Acute (R,S)-Ketamine Administration Induces Sex-Specific Behavioral Effects in Adolescent but Not Aged Mice
(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...
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2022.852010/full |
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| author | Alessia Mastrodonato Alessia Mastrodonato Ina Pavlova Ina Pavlova Noelle Kee Josephine C. McGowan J. John Mann Christine A. Denny Christine A. Denny |
| author_facet | Alessia Mastrodonato Alessia Mastrodonato Ina Pavlova Ina Pavlova Noelle Kee Josephine C. McGowan J. John Mann Christine A. Denny Christine A. Denny |
| author_sort | Alessia Mastrodonato |
| collection | DOAJ |
| description | (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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| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-10T03:57:10Z |
| publishDate | 2022-04-01 |
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| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-b2b4b515ab284740b3e5f0cddb7687ac2022-12-22T02:03:06ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2022-04-011610.3389/fnins.2022.852010852010Acute (R,S)-Ketamine Administration Induces Sex-Specific Behavioral Effects in Adolescent but Not Aged MiceAlessia Mastrodonato0Alessia Mastrodonato1Ina Pavlova2Ina Pavlova3Noelle Kee4Josephine C. McGowan5J. John Mann6Christine A. Denny7Christine A. Denny8Division of Systems Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH)/New York State Psychiatric Institute (NYSPI), New York, NY, United StatesDepartment of Psychiatry, Columbia University Irving Medical Center (CUIMC), New York, NY, United StatesDivision of Systems Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH)/New York State Psychiatric Institute (NYSPI), New York, NY, United StatesDepartment of Psychiatry, Columbia University Irving Medical Center (CUIMC), New York, NY, United StatesBarnard College, New York, NY, United StatesNeurobiology and Behavior (NB&B) Graduate Program, Columbia University, New York, NY, United StatesMolecular Imaging and the Neuropathology Division/Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), New York, NY, United StatesDivision of Systems Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH)/New York State Psychiatric Institute (NYSPI), New York, NY, United StatesDepartment of Psychiatry, Columbia University Irving Medical Center (CUIMC), New York, NY, United States(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.https://www.frontiersin.org/articles/10.3389/fnins.2022.852010/fulladolescenceagingbehavioral despaircontextual fear discriminationketamine |
| spellingShingle | Alessia Mastrodonato Alessia Mastrodonato Ina Pavlova Ina Pavlova Noelle Kee Josephine C. McGowan J. John Mann Christine A. Denny Christine A. Denny Acute (R,S)-Ketamine Administration Induces Sex-Specific Behavioral Effects in Adolescent but Not Aged Mice Frontiers in Neuroscience adolescence aging behavioral despair contextual fear discrimination ketamine |
| title | Acute (R,S)-Ketamine Administration Induces Sex-Specific Behavioral Effects in Adolescent but Not Aged Mice |
| title_full | Acute (R,S)-Ketamine Administration Induces Sex-Specific Behavioral Effects in Adolescent but Not Aged Mice |
| title_fullStr | Acute (R,S)-Ketamine Administration Induces Sex-Specific Behavioral Effects in Adolescent but Not Aged Mice |
| title_full_unstemmed | Acute (R,S)-Ketamine Administration Induces Sex-Specific Behavioral Effects in Adolescent but Not Aged Mice |
| title_short | Acute (R,S)-Ketamine Administration Induces Sex-Specific Behavioral Effects in Adolescent but Not Aged Mice |
| title_sort | acute r s ketamine administration induces sex specific behavioral effects in adolescent but not aged mice |
| topic | adolescence aging behavioral despair contextual fear discrimination ketamine |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2022.852010/full |
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