Abstract
Recent research into the rapid antidepressant effect of subanesthetic doses of ketamine have identified a series of relevant protein cascades activated within hours of administration. Prior to, or concurrent with, these activation cascades, ketamine treatment generates dissociative and psychotomimetic side effects along with an increase in circulating glucocorticoids. In rats, we observed an over 3-fold increase in corticosterone levels in both serum and brain tissue, within an hour of administration of low dose ketamine (10 mg/kg), but not with (2R, 6R)-hydroxynorketamine (HNK) (10 mg/kg), a ketamine metabolite shown to produce antidepressant-like action in rodents without inducing immediate side-effects. Hippocampal tissue from ketamine, but not HNK, injected animals displayed a significant increase in the expression of sgk1, a downstream effector of glucocorticoid receptor signaling. To examine the role conscious sensation of ketamine’s side effects plays in the release of corticosterone, we assessed serum corticosterone levels after ketamine administration while under isoflurane anesthesia. Under anesthesia, ketamine failed to increase circulating corticosterone levels relative to saline controls. Concurrent with its antidepressant effects, ketamine generates a release of glucocorticoids potentially linked to disturbing cognitive side effects and the activation of distinct molecular pathways which should be considered when attempting to delineate the molecular mechanisms of its antidepressant function.
Highlights
Ketamine, synthesized as a phenylcyclidine (PCP) derivative over 50 years ago, has long been used as general anesthetic acting primarily through blockade of NMDA receptors in the brain (Li and Vlisides, 2016)
Ketamine offers quick relief from depressive symptoms and suicidal ideation within a few hours, it is effective in a large subset of the treatment-resistant population who do not respond to current mainstream monoamine therapies (Aleksandrova et al, 2017)
In order to sensitize the CNS to ketamine and HNK treatment and amplify potential molecular differences we utilized a chemically-induced chronic stress model where rats were orally exposed to exogenous corticosterone for an extended period of time (Wellman 2001; Gourley et al, 2008; Gourley and Taylor 2009; Joffe et al, 2020)
Summary
Ketamine, synthesized as a phenylcyclidine (PCP) derivative over 50 years ago, has long been used as general anesthetic acting primarily through blockade of NMDA receptors in the brain (Li and Vlisides, 2016). At subanesthetic (0.1–0.5 mg/kg) doses, has emerged as a clinical rapid acting antidepressant (RAAD) (Krystal, et al, 1994; Berman et al, 2000). Accumulating evidence supports ketamine’s efficacy in the treatment of major depressive disorder (MDD) and other anxiety disorders with low dosage administration (Berman et al, 2000; Zarate et al, 2006; Zarate et al, 2012; Murrough et al, 2013). Ketamine offers quick relief from depressive symptoms and suicidal ideation within a few hours, it is effective in a large subset of the treatment-resistant population who do not respond to current mainstream monoamine therapies (Aleksandrova et al, 2017). Ketamine produces psychotomimetic and dissociative effects within minutes of administration, increasing the potential for abuse, largely restricting administration to a clinical setting
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