The Resilient Phenotype Induced by Prophylactic Ketamine Exposure During Adolescence Is Mediated by the Ventral Tegmental Area–Nucleus Accumbens Pathway

Parise, Eric M.; Parise, Lyonna F.; Sial, Omar K.; Cardona-Acosta, Astrid M.; Gyles, Trevonn; Juarez, Barbara; Chaudhury, Dipesh; Han, Ming; Nestler, Eric J.; Bolaños-Guzmán, Carlos A.

doi:10.1016/j.biopsych.2021.05.002

Cited by 20 publications

(8 citation statements)

References 73 publications

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“…To determine if an acute injection of ( R , S )-ketamine could impact behavior in adolescent or aged mice, male and female mice were injected with saline or ( R , S )-ketamine at varying doses ( Figure 1A ). Doses were chosen based on previous studies in adolescent ( Parise et al, 2021 ) and adult mice ( Brachman et al, 2016 ; McGowan et al, 2017 ; Mastrodonato et al, 2018 ; Chen et al, 2020 ). Since aged mice were bred in-house, and therefore, only a limited number of mice were available for each experiment, only the previously identified doses for adult mice (30 mg/kg for males and 10 mg/kg for females) were chosen for aged experiments.…”

Section: Resultsmentioning

confidence: 99%

Acute (R,S)-Ketamine Administration Induces Sex-Specific Behavioral Effects in Adolescent but Not Aged Mice

et al. 2022

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(R,S)-ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that was originally developed as an anesthetic. Most recently, (R,S)-ketamine has been used as a rapid-acting antidepressant, and we have reported that (R,S)-ketamine can also be a prophylactic against stress in adult mice. However, most pre-clinical studies have been performed in adult mice. It is still unknown how an acute (R,S)-ketamine injection influences behavior across the lifespan (e.g., to adolescent or aged populations). Here, we administered saline or (R,S)-ketamine at varying doses to adolescent (5-week-old) and aged (24-month-old) 129S6/SvEv mice of both sexes. One hour later, behavioral despair, avoidance, locomotion, perseverative behavior, or contextual fear discrimination (CFD) was assessed. A separate cohort of mice was sacrificed 1 h following saline or (R,S)-ketamine administration. Brains were processed to quantify the marker of inflammation Cyclooxygenase 2 (Cox-2) expression to determine whether the acute effects of (R,S)-ketamine were partially mediated by changes in brain inflammation. Our findings show that (R,S)-ketamine reduced behavioral despair and perseverative behavior in adolescent female, but not male, mice and facilitated CFD in both sexes at specific doses. (R,S)-ketamine reduced Cox-2 expression specifically in ventral CA3 (vCA3) of male mice. Notably, (R,S)-ketamine was not effective in aged mice. These results underscore the need for sex- and age-specific approaches to test (R,S)-ketamine efficacy across the lifespan.

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Section: Resultsmentioning

confidence: 99%

Acute (R,S)-Ketamine Administration Induces Sex-Specific Behavioral Effects in Adolescent but Not Aged Mice

et al. 2022

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“…1A ). Doses were chosen on previous studies in adolescent ( Parise et al, 2021 ) and adult mice ( Brachman et al, 2016 ; McGowan et al, 2017 ; Mastrodonato et al, 2018 ; Chen et al, 2020 ). Furthermore, since aged mice were bred in-house, and therefore, only a limited number of mice were available for each experiment, only the previously identified effective doses for adult mice (30 mg/kg for males and 10 mg/kg for females) were chosen for these studies.…”

Section: Resultsmentioning

confidence: 99%

Prophylactic (R,S)-Ketamine Is Effective Against Stress-Induced Behaviors in Adolescent but Not Aged Mice

