103 results on '"Holmes PV"'
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2. Studies on the morphology of the isolated perfused rabbit ovary. I. Effect of long-term perfusion
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Holmes Pv, K. Ahrén, Per Olof Janson, B. J. Källfelt, L. Bjersing, Stefan Cajander, and William J. LeMaire
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Ovulation ,Histology ,media_common.quotation_subject ,Ovary ,Biology ,In Vitro Techniques ,Pathology and Forensic Medicine ,Specimen Handling ,Andrology ,Ovarian Follicle ,medicine ,Animals ,media_common ,Lagomorpha ,Albumin ,Rabbit (nuclear engineering) ,Cell Biology ,Anatomy ,biology.organism_classification ,In vitro ,Perfusion ,Chemically defined medium ,medicine.anatomical_structure ,Female ,Rabbits - Abstract
Isolated ovaries from untreated, sexually mature rabbits were introduced into an in vitro perfusion system and perfused with a chemically defined medium containing albumin. The ovaries were perfused for up to 15 h (mean 11.5 h) and then processed for morphological investigation. Both at the light- and electron-microscopical levels, most of the ovaries exhibited a normal structure comparable with ovaries in situ. In two cases, however, marked accumulations of bacteria were found, although not inside the follicles. Since ovulation in the rabbit normally occurs between 9.5-13 h after mating or human chorionic gonadotrophin treatment, this model seems adequate for studies of ovulation in vitro. It is, however, important to study the ovaries microscopically after the perfusion to detect artifacts, e.g., bacterial infection, that may have influence on the process of ovulation.
- Published
- 1984
3. Studies on the morphology of the isolated perfused rabbit ovary. II. Ovulation in vitro after HCG-treatment in vivo
- Author
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B. J. Källfelt, Holmes Pv, William J. LeMaire, K. Ahrén, L. Bjersing, Stefan Cajander, and Per Olof Janson
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endocrine system ,medicine.medical_specialty ,Histology ,medicine.drug_class ,media_common.quotation_subject ,medicine.medical_treatment ,Ovary ,In Vitro Techniques ,Chorionic Gonadotropin ,Pathology and Forensic Medicine ,Ovulation Induction ,In vivo ,Internal medicine ,medicine ,Animals ,Ovulation ,reproductive and urinary physiology ,media_common ,Lagomorpha ,biology ,Cell Biology ,biology.organism_classification ,In vitro ,Microscopy, Electron ,Endocrinology ,medicine.anatomical_structure ,Ovulation induction ,Female ,Rabbits ,Gonadotropin ,Perfusion ,hormones, hormone substitutes, and hormone antagonists - Abstract
Ovulation was induced in rabbits by intravenous administration of human chorionic gonadotrophin (HCG), and 4-5 h later the ovaries were isolated and introduced into an in-vitro perfusion system containing synthetic medium with albumin. Rupture of follicles occurred in vitro within the physiological time range (mean 11.3 h after injection of HCG), although with a reduced frequency. Preovulatory and ruptured follicles were studied in detail by light and electron microscopy. In the granulosa layer of ruptured or preovulatory follicles cytoplasmic blebbing activity, disappearance of Call-Exner bodies and differentiation toward luteinized cells were found. Perhaps the most important sign of normal preovulatory development in vitro was that the basement membrane surrounding the granulosa layer was penetrated by projections of granulosa cells. In the absence of this penetration phenomenon the granulosa layer prolapsed out of the follicle. Immediately before rupture, follicles showed marked degeneration, restricted to the outer layers of the apical wall, which is compatible with the hypothesis that degradative enzymes are released close to the surface of preovulatory follicles. Although the majority of follicles that ovulated under in-vitro conditions showed the same kind of morphological alterations as can be seen in vivo, occasional atypical ruptures occurred without any overt signs during perfusion. Also technical manipulations of the perfusion system, e.g., nonphysiological increase of perfusion pressure, could force follicles to rupture. This illustrates the importance of careful morphological study of all ovaries perfused in vitro before conclusions are drawn.
- Published
- 1984
4. Prenatal Exposure to Bisphenol A and/or Diethylhexyl Phthalate Impacts Brain Monoamine Levels in Rat Offspring.
- Author
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Kaimal A, Hooversmith JM, Mansi MHA, Holmes PV, MohanKumar PS, and MohanKumar SMJ
- Abstract
This study examines the sex-specific effects of gestational exposure (days 6-21) to endocrine-disrupting chemicals such as bisphenol A (BPA), diethylhexyl phthalate (DEHP), or their combination on brain monoamine levels that play an important role in regulating behavior. Pregnant Sprague-Dawley rats were orally administered saline, low doses (5 µg/kg BW/day) of BPA or DEHP, and their combination or a high dose (7.5 mg/kg BW/day) of DEHP alone or in combination with BPA during pregnancy. The offspring were subjected to a behavioral test and sacrificed in adulthood, and the brains were analyzed for neurotransmitter levels. In the paraventricular nucleus, there was a marked reduction in dopamine levels ( p < 0.01) in male offspring from the BPA, DEHP, and B + D (HD) groups, which correlated well with their shock probe defensive burying times. Neurotransmitter changes in all brain regions examined were significant in female offspring, with DEHP (HD) females being affected the most, followed by the B + D groups. BPA and/or DEHP (LD) increased monoamine turnover in a region-specific manner in male offspring ( p < 0.05). Overall, prenatal exposure to BPA, DEHP, or their combination alters monoamine levels in a brain region-specific, sex-specific, and dose-dependent manner, which could have implications for their behavioral and neuroendocrine effects.
