Sub-Chronic Ketamine Administration Increases Dopamine Synthesis Capacity in the Mouse Midbrain: a Preclinical In Vivo PET Study

TY - JOUR

T1 - Sub-Chronic Ketamine Administration Increases Dopamine Synthesis Capacity in the Mouse Midbrain

T2 - a Preclinical In Vivo PET Study

AU - Petty, Alice

AU - Garcia-Hidalgo, Anna

AU - Halff, Els F.

AU - Natesan, Sridhar

AU - Withers, Dominic J.

AU - Irvine, Elaine E.

AU - Kokkinou, Michelle

AU - Wells, Lisa A.

AU - Bonsall, David R.

AU - Tang, Sac Pham

AU - Veronese, Mattia

AU - Howes, Oliver D.

N1 - Funding Information: This work was supported by grants from the Medical Research Council (MRC) UK (MC_A656_5QD30_2135 to OH and MC-A654-5QB40 to DJW) and the Wellcome Trust (094849/Z/10/Z to OH). MV is supported by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. Publisher Copyright: © 2023, The Author(s).

PY - 2023/12

Y1 - 2023/12

N2 - Purpose: There is robust evidence that people with schizophrenia show elevated dopamine (DA) synthesis capacity in the striatum. This finding comes from positron emission tomography (PET) studies using radiolabelled l-3,4-dihydroxyphenylalanine (18F-DOPA). DA synthesis capacity also appears to be elevated in the midbrain of people with schizophrenia compared to healthy controls. We therefore aimed to optimise a method to quantify 18F-DOPA uptake in the midbrain of mice, and to utilise this method to quantify DA synthesis capacity in the midbrain of the sub-chronic ketamine model of schizophrenia-relevant hyperdopaminergia. Procedures: Adult male C57Bl6 mice were treated daily with either ketamine (30 mg/kg, i.p.) or vehicle (saline) for 5 days. On day 7, animals were administered 18F-DOPA (i.p.) and scanned in an Inveon PET/CT scanner. Data from the saline-treated group were used to optimise an atlas-based template to position the midbrain region of interest and to determine the analysis parameters which resulted in the greatest intra-group consistency. These parameters were then used to compare midbrain DA synthesis capacity (K iMod) between ketamine- and saline-treated animals. Results: Using an atlas-based template to position the 3.7 mm3 midbrain ROI with a T*–T end window of 15–140 min to estimate K iMod resulted in the lowest intra-group variability and moderate test–retest agreement. Using these parameters, we found that K iMod was elevated in the midbrain of ketamine-treated animals in comparison to saline-treated animals (t (22) = 2.19, p = 0.048). A positive correlation between DA synthesis capacity in the striatum and the midbrain was also evident in the saline-treated animals (r 2 = 0.59, p = 0.005) but was absent in ketamine-treated animals (r 2 = 0.004, p = 0.83). Conclusions: Using this optimised method for quantifying 18F-DOPA uptake in the midbrain, we found that elevated striatal DA synthesis capacity in the sub-chronic ketamine model extends to the midbrain. Interestingly, the dysconnectivity between the midbrain and striatum seen in this model is also evident in the clinical population. This model may therefore be ideal for assessing novel compounds which are designed to modulate pre-synaptic DA synthesis capacity.

AB - Purpose: There is robust evidence that people with schizophrenia show elevated dopamine (DA) synthesis capacity in the striatum. This finding comes from positron emission tomography (PET) studies using radiolabelled l-3,4-dihydroxyphenylalanine (18F-DOPA). DA synthesis capacity also appears to be elevated in the midbrain of people with schizophrenia compared to healthy controls. We therefore aimed to optimise a method to quantify 18F-DOPA uptake in the midbrain of mice, and to utilise this method to quantify DA synthesis capacity in the midbrain of the sub-chronic ketamine model of schizophrenia-relevant hyperdopaminergia. Procedures: Adult male C57Bl6 mice were treated daily with either ketamine (30 mg/kg, i.p.) or vehicle (saline) for 5 days. On day 7, animals were administered 18F-DOPA (i.p.) and scanned in an Inveon PET/CT scanner. Data from the saline-treated group were used to optimise an atlas-based template to position the midbrain region of interest and to determine the analysis parameters which resulted in the greatest intra-group consistency. These parameters were then used to compare midbrain DA synthesis capacity (K iMod) between ketamine- and saline-treated animals. Results: Using an atlas-based template to position the 3.7 mm3 midbrain ROI with a T*–T end window of 15–140 min to estimate K iMod resulted in the lowest intra-group variability and moderate test–retest agreement. Using these parameters, we found that K iMod was elevated in the midbrain of ketamine-treated animals in comparison to saline-treated animals (t (22) = 2.19, p = 0.048). A positive correlation between DA synthesis capacity in the striatum and the midbrain was also evident in the saline-treated animals (r 2 = 0.59, p = 0.005) but was absent in ketamine-treated animals (r 2 = 0.004, p = 0.83). Conclusions: Using this optimised method for quantifying 18F-DOPA uptake in the midbrain, we found that elevated striatal DA synthesis capacity in the sub-chronic ketamine model extends to the midbrain. Interestingly, the dysconnectivity between the midbrain and striatum seen in this model is also evident in the clinical population. This model may therefore be ideal for assessing novel compounds which are designed to modulate pre-synaptic DA synthesis capacity.

KW - Dopamine

KW - F-DOPA

KW - Ketamine

KW - Midbrain

KW - PET

KW - Preclinical

KW - Schizophrenia

UR - http://www.scopus.com/inward/record.url?scp=85174578360&partnerID=8YFLogxK

U2 - 10.1007/s11307-023-01865-y

DO - 10.1007/s11307-023-01865-y

M3 - Article

C2 - 37872462

AN - SCOPUS:85174578360

SN - 1536-1632

VL - 25

SP - 1054

EP - 1062

JO - Molecular Imaging and Biology

JF - Molecular Imaging and Biology

IS - 6

ER -