(R,S)-Ketamine is
rapidly metabolized to form
a range of metabolites in vivo, including 12 unique
hydroxynorketamines (HNKs) that are distinguished by a cyclohexyl
ring hydroxylation at the 4, 5, or 6 position. While both (2R,6R)- and (2S,6S)-HNK readily penetrate the brain and exert rapid antidepressant-like
actions in preclinical tests following peripheral administration,
the pharmacokinetic profiles and pharmacodynamic actions of 10 other
HNKs have not been examined. We assessed the pharmacokinetic profiles
of all 12 HNKs in the plasma and brains of male and female mice and
compared the relative potencies of four (2,6)-HNKs
to induce antidepressant-relevant behavioral effects in the forced
swim test in male mice. While all HNKs were readily brain-penetrable
following intraperitoneal injection, there were robust differences
in peak plasma and brain concentrations and exposures. Forced swim
test immobility rank order of potency, from most to least potent,
was (2R,6S)-, (2S,6R)-, (2R,6R)-,
and (2S,6S)-HNK. We hypothesized
that distinct structure–activity relationships and the resulting
potency of each metabolite are linked to unique substitution patterns
and resultant conformation of the six-membered cyclohexanone ring
system. To explore this, we synthesized (5R)-methyl-(2R,6R)-HNK, which incorporates a methyl
substitution on the cyclohexanone ring. (5R)-Methyl-(2R,6R)-HNK exhibited similar antidepressant-like
potency to (2R,6S)-HNK. These results
suggest that conformation of the cyclohexanone ring system in the
(2,6)-HNKs is an important factor underlying potency
and that additional engineering of this structural feature may improve
the development of a new generation of HNKs. Such HNKs may represent
novel drug candidates for the treatment of depression.
Differential rodent responses to the sex of human experimenters could have far reaching consequences in preclinical studies. Here, we show that the sex of human experimenters affects mouse behaviours and responses to the rapid-acting antidepressant ketamine and its bioactive metabolite (2R,6R)-hydroxynorketamine. We found that mice manifest aversion to human male odours, preference to female odours, and increased susceptibility to stress when handled by male experimenters. This male induced aversion and stress susceptibility is mediated by the activation of brain corticotropin-releasing factor (CRF) neurons projecting from the entorhinal cortrex to hippocampal area CA1. We further establish that exposure to male scent prior to ketamine administration activates CRF neurons projecting from the entorhinal cortex to hippocampus, and that CRF is necessary and sufficient for the in vivo and in vitro actions of ketamine. Further understanding of the specific and quantitative contributions of the sex of human experimenters to different experimental outcomes in rodents may lead not only to reduced heterogeneity between studies, but also increased capability to uncover novel biological mechanisms.
In susceptible populations, stress is a major risk factor for the development of mental disorders, including depression. Estradiol, often considered a female hormone, is distributed in the male brain via aromatization of testosterone. The role of estrogen receptors (ERs) in male stress susceptibility and depression is not well understood. We found that absence of ERβ is associated with susceptibility to stress in male mice and that activity of ERβ-projecting neurons from the basolateral amygdala to nucleus accumbens is reduced in hypogonadal mice subjected to stress, while activation of this circuit reverses stress-induced maladaptive behaviors. We identified that absence of estradiol, but not testosterone per se, underlies stress susceptibility and that brain-selective delivery of estradiol prevents the development of depression-related behaviors. Our findings provide evidence for an estrogen-based mechanism underlying stress susceptibility and offer an unexpected therapeutic strategy for treating depression in males.
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