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- 2024
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5. Prenatal exposure to bisphenol A and/or diethylhexyl phthalate alters stress responses in rat offspring in a sex- and dose-dependent manner.
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Kaimal A, Hooversmith JM, Cherry AD, Garrity JT, Al Mansi MH, Martin NM, Buechter H, Holmes PV, MohanKumar PS, and MohanKumar SMJ
- Abstract
Background: Prenatal exposures to endocrine disrupting chemicals (EDCs) are correlated with adverse behavioral outcomes, but the effects of combinations of these chemicals are unclear. The aim of this study was to determine the dose-dependent effects of prenatal exposure to EDCs on male and female behavior. Methods: Pregnant Sprague-Dawley rats were orally dosed with vehicle, bisphenol A (BPA) (5 μg/kg body weight (BW)/day), low-dose (LD) diethylhexyl phthalate (DEHP) (5 μg/kg BW/day), high-dose (HD) DEHP (7.5 mg/kg BW/day), a combination of BPA and LD-DEHP (B + D (LD)), or a combination of BPA and HD-DEHP (B + D (HD)) on gestational days 6-21. Adult offspring were subjected to the Open Field Test (OFT), Elevated Plus Maze (EPM), and Shock Probe Defensive Burying test (SPDB) in adulthood. Body, adrenal gland, and pituitary gland weights were collected at sacrifice. Corticosterone (CORT) was measured in the serum. Results: Female EDC-exposed offspring showed anxiolytic effects in the OFT, while male offspring were unaffected. DEHP (HD) male offspring demonstrated a feminization of behavior in the EPM. Most EDC-exposed male offspring buried less in the SPDB, while their female counterparts showed reduced shock reactivity, indicating sex-specific maladaptive alterations in defensive behaviors. Additionally, DEHP (LD) males and females and B + D (LD) females displayed increased immobility in this test. DEHP (LD) alone and in combination with BPA led to lower adrenal gland weights, but only in male offspring. Finally, females treated with a mixture of B + D (HD) had elevated CORT levels. Conclusion: Prenatal exposure to BPA, DEHP, or a mixture of the two, affects behavior, CORT levels, and adrenal gland weights in a sex- and dose-dependent manner., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Kaimal, Hooversmith, Cherry, Garrity, Al Mansi, Martin, Buechter, Holmes, MohanKumar and MohanKumar.)
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- 2023
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6. The gut-brain axis mediates bacterial driven modulation of reward signaling.
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Kim JS, Williams KC, Kirkland RA, Schade R, Freeman KG, Cawthon CR, Rautmann AW, Smith JM, Edwards GL, Glenn TC, Holmes PV, de Lartigue G, and de La Serre CB
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- Rats, Male, Animals, 3,4-Dihydroxyphenylacetic Acid, Reward, Bacteria, Brain-Gut Axis, Feeding Behavior physiology
- Abstract
Objective: Our goal is to investigate if microbiota composition modulates reward signaling and assess the role of the vagus in mediating microbiota to brain communication., Methods: Male germ-free Fisher rats were colonized with gastrointestinal contents from chow (low fat (LF) ConvLF) or HF (ConvHF) fed rats., Results: Following colonization, ConvHF rats consumed significantly more food than ConvLF animals. ConvHF rats displayed lower feeding-induced extracellular DOPAC levels (a metabolite of dopamine) in the Nucleus Accumbens (NAc) as well as reduced motivation for HF foods compared to ConvLF rats. Dopamine receptor 2 (DDR2) expression levels in the NAc were also significantly lower in ConvHF animals. Similar deficits were observed in conventionally raised HF fed rats, showing that diet-driven alteration in reward can be initiated via microbiota. Selective gut to brain deafferentation restored DOPAC levels, DRD2 expression, and motivational drive in ConvHF rats., Conclusions: We concluded from these data that a HF-type microbiota is sufficient to alter appetitive feeding behavior and that bacteria to reward communication is mediated by the vagus nerve., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
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- 2023
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7. Engineered glycomaterial implants orchestrate large-scale functional repair of brain tissue chronically after severe traumatic brain injury.
