-12935 autoradiography. This negative result does not support the hypothesis that DAT changes are associated with S-ketamine's rapid antidepressant effects, but additional studies are warranted.

Original language	English
Article number	e22294
Journal	Synapse
Volume	78
Issue	4
ISSN	0887-4476
DOIs	https://doi.org/10.1002/syn.22294
Publication status	Published - Jul 2024

Keywords

Animals
Autoradiography
Corpus Striatum/metabolism
Dopamine Plasma Membrane Transport Proteins/metabolism
Female
Ketamine/pharmacology
Positron-Emission Tomography
Rats
Rats, Sprague-Dawley
fast-acting antidepressant
dopamine transporter (DAT)
PE2I
S-ketamine
PET
GBR-12935

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title = "Subanesthetic S-ketamine does not acutely alter striatal dopamine transporter binding in healthy Sprague Dawley female rats",

abstract = "Major depressive disorder is one of the most prevalent mental health disorders, posing a global socioeconomic burden. Conventional antidepressant treatments have a slow onset of action, and 30% of patients show no clinically significant treatment response. The recently approved fast-acting antidepressant S-ketamine, an N-methyl-D-aspartate receptor antagonist, provides a new approach for treatment-resistant patients. However, knowledge of S-ketamine's mechanism of action is still being established. Depressed human subjects have lower striatal dopamine transporter (DAT) availability compared to healthy controls. Rodent studies report increased striatal dopamine concentration in response to acute ketamine administration. In vivo [ 18F]FE-PE2I ([ 18F]-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4'-methyl-phenyl) nortropane) positron emission tomography (PET) imaging of the DAT has not previously been applied to assess the effect of acute subanesthetic S-ketamine administration on DAT availability. We applied translational in vivo [ 18F]FE-PE2I PET imaging of the DAT in healthy female rats to evaluate whether an acute subanesthetic intraperitoneal dose of 15 mg/kg S-ketamine alters DAT availability. We also performed [ 3H]GBR-12935 autoradiography on postmortem brain sections. We found no effect of acute S-ketamine administration on striatal DAT binding using [ 18F]FE-PE2I PET or [ 3H]GBR-12935 autoradiography. This negative result does not support the hypothesis that DAT changes are associated with S-ketamine's rapid antidepressant effects, but additional studies are warranted. ",

keywords = "Animals, Autoradiography, Corpus Striatum/metabolism, Dopamine Plasma Membrane Transport Proteins/metabolism, Female, Ketamine/pharmacology, Positron-Emission Tomography, Rats, Rats, Sprague-Dawley, fast-acting antidepressant, dopamine transporter (DAT), PE2I, S-ketamine, PET, GBR-12935",

author = "B{\ae}rentzen, {Simone Larsen} and Thomsen, {Jakob Borup} and Thomsen, {Majken Borup} and Steen Jakobsen and Simonsen, {Mette Theilgaard} and Gregers Wegener and Brooks, {David J} and Landau, {Anne M}",

year = "2024",

month = jul,

doi = "10.1002/syn.22294",

language = "English",

volume = "78",

journal = "Synapse",

issn = "0887-4476",

publisher = "Wiley-Liss Inc.",

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Subanesthetic S-ketamine does not acutely alter striatal dopamine transporter binding in healthy Sprague Dawley female rats. / Bærentzen, Simone Larsen; Thomsen, Jakob Borup; Thomsen, Majken Borup et al.
In: Synapse, Vol. 78, No. 4, e22294, 07.2024.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Subanesthetic S-ketamine does not acutely alter striatal dopamine transporter binding in healthy Sprague Dawley female rats

