Low Doses of Ketamine and Melatonin in Combination Produce Additive Antidepressant-like Effects in Mice

Abstract

Major depressive disorder is a disabling disease with the number of affected individuals increasing each year. Current antidepressant treatments take between three to six weeks to be effective with forty percent of patients being resistant to treatment, making it necessary to search for new antidepressant treatments. Ketamine, a phencyclidine hydrochloride derivative, given intravenously, induces a rapid antidepressant effect in humans. In mice, it causes increased neurogenesis and antidepressant-like effects. However, it also produces psychomimetic effects in humans and in rodents increases the locomotor activity. In contrast, melatonin, a hormone secreted by the pineal gland and synthesized in extrapineal sites, increases new neuron formation and causes antidepressant-like effects in adult rodents with no collateral effects. Here, we assessed the effects of a non-effective dose of ketamine in combination with melatonin (KET/MEL), both on neurogenesis as well as on the antidepressant-like effect in mice. Our results showed that KET/MEL combination increased neurogenesis and produced antidepressant-like effects without altering locomotor activity after both single and triple administration protocols. Our data strongly suggest that KET/MEL combination could be used to simultaneously promote neurogenesis, reverting neuronal atrophy and inducing antidepressant-like effects.

Further Evidence of the Melatonin Calmodulin Interaction: Effect on CaMKII Activity

“…Evidence from nuclear magnetic resonance-based studies and ligand-binding assays have shown that MEL can bind to Ca 2+ -CaM [ 10 , 16 , 17 ]. Exogenous MEL antidepressant-like effects in mice have been recently described [ 25 , 26 ], and modulation of neuroplasticity may underlie this effect. CaMKII plays a key role in neurogenesis and dendritogenesis which are processes stimulated by antidepressants and MEL [ 27 ].…”

“…Administration of MEL (16 mg/kg) was assessed by a three times dose injection of the VEH or MEL. First injection was administered 24 h before the sacrifice, and the second and third injections were administered 11 h and 30 min [ 26 ] before the anesthesia administration. Mice were perfused with paraformaldehyde 2% with CaCl 2 0.02%, and finally embedded in sucrose for cryopreservation [ 42 ].…”

Antidepressant Low Doses of Ketamine and Melatonin in Combination Produce Additive Neurogenesis in Human Olfactory Neuronal Precursors

“…The precise physiological meaning of high levels of MEL in the CNS is not known, but presumably, it is to protect neurons and glia from oxidative stress and inflammation, as well as to stimulate the formation of new neurons in specific niches [ 5 ]. In addition, MEL in the CNS has antidepressant-like effects, associated with neurogenesis and dendritogenesis produced in the dentate gyrus of the hippocampus of rodents [ 6 , 7 , 8 ]. Similar effects have been demonstrated for ISSR antidepressants in animal models and postulated as a therapeutic mechanism in humans [ 8 ].…”

“…In addition, MEL in the CNS has antidepressant-like effects, associated with neurogenesis and dendritogenesis produced in the dentate gyrus of the hippocampus of rodents [ 6 , 7 , 8 ]. Similar effects have been demonstrated for ISSR antidepressants in animal models and postulated as a therapeutic mechanism in humans [ 8 ].…”

“…Recently, we described that administration of MEL at non-effective antidepressant doses, in combination with non-effective psychomimetic doses of ketamine (KET), a N -methyl- D -aspartate (NMDA) receptor antagonist under single or triple administration protocols, causes antidepressant-like effects in mice associated with increased neurogenesis in the dentate gyrus of the hippocampus, without psychomimetic effects [ 8 ].…”