The effects of ketamine on dopaminergic function

Abstract

Schizophrenia is a chronic debilitating disorder which affects about 21 million people worldwide. One of the robust neurochemical abnormalities in schizophrenia is significantly elevated striatal dopamine synthesis capacity in patients compared to controls. Ketamine is a club drug of abuse and induces psychotomimetic effects at sub-anaesthetic doses in healthy human and exacerbates psychotic symptoms in patients with schizophrenia. Therefore it has been used to model neurochemical alterations seen in schizophrenia such as dopaminergic overactivity. However, the effect of sub-chronic ketamine on dopamine synthesis capacity in vivo is not known. This thesis synthesizes the evidence of sub-chronic ketamine’s action on the dopaminergic function and behavioural measures previously associated with the dopaminergic system in the male mouse and it can be divided into four key findings. Firstly, sub-chronic ketamine administration significantly increases presynaptic striatal dopamine synthesis capacity as measured by 3,4-dihydroxy-6-[(18)F]-fluoro-l-phenylalanine ([18F]-DOPA) positron emission tomography (PET) imaging and induces locomotor sensitization. Secondly, inhibiting midbrain dopamine neuron firing using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in vivo prevents the effects of sub-chronic ketamine administration on the presynaptic striatal dopaminergic function and locomotor sensitization. Thirdly, there are no alterations in latent inhibition in a conditioned fear paradigm and no alterations in incentive motivation following sub-chronic ketamine administration relative to control conditions. Lastly, mice sub-chronically treated with ketamine or saline demonstrate cocaine-induced locomotor sensitization. Collectively I show that sub-chronic ketamine results in the elevation in striatal dopamine synthesis capacity and locomotor sensitization and that these effects require midbrain dopamine neuron activation. I propose a model for the mechanism of action of ketamine on the dopaminergic function and discuss the implications for understanding schizophrenia, the potential antidepressant properties of ketamine and substance abuse.