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

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.

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_i^Mod) between ketamine- and saline-treated animals.

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_i^Mod resulted in the lowest intra-group variability and moderate test-retest agreement. Using these parameters, we found that K_i^Mod 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 (r² = 0.59, p = 0.005) but was absent in ketamine-treated animals (r² = 0.004, p = 0.83).

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.