Fig. 2: Midbrain dopamine neuron firing is necessary for ketamine-induced increases in dopamine synthesis capacity and locomotor activity. | Molecular Psychiatry

Fig. 2: Midbrain dopamine neuron firing is necessary for ketamine-induced increases in dopamine synthesis capacity and locomotor activity.

From: Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine

Fig. 2

a Experimental timeline and drug treatment paradigm used to assess the effect of midbrain dopamine neuron inhibition on the sub-chronic ketamine-induced increase in striatal dopamine synthesis capacity and locomotor activity. Two weeks after stereotaxic injection of AAV-hM4Di-mCherry, mice received 0.1 mg/kg CNO or vehicle followed by ketamine (30 mg/kg) or vehicle 30 min later for 5 consecutive days. Mice underwent a dynamic PET/CT scan 2 days after the last drug administration. b Bilateral infusion of AAV-hM4Di-mCherry into the VTA and SNc of DAT::Cre mice was used to selectively express DREADD receptors in dopamine neurons. c Fluorescence confocal images of representative midbrain fields depicting co-expression (white) of mCherry (magenta) and TH (green)  immunofluorescence. d Percentage of TH+ neurons co-expressing mCherry (47 out of total 65 TH+ neurons; 71.7 ± 11%) and percentage of mCherry+ which do not express TH (1 out of total 48 mCherry + neurons, 1.5 ± 1.5%) in the VTA. Percentage of TH+ neurons co-expressing mCherry (47 out of total 52 TH+ neurons; 89.6% ± 5.4) and percentage of mCherry+ which do not express TH (1 out of total 48 mCherry+ neurons, 1.5 ± 1.5%) in the SNc. e Striatal dopamine synthesis capacity (Kimod/min) is significantly reduced in CNO/Ket compared with Sal/Ket group (***P < 0.001) (Sal/Sal (n = 12), CNO/Sal (n = 13), Sal/Ket (n = 12) and CNO/Ket-treated (n = 11) groups). f Total distance travelled during 30 min post drug administration. Sub-chronic ketamine treatment induced locomotor sensitization that was prevented by inhibition of midbrain dopamine neuron firing prior to ketamine treatment. g Percentage locomotor sensitization between day 1 and day 5. Data represent mean ± S.E.M. ****P < 0.0001; ***P < 0.001; **P < 0.01; *P < 0.05. Sal saline, Ket ketamine, CNO clozapine N-oxide, TH tyrosine hydroxylase, PET positron emission tomography, CT computed tomography, VTA ventral tegmental area, SNc substantia nigra pas compacta.

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