Table 2.
Behavioral and Molecular Effects of Ketamine in Animal Models of Depression
| Reference | Depression Model | Intervention | Behavioral Effects | Molecular Effects |
|---|---|---|---|---|
| Autry et al 2011 (18) | Mice (wild-type or BDNF/Trk B-knockout); FST; NSFT; LH; CMS | Ketamine 3.0 mg/kg IP (single dose) |
Acute antidepressant effects observed in non-stressed animals and CMS; antidepressant effects blocked by BDNF or TrK B knockout or NBQX | Antidepressant effects dependent on rapid (transient) synthesis of BDNF; ketamine blockade of NMDAR resulted in deactivation of eEF2 kinase, decreased eEF2 phosphorylation and de-suppression of BDNF translation |
| Garcia et al 2008 (39) | Rats; FST | Ketamine 5, 10 or 15 mg/kg IP (single dose) |
Acute antidepressant effects observed in response to 10 and 15 (but not 5) mg/kg dose | Ketamine resulted in increased BDNF levels in hippocampus (only at higher 15 mg/kg dose) |
| Garcia et al 2009 (21) | Rats; CMS (40 days) | Ketamine 15 mg/kg IP (single dose or daily for 7 days) |
Antidepressant effects observed in CMS model following repeated but not acute treatment | Acute and chronic treatment reversed CMS-induced weight loss and normalized corticosterone and ACTH levels; ketamine did not alter hippocampal BDNF protein levels |
| Koike et al 2011 (40) | Mice or rats; TST (used mice), LH (used rats) | Ketamine 10 or 30 mg/kg IP | Acute antidepressant effects observedin both LH and TST; TST effect persisted for 72h; antidepressant effects blocked by NBQX | None reported |
| Li et al 2010 (17) | Rats; FST; LH; NSFT | Ketamine 10 mg/kg IP (single dose) |
Acute antidepressant effects observed in all three tests; effects blocked by rapamycin infusion into MPFC or administration of NBQX | Ketamine rapidly activated the mTOR signaling pathway in the PFC (increased activation/phosphorylation of 4E-BP1, p70S6K, and mTOR); ketamine increased levels of postsynaptic (PSD95, GluR1) and presynaptic (synapsin I) proteins and increased spine density and EPSC frequency and amplitude |
| Li et al 2011 (19) | Rats; CMS (21 days); SPT, NSFT | Ketamine 10 mg/kg IP (single dose) |
Antidepressant effects observed in both tests (ketamine reversed CMS-induced behavioral abnormalities); effects lasted up to 7 days; effects blocked by ICV infusion of rapamycin | Ketamine rapidly reversed CMS-induced deficits in synaptic proteins (PSD95, GluR1, synapsin I), spine density and EPSC frequency/amplitude in PFC; molecular effects of ketamine blocked by inhibition of mTOR signaling pathway |
| Maeng et al 2008 (23) | Mice; FST, LH | Ketamine 0.5, 2.5 or 10 mg/kg IP (single dose) |
Acute antidepressant effects observed in both tests and maintained for two weeks (in FST); effect in FST blocked by NBQX | Ketamine resulted in lower levels of phosphorylated GluR1 (S845) AMPAR subunit; effect blocked by NBQX |
Table presents a selective summary of preclinical studies of ketamine in animal models of depression.
ACTH: Adrenocorticotropic hormone; AMPA: α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; AMPAR: AMPA receptor; BDNF: brain-derived neurotrophic factor; CMS: chronic mild stress; CREB: cAMP response element binding protein; eEF2: eukaryotic elongation factor 2; EPSC: excitatory postsynaptic current; FST: forced swim test; GluR1: glutamate receptor 1; HPA: hypothalamic–pituitary–adrenal; ICV: intracerebroventricular; LH: learned helplessness; mTOR: mammalian target of rapamycin; MPFC: medial prefrontal cortex; NBQX: 2,3-dihydroxy-6-nitro-7-sulfoamoylbenzo(f)-quinozaline; NMDA: N-methyl-D-aspartate; NMDAR: NMDA receptor; NSFT: novelty suppressed feeding test; PAC: passive avoidance conditioning; PSD95: postsynaptic density protein 95; p70S6K: p70S6 kinase; PKA: protein kinase A; PKC: protein kinase C; SPT: sucrose preference test; TrK B: tyrosine kinase receptor B; 4E-BP1: eukaryotic initiation factor 4E binding protein 1