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Latchoumane CV, Betancur MI, Simchick GA, Sun MK, Forghani R, Lenear CE, Ahmed A, Mohankumar R, Balaji N, Mason HD, Archer-Hartmann SA, Azadi P, Holmes PV, Zhao Q, Bellamkonda RV, and Karumbaiah L
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- Animals, Brain, Rats, Regeneration, Brain Injuries, Traumatic therapy, Neural Stem Cells
- Abstract
Severe traumatic brain injury (sTBI) survivors experience permanent functional disabilities due to significant volume loss and the brain's poor capacity to regenerate. Chondroitin sulfate glycosaminoglycans (CS-GAGs) are key regulators of growth factor signaling and neural stem cell homeostasis in the brain. However, the efficacy of engineered CS (eCS) matrices in mediating structural and functional recovery chronically after sTBI has not been investigated. We report that neurotrophic factor functionalized acellular eCS matrices implanted into the rat M1 region acutely after sTBI significantly enhanced cellular repair and gross motor function recovery when compared to controls 20 weeks after sTBI. Animals subjected to M2 region injuries followed by eCS matrix implantations demonstrated the significant recovery of "reach-to-grasp" function. This was attributed to enhanced volumetric vascularization, activity-regulated cytoskeleton (Arc) protein expression, and perilesional sensorimotor connectivity. These findings indicate that eCS matrices implanted acutely after sTBI can support complex cellular, vascular, and neuronal circuit repair chronically after sTBI., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
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- 2021
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8. Chronic Environmental or Genetic Elevation of Galanin in Noradrenergic Neurons Confers Stress Resilience in Mice.
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Tillage RP, Wilson GE, Liles LC, Holmes PV, and Weinshenker D
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- Adrenergic Neurons physiology, Animals, Female, Galanin genetics, Male, Mice, Mice, Inbred C57BL, Motor Activity, Stress, Psychological genetics, Stress, Psychological physiopathology, Adrenergic Neurons metabolism, Galanin metabolism, Stress, Psychological metabolism
- Abstract
The neuropeptide galanin has been implicated in stress-related neuropsychiatric disorders in humans and rodent models. While pharmacological treatments for these disorders are ineffective for many individuals, physical activity is beneficial for stress-related symptoms. Galanin is highly expressed in the noradrenergic system, particularly the locus coeruleus (LC), which is dysregulated in stress-related disorders and activated by exercise. Galanin expression is elevated in the LC by chronic exercise, and blockade of galanin transmission attenuates exercise-induced stress resilience. However, most research on this topic has been done in rats, so it is unclear whether the relationship between exercise and galanin is species specific. Moreover, use of intracerebroventricular (ICV) galanin receptor antagonists in prior studies precluded defining a causal role for LC-derived galanin specifically. Therefore, the goals of this study were twofold. First, we investigated whether physical activity (chronic wheel running) increases stress resilience and galanin expression in the LC of male and female mice. Next, we used transgenic mice that overexpress galanin in noradrenergic neurons (Gal OX) to determine how chronically elevated noradrenergic-derived galanin, alone, alters anxiogenic-like responses to stress. We found that three weeks of ad libitum access to a running wheel in their home cage increased galanin mRNA in the LC of mice, which was correlated with and conferred resilience to stress. The effects of exercise were phenocopied by galanin overexpression in noradrenergic neurons, and Gal OX mice were resistant to the anxiogenic effect of optogenetic LC activation. These findings support a role for chronically increased noradrenergic galanin in mediating resilience to stress. SIGNIFICANCE STATEMENT Understanding the neurobiological mechanisms underlying behavioral responses to stress is necessary to improve treatments for stress-related neuropsychiatric disorders. Increased physical activity is associated with stress resilience in humans, but the neurobiological mechanisms underlying this effect are not clear. Here, we investigate a potential causal mechanism of this effect driven by the neuropeptide galanin from the main noradrenergic nucleus, the locus coeruleus (LC). We show that chronic voluntary wheel running in mice increases stress resilience and increases galanin expression in the LC. Furthermore, we show that genetic overexpression of galanin in noradrenergic neurons causes resilience to a stressor and the anxiogenic effects of optogenetic LC activation. These findings support a role for chronically increased noradrenergic galanin in mediating resilience to stress., (Copyright © 2020 the authors.)
- Published
- 2020
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9. Extracellular Vesicles Mediate Neuroprotection and Functional Recovery after Traumatic Brain Injury.
