Bryan W Jenkins, Hayley A Spina, Kate Nicholson, Amy E M Newman, Jibran Y Khokhar
{"title":"大麻二酚（CBD）增强了雌性和雄性小鼠下丘脑-垂体-肾上腺（HPA）轴反应性的生理和行为标记。","authors":"Bryan W Jenkins, Hayley A Spina, Kate Nicholson, Amy E M Newman, Jibran Y Khokhar","doi":"10.1007/s00213-024-06737-z","DOIUrl":null,"url":null,"abstract":"<p><strong>Rationale: </strong>Clinical literature indicates there may be a therapeutic use of cannabidiol (CBD) for stress-related disorders. Preclinical literature remains conflicted regarding the underlying neurobehavioral mechanisms, reporting mixed effects of CBD (increased, decreased, or no effect) on anxiety- and fear-related behaviors. Preclinical data demonstrated that CBD modulates hypothalamus-pituitary-adrenal (HPA) axis gene expression; it is unknown whether CBD changes HPA axis responsivity and how this relates to altered behavior.</p><p><strong>Objectives: </strong>We aimed to evaluate whether acute or chronic CBD administration would alter physiological and behavioral measures of HPA axis responsivity in male or female mice.</p><p><strong>Methods: </strong>C57BL/6 mice of both sexes were injected with vehicle or CBD (30 mg/kg, i.p.) daily for 26 days. Plasma corticosterone (CORT) levels were evaluated following dexamethasone suppression and adrenocorticotropin hormone stimulation tests after acute and chronic CBD exposure. After chronic CBD, mice were tested for anxiety-like behavior using an elevated plus maze (EPM) and associative fear learning and memory using a trace fear conditioning (FC) protocol.</p><p><strong>Results: </strong>Compared to vehicle, CBD induced a state of HPA axis hyperactivation, an effect which was significant in males; it also normalized anxiety-like behavior in female mice classified as having HPA axis hypofunction and primed all female mice for enhanced conditioned responding. Significant sex differences were also detected: females had greater plasma CORT levels and HPA axis responsivity than males, exhibited less EPM anxiety-like behavior, and were more responsive during FC.</p><p><strong>Conclusions: </strong>CBD potentiated physiological and behavioral markers of HPA axis function and normalized anxiety-like behavior in a sex-specific manner. This observation has implications for cannabinoid-based drug development targeting individuals with stress-related disorders involving HPA axis hypofunction pathology.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5000,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Cannabidiol (CBD) potentiates physiological and behavioral markers of hypothalamic-pituitary-adrenal (HPA) axis responsivity in female and male mice.\",\"authors\":\"Bryan W Jenkins, Hayley A Spina, Kate Nicholson, Amy E M Newman, Jibran Y Khokhar\",\"doi\":\"10.1007/s00213-024-06737-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Rationale: </strong>Clinical literature indicates there may be a therapeutic use of cannabidiol (CBD) for stress-related disorders. Preclinical literature remains conflicted regarding the underlying neurobehavioral mechanisms, reporting mixed effects of CBD (increased, decreased, or no effect) on anxiety- and fear-related behaviors. Preclinical data demonstrated that CBD modulates hypothalamus-pituitary-adrenal (HPA) axis gene expression; it is unknown whether CBD changes HPA axis responsivity and how this relates to altered behavior.</p><p><strong>Objectives: </strong>We aimed to evaluate whether acute or chronic CBD administration would alter physiological and behavioral measures of HPA axis responsivity in male or female mice.</p><p><strong>Methods: </strong>C57BL/6 mice of both sexes were injected with vehicle or CBD (30 mg/kg, i.p.) daily for 26 days. Plasma corticosterone (CORT) levels were evaluated following dexamethasone suppression and adrenocorticotropin hormone stimulation tests after acute and chronic CBD exposure. After chronic CBD, mice were tested for anxiety-like behavior using an elevated plus maze (EPM) and associative fear learning and memory using a trace fear conditioning (FC) protocol.</p><p><strong>Results: </strong>Compared to vehicle, CBD induced a state of HPA axis hyperactivation, an effect which was significant in males; it also normalized anxiety-like behavior in female mice classified as having HPA axis hypofunction and primed all female mice for enhanced conditioned responding. Significant sex differences were also detected: females had greater plasma CORT levels and HPA axis responsivity than males, exhibited less EPM anxiety-like behavior, and were more responsive during FC.</p><p><strong>Conclusions: </strong>CBD potentiated physiological and behavioral markers of HPA axis function and normalized anxiety-like behavior in a sex-specific manner. 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Cannabidiol (CBD) potentiates physiological and behavioral markers of hypothalamic-pituitary-adrenal (HPA) axis responsivity in female and male mice.
Rationale: Clinical literature indicates there may be a therapeutic use of cannabidiol (CBD) for stress-related disorders. Preclinical literature remains conflicted regarding the underlying neurobehavioral mechanisms, reporting mixed effects of CBD (increased, decreased, or no effect) on anxiety- and fear-related behaviors. Preclinical data demonstrated that CBD modulates hypothalamus-pituitary-adrenal (HPA) axis gene expression; it is unknown whether CBD changes HPA axis responsivity and how this relates to altered behavior.
Objectives: We aimed to evaluate whether acute or chronic CBD administration would alter physiological and behavioral measures of HPA axis responsivity in male or female mice.
Methods: C57BL/6 mice of both sexes were injected with vehicle or CBD (30 mg/kg, i.p.) daily for 26 days. Plasma corticosterone (CORT) levels were evaluated following dexamethasone suppression and adrenocorticotropin hormone stimulation tests after acute and chronic CBD exposure. After chronic CBD, mice were tested for anxiety-like behavior using an elevated plus maze (EPM) and associative fear learning and memory using a trace fear conditioning (FC) protocol.
Results: Compared to vehicle, CBD induced a state of HPA axis hyperactivation, an effect which was significant in males; it also normalized anxiety-like behavior in female mice classified as having HPA axis hypofunction and primed all female mice for enhanced conditioned responding. Significant sex differences were also detected: females had greater plasma CORT levels and HPA axis responsivity than males, exhibited less EPM anxiety-like behavior, and were more responsive during FC.
Conclusions: CBD potentiated physiological and behavioral markers of HPA axis function and normalized anxiety-like behavior in a sex-specific manner. This observation has implications for cannabinoid-based drug development targeting individuals with stress-related disorders involving HPA axis hypofunction pathology.
期刊介绍：
Official Journal of the European Behavioural Pharmacology Society (EBPS)
Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields:
Human Psychopharmacology: Experimental
This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered.
Human Psychopharmacology: Clinical and Translational
This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects.
Preclinical psychopharmacology: Behavioral and Neural
This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels.
Preclinical Psychopharmacology: Translational
This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways.
Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic
This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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