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

• Published in: Synapse (New York, N.Y.) Vol. 78; no. 4; pp. e22294 - n/a
• Main Authors: Bærentzen, Simone Larsen, Thomsen, Jakob Borup, Thomsen, Majken Borup, Jakobsen, Steen, Simonsen, Mette Theilgaard, Wegener, Gregers, Brooks, David J., Landau, Anne M.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.07.2024
• Subjects: Animals; Autoradiography; Corpus Striatum - diagnostic imaging; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Dopamine; Dopamine Plasma Membrane Transport Proteins - drug effects; Dopamine Plasma Membrane Transport Proteins - metabolism; Dopamine transporter; dopamine transporter (DAT); fast‐acting antidepressant; Female; GBR‐12935; Ketamine; Ketamine - pharmacology; Neostriatum; Neuroimaging; PE2I; PET; Positron emission tomography; Rats; Rats, Sprague-Dawley; S‐ketamine; S‐ketamine; PE2I; GBR‐12935; fast‐acting antidepressant; dopamine transporter (DAT); PET
• ISSN: 0887-4476; 1098-2396; 1098-2396
• DOI: 10.1002/syn.22294

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. We performed in vivo [18F]FE‐PE2I PET imaging of the dopamine transporter in healthy female rats to evaluate whether an acute subanesthetic dose of 15 mg/kg S‐ketamine i.p. alters dopamine transporter availability compared to rats injected with saline. We also performed [3H]GBR‐12935 autoradiography on postmortem brain sections. We found no effect of acute S‐ketamine administration on striatal dopamine transporter binding using [18F]FE‐PE2I PET or [3H]GBR‐12935 autoradiography.