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Sun MK, Passaro AP, Latchoumane CF, Spellicy SE, Bowler M, Goeden M, Martin WJ, Holmes PV, Stice SL, and Karumbaiah L
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- Animals, Brain Injuries, Traumatic physiopathology, Cell Movement physiology, Female, Humans, Injections, Intravenous, Male, Neural Stem Cells physiology, Neural Stem Cells transplantation, Rats, Rats, Sprague-Dawley, Brain Injuries, Traumatic therapy, Extracellular Vesicles physiology, Extracellular Vesicles transplantation, Neuroprotection physiology, Recovery of Function physiology, Stem Cell Transplantation methods
- Abstract
The lack of effective therapies for moderate-to-severe traumatic brain injuries (TBIs) leaves patients with lifelong disabilities. Neural stem cells (NSCs) have demonstrated great promise for neural repair and regeneration. However, direct evidence to support their use as a cell replacement therapy for neural injuries is currently lacking. We hypothesized that NSC-derived extracellular vesicles (NSC EVs) mediate repair indirectly after TBI by enhancing neuroprotection and therapeutic efficacy of endogenous NSCs. We evaluated the short-term effects of acute intravenous injections of NSC EVs immediately following a rat TBI. Male NSC EV-treated rats demonstrated significantly reduced lesion sizes, enhanced presence of endogenous NSCs, and attenuated motor function impairments 4 weeks post-TBI, when compared with vehicle- and TBI-only male controls. Although statistically not significant, we observed a therapeutic effect of NSC EVs on brain lesion volume, nestin expression, and behavioral recovery in female subjects. Our study demonstrates the neuroprotective and functional benefits of NSC EVs for treating TBI and points to gender-dependent effects on treatment outcomes, which requires further investigation.
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- 2020
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10. Galanin administration into the prelimbic cortex impairs consolidation and expression of contextual fear conditioning.
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Hooversmith JM, Bhatti DL, and Holmes PV
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- Animals, Conditioning, Classical drug effects, Conditioning, Operant drug effects, Disease Models, Animal, Extinction, Psychological drug effects, Fear physiology, Galanin metabolism, Male, Memory physiology, Prefrontal Cortex metabolism, Rats, Rats, Sprague-Dawley, Stress Disorders, Post-Traumatic drug therapy, Galanin pharmacology, Memory Consolidation drug effects, Prefrontal Cortex drug effects
- Abstract
The neuropeptide galanin is a potential therapeutic target for treating stress-related disorders, such as post-traumatic stress disorder (PTSD); however, its effects on contextual fear conditioning (CFC), an accepted animal model of PTSD, are not well understood. Dysregulation of the medial prefrontal cortex (mPFC) is implicated in PTSD. We investigated the effects of galanin (1 ug) administrated bilaterally into the prelimbic cortex, a division of the mPFC, on the consolidation, expression, and extinction of CFC of male Sprague-Dawley rats. Galanin administration significantly reduced consolidation and expression of CFC, but had no effect on retention or retrieval of extinction learning. These data further implicate galanin as a potential therapeutic target for treating stress-related disorders, particularly those characterized by aberrant emotional memory., (Copyright © 2019 Elsevier B.V. All rights reserved.)
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- 2019
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11. Effects of macular xanthophyll supplementation on brain-derived neurotrophic factor, pro-inflammatory cytokines, and cognitive performance.
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Stringham NT, Holmes PV, and Stringham JM
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- Adolescent, Adult, Dietary Supplements, Double-Blind Method, Female, Healthy Volunteers, Humans, Male, Neuropsychological Tests, Young Adult, Brain-Derived Neurotrophic Factor blood, Cognition drug effects, Interleukin-1beta blood, Interleukin-6 blood, Lutein pharmacology, Tumor Necrosis Factor-alpha blood, Zeaxanthins pharmacology
- Abstract
Purpose: Oxidative and inflammatory processes play a major role in stress-induced neural atrophy. There is a wide body of literature linking oxidative and inflammatory stress with reductions in neurotrophic factors, stress resilience, and cognitive function. Based on their antioxidant and anti-inflammatory capacity, we investigated the effect of the dietary carotenoids lutein and zeaxanthin, along with the zeaxanthin isomer meso-zeaxanthin (collectively the "macular xanthophylls" [MXans]) on systemic brain-derived neurotrophic factor (BDNF) and anti-oxidant capacity (AOC), and the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. To investigate higher-order effects, we assessed cognitive performance., Methods: 59 young (18-25 yrs.), healthy subjects participated in a 6-month, double-blind, placebo-controlled trial to evaluate the effects of MXan supplementation on the aforementioned serum parameters and cognitive performance. Subjects were randomly assigned to one of three groups: placebo, 13 mg, or 27 mg/day total MXans; all measures were taken at baseline and 6 months. Blood was obtained via fasting blood draw, and MXan concentration in the retina (termed macular pigment optical density [MPOD]) was measured via customized heterochromatic flicker photometry. Serum BDNF and cytokines were assessed via ELISA. Serum antioxidant capacity (AOC) and serum MXan