Patients with
schizophrenia show increased striatal
dopamine synthesis capacity in imaging studies. The mechanism underlying this is unclear but may be due to
N-methyl-D-aspartate receptor (NMDAR) hypofunction and
parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we develop a translational mouse model of the
dopamine pathophysiology seen in
schizophrenia and test approaches to reverse the
dopamine changes. Mice were treated with sub-chronic
ketamine (30 mg/kg) or saline and then received in vivo positron emission tomography of striatal
dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open-field test. In vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and
RNA sequencing were used to investigate molecular mechanisms. Sub-chronic
ketamine increased striatal
dopamine synthesis capacity (Cohen's d = 2.5) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of PV interneurons in pre-limbic cortex and ventral subiculum of the hippocampus. Sub-chronic
ketamine reduced PV expression in these cortical and hippocampal regions. Pharmacological intervention with
SEP-363856, a novel psychotropic agent with agonism at
trace amine receptor 1 (TAAR1) and 5-HT1A receptors but no appreciable action at
dopamine D2 receptors, significantly reduced the
ketamine-induced increase in
dopamine synthesis capacity. These results show that sub-chronic
ketamine treatment in mice mimics the dopaminergic alterations in patients with
psychosis, that this requires activation of midbrain dopamine neurons, and can be ameliorated by activating PV interneurons and by a TAAR1/
5-HT1A agonist. This identifies novel therapeutic approaches for targeting presynaptic
dopamine dysfunction in patients with
schizophrenia and effects of
ketamine relevant to its
therapeutic use for treating major depression.