Mastrodonato

Pavlova

Kee

et al. 2022

International Journal of Neuropsychopharmacology

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Background (R,S)-ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is frequently used as an anesthetic and as a rapid-acting antidepressant. We and others have reported that (R,S)-ketamine is prophylactic against stress in adult mice, but have yet to test its efficacy in adolescent or aged populations. Methods Here, we administered saline or (R,S)-ketamine as a prophylactic at varying doses to adolescent (5-week-old) and aged (24-month-old) 129S6/SvEv mice of both sexes 1 week before a 3-shock contextual fear conditioning (CFC) stressor. Following CFC, we assessed behavioral despair, avoidance, perseverative behavior, locomotion, and contextual fear discrimination (CFD). To assess whether the prophylactic effect could persist into adulthood, adolescent mice were injected with saline or varying doses of (R,S)-ketamine, and administered a 3-shock contextual fear conditioning (CFC) as a stressor 1 month later. Mice were then re-exposed to the aversive context 5 days later and administered behavioral tests as aforementioned. Brains were also processed to quantify Cyclooxygenase 2 (Cox-2) expression as a proxy for inflammation to determine whether the prophylactic effects of (R,S)-ketamine were partially due to changes in brain inflammation. Results Our data indicate that (R,S)-ketamine is prophylactic at sex-specific doses in adolescent, but not aged mice. (R,S)-ketamine attenuated learned fear and perseverative behavior in females and reduced behavioral despair in males, and facilitated CFD in both sexes. (R,S)-ketamine reduced Cox-2 expression specifically in ventral CA3 (vCA3) of male mice. Conclusions These findings demonstrate that prophylactic (R,S)-ketamine efficacy is sex-, dose-, and age-dependent and will inform future studies investigating (R,S)-ketamine efficacy across the lifespan.

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“…The second is a standardized procedure used to study stress outcomes in female mice, which chronically witness a co-specific male mouse undergoing social defeat ( 23 – 25 ). SSDS is used to study stress susceptibility, using a 1-day social defeat stress that is not sufficient to induce susceptible outcomes in naïve mice ( 6 , 21 , 22 , 33 ).…”

Section: Discussionmentioning

confidence: 99%

The BDNF-TrkB Pathway Acts Through Nucleus Accumbens D2 Expressing Neurons to Mediate Stress Susceptible Outcomes

et al. 2022

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Brain-derived neurotrophic factor (BDNF) has a critical role in stress response including neuropsychiatric disorders that are precipitated by stress, such as major depressive disorder (MDD). BDNF acts through its full-length BDNF receptor tyrosine kinase B (TrkB) to trigger a pro-plasticity effect. In contrast, the truncated isoform of the BDNF receptor (TrkB.t1) triggers an anti-plasticity effect. In stress outcomes, BDNF acting in the hippocampus has a stress resilience effect, and, inversely, in the nucleus accumbens (NAc), BDNF acts as a stress susceptible molecule. It is unknown if BDNF-TrkB acts on a specific NAc projection neuron, i.e., medium spiny neuron (MSN or spiny projection neuron), a subtype in stress outcomes. To determine this, we performed chronic social or vicarious witness defeat stress (CSDS or CWDS) in mice expressing TrkB.t1 in dopamine receptor 1 or 2 containing MSNs (D1- or D2-MSNs). Our results showed that TrkB.t1 overexpression in NAc D2-MSNs prevented the CSDS-induced social avoidance or other stress susceptible behaviors in male and female mice. We further showed that this overexpression in D2-MSNs blocked stress susceptible behavior induced by intra-NAc BDNF infusion. In contrast, our results demonstrate that overexpression of TrkB.t1 on NAc D1-MSNs facilitates the SDS susceptible behaviors. Our study provides enhanced details into the NAc cell subtype role of BDNF-TrkB signaling in stress outcomes.

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The Resilient Phenotype Induced by Prophylactic Ketamine Exposure During Adolescence Is Mediated by the Ventral Tegmental Area–Nucleus Accumbens Pathway

Cited by 20 publications

References 73 publications

Acute (R,S)-Ketamine Administration Induces Sex-Specific Behavioral Effects in Adolescent but Not Aged Mice

Acute (R,S)-Ketamine Administration Induces Sex-Specific Behavioral Effects in Adolescent but Not Aged Mice

Prophylactic (R,S)-Ketamine Is Effective Against Stress-Induced Behaviors in Adolescent but Not Aged Mice

The BDNF-TrkB Pathway Acts Through Nucleus Accumbens D2 Expressing Neurons to Mediate Stress Susceptible Outcomes

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