concentrations were quantified via colorimetric microplate assay, and high-performance liquid chromatography, respectively. Cognitive performance was measured via a computer-based assessment tool (CNS Vital Signs)., Results: BDNF, MPOD, serum MXans, and AOC all increased significantly versus placebo in both treatment groups over the 6-month study period (p < .05 for all). IL-1β decreased significantly versus placebo in both treatment groups (p = .0036 and p = .006, respectively). For cognitive measures, scores for composite memory, verbal memory, sustained attention, psychomotor speed, and processing speed all improved significantly in treatment groups (p < .05 for all) and remained unchanged in the placebo group. Several measures were found to be significantly associated in terms of relational changes over the course of the study. Notably, change in BDNF was related to change in IL-1β (r = -0.47; p < .001) and MPOD (r = 0.44; p = .0086). Additionally, changes in serum MXans were strongly related to AOC (r = 0.79 & 0.61 for lutein and zeaxanthin isomers respectively; p < .001). For cognitive scores, change in BDNF was correlated to change in composite memory (r = 0.32; p = .014) and verbal memory (r = 0.35; p = .007), whereas change in MPOD was correlated with change in both psychomotor speed (r = 0.38; p = .003), and processing speed (r = 0.35; p = .007). Change in serum lutein was found to be significantly correlated to change in verbal memory (r = 0.41; p < .001), composite memory (r = 0.31; p = .009), and sustained attention (r = 0.28; p = .036). Change in serum zeaxanthin isomers was significantly correlated with change in verbal memory (r = 0.33; p = .017). Lastly, change in AOC was significantly associated with verbal memory (r = 0.34; p = .021), composite memory (r = 0.29; p = .03), and sustained attention (r = 0.35; p = .016). No significant relational changes in any cognitive parameter were found for the placebo group., Conclusions: Six months of daily supplementation with at least 13 mg of MXans significantly reduces serum IL-1β, significantly increases serum MXans, BDNF, MPOD, and AOC, and improves several parameters of cognitive performance. Findings suggest that increased systemic antioxidant/anti-inflammatory capacity (and not necessarily deposition of the carotenoids in neural tissues), may explain many of the effects determined in this study. The significant relationship between change in BDNF and IL-1β over the course of the study suggests that regular consumption of MXans interrupts the inflammatory cascade that can lead to reduction of BDNF. Changes in MPOD and BDNF appear to account for enhancement in cognitive parameters that involve speed of processing and complex processing, respectively. ISRCTN Clinical Trial Registration: ISRCTN16156382., (Copyright © 2019. Published by Elsevier Inc.)
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- 2019
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12. Supplementation with macular carotenoids reduces psychological stress, serum cortisol, and sub-optimal symptoms of physical and emotional health in young adults.
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Stringham NT, Holmes PV, and Stringham JM
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- Adolescent, Adult, Behavioral Symptoms psychology, Dietary Supplements, Double-Blind Method, Female, Humans, Lutein administration & dosage, Lutein blood, Macula Lutea, Macular Pigment pharmacology, Male, Retinal Pigments, Self Report, Young Adult, Zeaxanthins administration & dosage, Zeaxanthins blood, Antioxidants administration & dosage, Carotenoids administration & dosage, Hydrocortisone blood, Stress, Psychological diet therapy
- Abstract
Purpose: Oxidative stress and systemic inflammation are the root cause of several deleterious effects of chronic psychological stress. We hypothesize that the antioxidant and anti-inflammatory capabilities of the macular carotenoids (MCs) lutein, zeaxanthin, and meso-zeaxanthin could, via daily supplementation, provide a dietary means of benefit., Methods: A total of 59 young healthy subjects participated in a 12-month, double-blind, placebo-controlled trial to evaluate the effects of MC supplementation on blood cortisol, psychological stress ratings, behavioural measures of mood, and symptoms of sub-optimal health. Subjects were randomly assigned to one of three groups: placebo, 13 mg, or 27 mg / day total MCs. All parameters were assessed at baseline, 6 months, and 12 months. Serum MCs were determined via HPLC, serum cortisol via ELISA, and macular pigment optical density (MPOD) via customized heterochromatic flicker photometry. Behavioural data were obtained via questionnaire., Results: Significant baseline correlations were found between MPOD and Beck anxiety scores (r = -0.28; P = 0.032), MPOD and Brief Symptom Inventory scores (r = 0.27; P = 0.037), and serum cortisol and psychological stress scores (r = 0.46; P < 0.001). Supplementation for 6 months improved psychological stress, serum cortisol, and measures of emotional and physical health (P < 0.05 for all), versus placebo. These outcomes were either maintained or improved further at 12 months., Conclusions: Supplementation with the MCs significantly reduces stress, cortisol, and symptoms of sub-optimal emotional and physical health. Determining the basis for these effects, whether systemic or a more central (i.e. brain) is a question that warrants further study.
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- 2018
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13. Chondroitin Sulfate Glycosaminoglycan Matrices Promote Neural Stem Cell Maintenance and Neuroprotection Post-Traumatic Brain Injury.
