Sub-anesthetic doses of ketamine exert antidepressant-like effects and upregulate the expression of glutamate transporters in the hippocampus of rats

Introduction

Depression is a common, disabling disorder for which conventional antidepressants (for example MAOIs and SSRIs) are slow to act and leave a substantial proportion of patients refractory or intolerant to treatment. Emerging clinical work has shown that the NMDA receptor antagonist ketamine can produce rapid antidepressant effects, but the molecular mechanisms mediating this response remain unclear. Previous research implicates abnormalities in glutamatergic neurotransmission in depression, and excitatory amino acid transporters (EAATs) — the principal proteins responsible for clearing extracellular glutamate — are proposed to be important in maintaining synaptic glutamate homeostasis. Zhu and colleagues note that EAAT2 expression was reduced in the hippocampus in prior animal work, and raise the question of whether ketamine’s antidepressant actions involve modulation of EAAT-mediated glutamate reuptake. This study set out to test whether sub-anesthetic doses of ketamine produce antidepressant-like behavioural effects in rats subjected to chronic unpredictable mild stress (CUMS), and whether those effects are associated with changes in the hippocampal expression of EAAT1, EAAT2 and EAAT3 and with extracellular glutamate concentrations. The investigation therefore combines behavioural assays, in vivo microdialysis for extracellular glutamate, and protein quantification by Western blot to explore links between ketamine dosing, EAAT expression, glutamate levels and depressive-like behaviours in rats.