AU - Bærentzen, Simone Larsen

AU - Thomsen, Jakob Borup

AU - Thomsen, Majken Borup

AU - Jakobsen, Steen

AU - Simonsen, Mette Theilgaard

AU - Wegener, Gregers

AU - Brooks, David J

AU - Landau, Anne M

PY - 2024/7

Y1 - 2024/7

N2 - Major depressive disorder is one of the most prevalent mental health disorders, posing a global socioeconomic burden. Conventional antidepressant treatments have a slow onset of action, and 30% of patients show no clinically significant treatment response. The recently approved fast-acting antidepressant S-ketamine, an N-methyl-D-aspartate receptor antagonist, provides a new approach for treatment-resistant patients. However, knowledge of S-ketamine's mechanism of action is still being established. Depressed human subjects have lower striatal dopamine transporter (DAT) availability compared to healthy controls. Rodent studies report increased striatal dopamine concentration in response to acute ketamine administration. In vivo [ 18F]FE-PE2I ([ 18F]-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4'-methyl-phenyl) nortropane) positron emission tomography (PET) imaging of the DAT has not previously been applied to assess the effect of acute subanesthetic S-ketamine administration on DAT availability. We applied translational in vivo [ 18F]FE-PE2I PET imaging of the DAT in healthy female rats to evaluate whether an acute subanesthetic intraperitoneal dose of 15 mg/kg S-ketamine alters DAT availability. We also performed [ 3H]GBR-12935 autoradiography on postmortem brain sections. We found no effect of acute S-ketamine administration on striatal DAT binding using [ 18F]FE-PE2I PET or [ 3H]GBR-12935 autoradiography. This negative result does not support the hypothesis that DAT changes are associated with S-ketamine's rapid antidepressant effects, but additional studies are warranted.

AB - Major depressive disorder is one of the most prevalent mental health disorders, posing a global socioeconomic burden. Conventional antidepressant treatments have a slow onset of action, and 30% of patients show no clinically significant treatment response. The recently approved fast-acting antidepressant S-ketamine, an N-methyl-D-aspartate receptor antagonist, provides a new approach for treatment-resistant patients. However, knowledge of S-ketamine's mechanism of action is still being established. Depressed human subjects have lower striatal dopamine transporter (DAT) availability compared to healthy controls. Rodent studies report increased striatal dopamine concentration in response to acute ketamine administration. In vivo [ 18F]FE-PE2I ([ 18F]-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4'-methyl-phenyl) nortropane) positron emission tomography (PET) imaging of the DAT has not previously been applied to assess the effect of acute subanesthetic S-ketamine administration on DAT availability. We applied translational in vivo [ 18F]FE-PE2I PET imaging of the DAT in healthy female rats to evaluate whether an acute subanesthetic intraperitoneal dose of 15 mg/kg S-ketamine alters DAT availability. We also performed [ 3H]GBR-12935 autoradiography on postmortem brain sections. We found no effect of acute S-ketamine administration on striatal DAT binding using [ 18F]FE-PE2I PET or [ 3H]GBR-12935 autoradiography. This negative result does not support the hypothesis that DAT changes are associated with S-ketamine's rapid antidepressant effects, but additional studies are warranted.

KW - Animals

KW - Autoradiography

KW - Corpus Striatum/metabolism

KW - Dopamine Plasma Membrane Transport Proteins/metabolism

KW - Female

KW - Ketamine/pharmacology

KW - Positron-Emission Tomography

KW - Rats

KW - Rats, Sprague-Dawley

KW - fast-acting antidepressant

KW - dopamine transporter (DAT)

KW - PE2I

KW - S-ketamine

KW - PET

KW - GBR-12935

UR - http://www.scopus.com/inward/record.url?scp=85194828364&partnerID=8YFLogxK

U2 - 10.1002/syn.22294

DO - 10.1002/syn.22294

M3 - Journal article

C2 - 38813759

SN - 0887-4476

VL - 78

JO - Synapse

JF - Synapse

IS - 4

M1 - e22294

ER -

Subanesthetic S-ketamine does not acutely alter striatal dopamine transporter binding in healthy Sprague Dawley female rats

Abstract

Keywords

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