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Betancur MI, Mason HD, Alvarado-Velez M, Holmes PV, Bellamkonda RV, and Karumbaiah L
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There are currently no effective treatments for moderate-to-severe traumatic brain injuries (TBIs). The paracrine functions of undifferentiated neural stem cells (NSCs) are believed to play a significant role in stimulating the repair and regeneration of injured brain tissue. We therefore hypothesized that fibroblast growth factor (FGF2) enriching chondroitin sulfate glycosaminoglycan (CS-GAG) matrices can maintain the undifferentiated state of neural stem cells (NSCs) and facilitate brain tissue repair subacutely post-TBI. Rats subjected to a controlled cortical impactor (CCI) induced TBI were intraparenchymally injected with CS-GAG matrices alone or with CS-GAG matrices containing PKH26GL labeled allogeneic NSCs. Nissl staining of brain tissue 4 weeks post-TBI demonstrated the significantly enhanced ( p < 0.05) tissue protection in CS-GAG treated animals when compared to TBI only control, and NSC only treated animals. CS-GAG-NSC treated animals demonstrated significantly enhanced ( p < 0.05) FGF2 retention, and maintenance of PKH26GL labeled NSCs as indicated by enhanced Sox1+ and Ki67+ cell presence over other differentiated cell types. Lastly, all treatment groups and sham controls exhibited a significantly ( p < 0.05) attenuated GFAP+ reactive astrocyte presence in the lesion site when compared to TBI only controls., Competing Interests: Notes The authors declare no competing financial interest.
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- 2017
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14. Appendix G: Vitrification of Blastocysts Using VitriBlast TM and ThermoBlast TM : Nidacon.
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Laessker AN, Hardarsson T, Forsberg AS, Mukaida T, and Holmes PV
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- Animals, Female, Humans, Blastocyst cytology, Cryopreservation methods, Cryoprotective Agents, Vitrification
- Abstract
This appendix describes the vitrification of blastocysts using VitriBlast™ (VBK) and ThermoBlast™ (TBK) from Nidacon, Mölndal, Sweden. The technique used and the reason for not including DMSO in the medium at the production stage, but including it separately in the kit, and the importance of collapsing the blastocyst prior to vitrification will be explained and described.
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- 2017
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15. Pharmacological stimulation of GAL1R but not GAL2R attenuates kainic acid-induced neuronal cell death in the rat hippocampus.
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Webling K, Groves-Chapman JL, Runesson J, Saar I, Lang A, Sillard R, Jakovenko E, Kofler B, Holmes PV, and Langel Ü
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- Animals, Bradykinin pharmacology, Cell Death drug effects, Cell Line, Tumor, Cyclic AMP metabolism, Galanin pharmacology, Hippocampus drug effects, Humans, Kainic Acid toxicity, Ligands, Male, Neurons drug effects, Protein Binding, Rats, Rats, Sprague-Dawley, Receptor, Galanin, Type 1 agonists, Receptor, Galanin, Type 2 agonists, Bradykinin analogs & derivatives, Galanin analogs & derivatives, Hippocampus pathology, Neurons metabolism, Neurons pathology, Peptide Fragments pharmacology, Receptor, Galanin, Type 1 metabolism, Receptor, Galanin, Type 2 metabolism
- Abstract
The neuropeptide galanin is widely distributed in the central and peripheral nervous systems and part of a bigger family of bioactive peptides. Galanin exerts its biological activity through three G-protein coupled receptor subtypes, GAL1-3R. Throughout the last 20years, data has accumulated that galanin can have a neuroprotective effect presumably mediated through the activation of GAL1R and GAL2R. In order to test the pharmaceutical potential of galanin receptor subtype selective ligands to inhibit excitotoxic cell death, the GAL1R selective ligand M617 and the GAL2R selective ligand M1145 were compared to the novel GAL1/2R ligand M1154, in their ability to reduce the excitotoxic effects of intracerebroventricular injected kainate acid in rats. The peptide ligands were evaluated in vitro for their binding preference in a competitive (125)I-galanin receptor subtype binding assay, and G-protein signaling was evaluated using both classical signaling and a label-free real-time technique. Even though there was no significant difference in the time course or severity of the kainic acid induced epileptic behavior in vivo, administration of either M617 or M1154 before kainic acid administration significantly attenuated the neuronal cell death in the hippocampus. Our results indicate the potential therapeutic value of agonists selective for GAL1R in the prevention of neuronal cell death., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2016
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16. Regulation of neurological and neuropsychiatric phenotypes by locus coeruleus-derived galanin.
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Weinshenker D and Holmes PV
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- Animals, Humans, Locus Coeruleus anatomy & histology, Neural Pathways anatomy & histology, Neural Pathways metabolism, Neurons cytology, Neurons metabolism, Phenotype, Behavior physiology, Galanin metabolism, Locus Coeruleus metabolism
- Abstract
Decades of research confirm that noradrenergic locus coeruleus (LC) neurons are essential for arousal, attention, motivation, and stress responses. While most studies on LC transmission focused unsurprisingly on norepinephrine (NE), adrenergic signaling cannot account for all the consequences of LC activation. Galanin coexists with NE in the vast majority of LC neurons, yet the precise function of this neuropeptide has proved to be surprisingly elusive given our solid understanding of the LC system. To elucidate the contribution of galanin to LC physiology, here we briefly summarize the nature of stimuli that drive LC activity from a neuroanatomical perspective. We go on to describe the LC pathways in which galanin most likely exerts its effects on behavior, with a focus on addiction, depression, epilepsy, stress, and Alzheimer׳s disease. We propose a model in which LC-derived galanin has two distinct functions: as a neuromodulator, primarily acting via the galanin 1 receptor (GAL1), and as a trophic factor, primarily acting via galanin receptor 2 (GAL2). Finally, we discuss how the recent advances in neuropeptide detection, optogenetics and chemical genetics, and galanin receptor pharmacology can be harnessed to identify the roles of LC-derived galanin definitively. This article is part of a Special Issue entitled SI: Noradrenergic System., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2016
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17. Ethinyl estradiol and levonorgestrel alter cognition and anxiety in rats concurrent with a decrease in tyrosine hydroxylase expression in the locus coeruleus and brain-derived neurotrophic factor expression in the hippocampus.
