Lithium, a mood stabilizer and common adjunctive treatment for
refractory depression, shares overlapping mechanisms of action with
ketamine and enhances the duration of
ketamine's
antidepressant actions in rodent models at sub-therapeutic doses. Yet, in a recent clinical trial,
lithium co-treatment with
ketamine failed to improve
antidepressant outcomes in subjects previously shown to respond to
ketamine alone. The potential for
lithium augmentation to improve
antidepressant outcomes in
ketamine nonresponders, however, has not been explored. The current study examined the behavioral, molecular and metabolic actions of
lithium and
ketamine co-treatment in a rodent model of
antidepressant resistance. Male Wistar rats were administered
adrenocorticotropic hormone (
ACTH; 100 µg/day, i.p. over 14 days) and subsequently treated with
ketamine (10 mg/kg; 2 days; n = 12),
lithium (37 mg/kg; 2 days; n = 12), ketamine + lithium (10 mg/kg + 37 mg/kg; 2 days; n = 12), or vehicle
saline (0.9%; n = 12). Rats were subjected to open field (6 min) and forced swim tests (6 min). Peripheral blood and brain prefrontal cortical (PFC) tissue was collected one hour following stress exposure. Western blotting was used to determine the effects of treatment on
extracellular signal-regulated kinase (ERK);
mammalian target of rapamycin (mTOR), phospho
kinase B (Akt), and
glycogen synthase kinase-3ß (GSK3ß)
protein levels in the infralimbic (IL) and prelimbic (PL) subregions of the PFC. Prefrontal oxygen consumption rate (OCR) and extracellular acidification rates (ECAR) were also determined in anterior PFC tissue at rest and following stimulation with
brain-derived neurotrophic factor (
BDNF) and
tumor necrosis factor α (TNFα). Blood plasma levels of mTOR and
insulin were determined using
enzyme-linked
immunosorbent assays (ELISAs). Overall, rats receiving ketamine+lithium displayed a robust
antidepressant response to the combined treatment as demonstrated through significant reductions in immobility time (p < 0.05) and latency to immobility (p < 0.01). These animals also had higher expression of plasma mTOR (p < 0.01) and
insulin (p < 0.001). Tissue bioenergetics analyses revealed that combined ketamine+lithium treatment did not significantly alter the respiratory response to
BDNF or TNFα. Animals receiving both
ketamine and
lithium had significantly higher phosphorylation (p)-to-total expression ratios of mTOR (p < 0.001) and Akt (p < 0.01), and lower ERK in the IL compared to control animals. In contrast, pmTOR/mTOR levels were reduced in the PL of ketamine+lithium treated animals, while pERK/ERK expression levels were elevated. Taken together, these data demonstrate that
lithium augmentation of
ketamine in
antidepressant nonresponsive animals improves
antidepressant-like behavioral responses under stress, together with peripheral
insulin efflux and region-specific PFC
insulin signaling.