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Abstract:
Sub-anesthetic ketamine elicits rapid antidepressant response in patients via modulation of glutamatergic system and synaptic plasticity. Specifically, 24h after infusion ketamine induces changes in glutamine-glutamate cycling in pregenual anterior cingulate cortex (pgACC) in healthy controls (HC). Microtubule dynamics is essential for neural plasticity and post-translational modifications of α-tubulin are considered markers of microtubule dynamics. Acetylation of α-tubulin (Acet-Tub) associates with less dynamic microtubules and appears involved in the pathogenesis and treatment of depression. Here, we examined Acet-Tub as a peripheral marker of microtubule dynamics and well-established changes in glutamatergic system 24h after infusion. Moreover, we investigated correlations with acute dissociative symptoms. In a placebo-controlled study 81 healthy controls received 40 min infusion of vehicle or 0.5 mg/kg of ketamine. At baseline and 24h post-infusion, glutamate (Glu) levels were assessed in pgACC by 7T magnetic resonance spectroscopy (MRS), and blood was sampled. The dissociative symptoms were evaluated using CADSS right after the infusion. MRS data were processed with LCModel, Glu was normalized to creatine, and grey matter (GM) partial volume was calculated. Plasma Acet-Tub and Transferrin (TRF) expression was analyzed using infrared western blot. RmANCOVA tested Glu and Ace-Tub/TRF change, with treatment, sex as factors, and age, BMI, (GM) as covariates of nuisance. The relationship between relative changes and CADSS was assessed with non-parametric partial correlations in ketamine group. Ketamine effect was present in both Glu (time-by-treatment, p=0.044) and Ace-Tub/TRF (time-by-treatment-by-sex, p=0.023), where a decrease in pgACC Glu and an increase in Ace-Tub/TRF was observed. Markers of sustained effect were negatively associated with each other only in the ketamine group (p=0.001) vs. vehicle (p=0.20). Marker of acute effect CADSS trend-wise positively correlated to Ace-Tub/TRF (p=0.06) in the ketamine group, but not with pgACC Glu (p=0.21). Results confirm effects of single dose of ketamine on Glu 24h after infusion in the pgACC, a region important for affect processing and neuronal mechanisms of depression. In parallel, plasma Acet-Tub increased suggesting peripheral decreased microtubule dynamics which may be reflected centrally. The neuronal representation of ketamine was negatively associated with Acet-Tub/TRF, indicating similar time-frame of plasticity processes in brain and blood. Interestingly, only Acet-Tub/TRF was positively associated with degree of acute dissociative symptoms.