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Simone J, Bogue EA, Bhatti DL, Day LE, Farr NA, Grossman AM, and Holmes PV
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- Animals, Behavior, Animal drug effects, Brain-Derived Neurotrophic Factor genetics, Female, Hippocampus metabolism, Learning drug effects, Locus Coeruleus metabolism, Memory drug effects, Rats, Tyrosine 3-Monooxygenase genetics, Anxiety metabolism, Brain-Derived Neurotrophic Factor metabolism, Cognition drug effects, Ethinyl Estradiol pharmacology, Hippocampus drug effects, Levonorgestrel pharmacology, Locus Coeruleus drug effects, Tyrosine 3-Monooxygenase metabolism
- Abstract
In the United States, more than ten million women use contraceptive hormones. Ethinyl estradiol and levonorgestrel have been mainstay contraceptive hormones for the last four decades. Surprisingly, there is scant information regarding their action on the central nervous system and behavior. Intact female rats received three weeks of subcutaneous ethinyl estradiol (10 or 30μg/rat/day), levonorgestrel (20 or 60μg/rat/day), a combination of both (10/20μg/rat/day and 30/60μg/rat/day), or vehicle. Subsequently, the rats were tested in three versions of the novel object recognition test to assess learning and memory, and a battery of tests for anxiety-like behavior. Serum estradiol and ovarian weights were measured. All treatment groups exhibited low endogenous 17β-estradiol levels at the time of testing. Dose-dependent effects of drug treatment manifested in both cognitive and anxiety tests. All low dose drugs decreased anxiety-like behavior and impaired performance on novel object recognition. In contrast, the high dose ethinyl estradiol increased anxiety-like behavior and improved performance in cognitive testing. In the cell molecular analyses, low doses of all drugs induced a decrease in tyrosine hydroxylase mRNA and protein in the locus coeruleus. At the same time, low doses of ethinyl estradiol and ethinyl estradiol/levonorgestrel increased galanin protein in this structure. Consistent with the findings above, the low dose treatments of ethinyl estradiol and combination ethinyl estradiol/levonorgestrel reduced brain-derived neurotrophic factor mRNA in the hippocampus. These effects of ethinyl estradiol 10μg alone and in combination with levonorgestrel 20μg suggest a diminution of norepinephrine input into the hippocampus resulting in a decline in learning and memory., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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18. The galanin receptor agonist, galnon, attenuates cocaine-induced reinstatement and dopamine overflow in the frontal cortex.
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Ogbonmwan YE, Sciolino NR, Groves-Chapman JL, Freeman KG, Schroeder JP, Edwards GL, Holmes PV, and Weinshenker D
- Subjects
- Animals, Cocaine-Related Disorders physiopathology, Cocaine-Related Disorders prevention & control, Conditioning, Operant, Dopamine metabolism, Drug-Seeking Behavior drug effects, Eating drug effects, Extinction, Psychological drug effects, Galanin antagonists & inhibitors, Male, Microdialysis, Motor Activity drug effects, Nucleus Accumbens metabolism, Rats, Sprague-Dawley, Recurrence, Reinforcement, Psychology, Self Administration, Cocaine pharmacology, Coumarins pharmacology, Dopamine Uptake Inhibitors pharmacology, Frontal Lobe metabolism
- Abstract
Relapse represents one of the most significant problems in the long-term treatment of drug addiction. Cocaine blocks plasma membrane monoamine transporters and increases dopamine (DA) overflow in the brain, and DA is critical for the motivational and primary reinforcing effects of the drug as well as cocaine-primed reinstatement of cocaine seeking in rats, a model of relapse. Thus, modulators of the DA system may be effective for the treatment of cocaine dependence. The endogenous neuropeptide galanin inhibits DA transmission, and both galanin and the synthetic galanin receptor agonist, galnon, interfere with some rewarding properties of cocaine. The purpose of this study was to further assess the effects of galnon on cocaine-induced behaviors and neurochemistry in rats. We found that galnon attenuated cocaine-induced motor activity, reinstatement and DA overflow in the frontal cortex at a dose that did not reduce baseline motor activity, stable self-administration of cocaine, baseline extracellular DA levels or cocaine-induced DA overflow in the nucleus accumbens (NAc). Similar to cocaine, galnon had no effect on stable food self-administration but reduced food-primed reinstatement. These results indicate that galnon can diminish cocaine-induced hyperactivity and relapse-like behavior, possibly in part by modulating DA transmission in the frontal cortex., (© 2014 Society for the Study of Addiction.)
