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The dual orexinergic receptor antagonist DORA-22 improves the sleep disruption and memory impairment produced by a rodent insomnia model.
Sleep 2019S

Abstract

Insomnia-related sleep disruption can contribute to impaired learning and memory. Treatment of insomnia should ideally improve the sleep profile while minimally impacting mnemonic function, yet many hypnotic drugs (e.g., benzodiazepines) are known to impair memory. Here, we used a rat model of insomnia to determine if the novel hypnotic drug DORA-22, a dual orexin receptor antagonist, improves mild stress-induced insomnia with minimal effect on memory. Animals were first trained to remember the location of a hidden platform (acquisition) in the Morris Water Maze, then administered DORA-22 (10, 30, or 100mg/kg doses) or vehicle control. Animals were then subjected to a rodent insomnia model involving two exposures to dirty cages over a six-hour time period (at timepoints 0 and 3 hours), followed immediately by a probe trial in which memory of the water maze platform location was evaluated. DORA-22 treatment improved the insomnia-related sleep disruption - wake was attenuated and NREM sleep was normalized. REM sleep amounts were enhanced compared to vehicle treatment for one dose (30mg/kg). In the first hour of insomnia model exposure, DORA-22 promoted the number and average duration of NREM sleep spindles, which have been previously proposed to play a role in memory consolidation (all doses). Water maze measures revealed probe trial performance improvement for select doses of DORA-22, including increased time spent in the platform quadrant (10 and 30 mg/kg); and time spent in platform location and number of platform crossings (10mg/kg only). In conclusion, DORA-22 treatment improved insomnia-related sleep disruption and memory consolidation deficits.

Authors+Show Affiliations

Boston VA Research Institute, Inc., Jamaica Plain, MA. VA Boston Healthcare System, West Roxbury, MA.Boston VA Research Institute, Inc., Jamaica Plain, MA. VA Boston Healthcare System, West Roxbury, MA. Harvard Medical School, Department of Psychiatry, West Roxbury, MA.Boston VA Research Institute, Inc., Jamaica Plain, MA. VA Boston Healthcare System, West Roxbury, MA. Stonehill College, Easton, MA.Boston VA Research Institute, Inc., Jamaica Plain, MA. VA Boston Healthcare System, West Roxbury, MA. Harvard Medical School, Department of Psychiatry, West Roxbury, MA.Boston VA Research Institute, Inc., Jamaica Plain, MA. VA Boston Healthcare System, West Roxbury, MA. Harvard Medical School, Department of Psychiatry, West Roxbury, MA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31595304

Citation

Gamble, Mackenzie C., et al. "The Dual Orexinergic Receptor Antagonist DORA-22 Improves the Sleep Disruption and Memory Impairment Produced By a Rodent Insomnia Model." Sleep, 2019.
Gamble MC, Katsuki F, McCoy JG, et al. The dual orexinergic receptor antagonist DORA-22 improves the sleep disruption and memory impairment produced by a rodent insomnia model. Sleep. 2019.
Gamble, M. C., Katsuki, F., McCoy, J. G., Strecker, R. E., & McKenna, J. T. (2019). The dual orexinergic receptor antagonist DORA-22 improves the sleep disruption and memory impairment produced by a rodent insomnia model. Sleep, doi:10.1093/sleep/zsz241.
Gamble MC, et al. The Dual Orexinergic Receptor Antagonist DORA-22 Improves the Sleep Disruption and Memory Impairment Produced By a Rodent Insomnia Model. Sleep. 2019 Oct 9; PubMed PMID: 31595304.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The dual orexinergic receptor antagonist DORA-22 improves the sleep disruption and memory impairment produced by a rodent insomnia model. AU - Gamble,Mackenzie C, AU - Katsuki,Fumi, AU - McCoy,John G, AU - Strecker,Robert E, AU - McKenna,James T, Y1 - 2019/10/09/ PY - 2019/07/16/received PY - 2019/10/10/entrez PY - 2019/10/9/pubmed PY - 2019/10/9/medline KW - EEG spectral analysis KW - animal models KW - effects of sleep restriction on cognition and affect KW - insomnia KW - pharmacology-hypnotics KW - sleep and memory JF - Sleep JO - Sleep N2 - Insomnia-related sleep disruption can contribute to impaired learning and memory. Treatment of insomnia should ideally improve the sleep profile while minimally impacting mnemonic function, yet many hypnotic drugs (e.g., benzodiazepines) are known to impair memory. Here, we used a rat model of insomnia to determine if the novel hypnotic drug DORA-22, a dual orexin receptor antagonist, improves mild stress-induced insomnia with minimal effect on memory. Animals were first trained to remember the location of a hidden platform (acquisition) in the Morris Water Maze, then administered DORA-22 (10, 30, or 100mg/kg doses) or vehicle control. Animals were then subjected to a rodent insomnia model involving two exposures to dirty cages over a six-hour time period (at timepoints 0 and 3 hours), followed immediately by a probe trial in which memory of the water maze platform location was evaluated. DORA-22 treatment improved the insomnia-related sleep disruption - wake was attenuated and NREM sleep was normalized. REM sleep amounts were enhanced compared to vehicle treatment for one dose (30mg/kg). In the first hour of insomnia model exposure, DORA-22 promoted the number and average duration of NREM sleep spindles, which have been previously proposed to play a role in memory consolidation (all doses). Water maze measures revealed probe trial performance improvement for select doses of DORA-22, including increased time spent in the platform quadrant (10 and 30 mg/kg); and time spent in platform location and number of platform crossings (10mg/kg only). In conclusion, DORA-22 treatment improved insomnia-related sleep disruption and memory consolidation deficits. SN - 1550-9109 UR - https://www.unboundmedicine.com/medline/citation/31595304/The_dual_orexinergic_receptor_antagonist_DORA-22_improves_the_sleep_disruption_and_memory_impairment_produced_by_a_rodent_insomnia_model L2 - https://academic.oup.com/sleep/article-lookup/doi/10.1093/sleep/zsz241 DB - PRIME DP - Unbound Medicine ER -