The effects of ketamine on dopaminergic function:meta-analysis and review of the implications for neuropsychiatric disorders

Ketamine is a non-competitive antagonist at the N-methyl-D-aspartate receptor. It has recently been found to have anti-depressant effects and is a drug of abuse, suggesting it may have dopaminergic effects. To examine the effect of ketamine on the dopamine systems, we carried out a systematic review and meta-analysis of dopamine measures in the rodent, human and primate brain following acute and chronic ketamine administration relative to a drug free baseline or control condition. Systematic search of PubMed and PsychInfo electronic databases yielded 40 original peer-reviewed studies. There were sufficient rodent studies of the acute effects of ketamine at sub-anaesthetic doses for meta-analysis. Acute ketamine administration in rodents is associated with significantly increased dopamine levels in the cortex (Hedge’s g= 1.33, p <0.01), striatum (Hedge’s g= 0.57, p <0.05) and the nucleus accumbens (Hedge’s g=1.30, p < 0.05) compared to control conditions, and 62-180% increases in dopamine neuron population activity. Sub-analysis indicated elevations were more marked in in vivo (g=1.93) than ex vivo (g=0.50) studies. There were not enough studies for meta-analysis in other brain regions studied (hippocampus, ventral pallidum and cerebellum), or of the effects of chronic ketamine administration, although consistent increases in cortical dopamine levels (from 88% to 180%) were reported in the latter studies. In contrast, no study showed an effect of anaesthetic doses (>100mg/kg) of ketamine on dopamine levels ex vivo, although this remains to be tested in vivo. Findings in non-human primates and in human studies using positron emission tomography (PET) were not consistent. The studies reviewed here provide evidence that acute ketamine administration leads to dopamine release in the rodent brain. We discuss the inter-species variation in the ketamine induced dopamine release as well as the implications for understanding psychiatric disorders, in particular substance abuse, schizophrenia, and the potential anti-depressant properties of ketamine, and comparisons with stimulants and other NMDA antagonists. Finally we identify future research needs