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- 2015
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19. Chronic exercise dampens hippocampal glutamate overflow induced by kainic acid in rats.
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Holmes PV, Reiss JI, Murray PS, Dishman RK, and Spradley JM
- Subjects
- Animals, Disease Models, Animal, Electroencephalography, Housing, Animal, Kainic Acid, Male, Random Allocation, Rats, Sprague-Dawley, Telemetry, Glutamic Acid metabolism, Hippocampus physiopathology, Running physiology, Seizures physiopathology
- Abstract
Our laboratory has previously reported that chronic, voluntary exercise diminishes seizure-related behaviors induced by convulsant doses of kainic acid. The present experiments tested the hypothesis that exercise exerts this protective effect through a mechanism involving suppression of glutamate release in the hippocampal formation. Following three weeks of voluntary wheel running or sedentary conditions, rats were injected with 10 mg/kg of kainic acid, and hippocampal glutamate was measured in real time using a telemetric, in vivo voltammetry system. A separate experiment measured electroencephalographic (EEG) activity following kainic acid treatment. Results of the voltammetry experiment revealed that the rise in hippocampal glutamate induced by kainic acid is attenuated in exercising rats compared to sedentary controls, indicating that the exercise-induced protection against seizures involves regulation of hippocampal glutamate release. The findings reveal the potential benefit of regular exercise in the treatment and prevention of seizure disorders and suggest a possible neurobiological mechanism underlying this effect., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
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20. The effects of post-extinction exercise on cocaine-primed and stress-induced reinstatement of cocaine seeking in rats.
- Author
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Ogbonmwan YE, Schroeder JP, Holmes PV, and Weinshenker D
- Subjects
- Animals, Cocaine-Related Disorders prevention & control, Cocaine-Related Disorders psychology, Male, Motor Activity drug effects, Motor Activity physiology, Physical Conditioning, Animal physiology, Rats, Rats, Sprague-Dawley, Self Administration, Stress, Psychological complications, Behavior, Addictive prevention & control, Behavior, Addictive psychology, Cocaine administration & dosage, Extinction, Psychological physiology, Physical Conditioning, Animal psychology, Stress, Psychological psychology
- Abstract
Rationale: Voluntary aerobic exercise has shown promise as a treatment for substance abuse, reducing relapse in cocaine-dependent people. Wheel running also attenuates drug-primed and cue-induced reinstatement of cocaine seeking in rats, an animal model of relapse. However, in most of these studies, wheel access was provided throughout cocaine self-administration and/or extinction and had effects on several parameters of drug seeking. Moreover, the effects of exercise on footshock stress-induced reinstatement have not been investigated., Objectives: The purposes of this study were to isolate and specifically examine the protective effect of exercise on relapse-like behavior elicited by a drug prime or stress., Methods: Rats were trained to self-administer cocaine at a stable level, followed by extinction training. Once extinction criteria were met, rats were split into exercise (24 h, continuous access to running wheel) and sedentary groups for 3 weeks, after which, drug-seeking behavior was assessed following a cocaine prime or footshock. We also measured galanin messenger RNA (mRNA) in the locus coeruleus and A2 noradrenergic nucleus., Results: Exercising rats ran ∼4-6 km/day, comparable to levels previously reported for rats without a history of cocaine self-administration. Post-extinction exercise significantly attenuated cocaine-primed, but not footshock stress-induced, reinstatement of cocaine seeking, and increased galanin mRNA expression in the LC but not A2., Conclusion: These results indicate that chronic wheel running can attenuate some forms of reinstatement, even when initiated after the cessation of cocaine self-administration, supporting the idea that voluntary exercise programs may help maintain abstinence in clinical populations.
- Published
- 2015
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21. Galanin mediates features of neural and behavioral stress resilience afforded by exercise.
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Sciolino NR, Smith JM, Stranahan AM, Freeman KG, Edwards GL, Weinshenker D, and Holmes PV
- Subjects
- Animals, Anxiety pathology, Anxiety rehabilitation, Brain metabolism, Chromatography, High Pressure Liquid, Disease Models, Animal, Electroshock adverse effects, Enzyme-Linked Immunosorbent Assay, Exploratory Behavior drug effects, Galanin administration & dosage, Galanin agonists, Galanin analogs & derivatives, Infusions, Intraventricular, Male, Maze Learning drug effects, Microdialysis, Neurons ultrastructure, Peptide Fragments administration & dosage, Rats, Rats, Sprague-Dawley, Silver Staining, Stress, Psychological etiology, Brain pathology, Galanin metabolism, Neurons metabolism, Physical Conditioning, Animal methods, Stress, Psychological pathology, Stress, Psychological rehabilitation
- Abstract
Exercise promotes resilience to stress and increases galanin in the locus coeruleus (LC), but the question of whether changes in galanin signaling mediate the stress-buffering effects of exercise has never been addressed. To test the contributions of galanin to stress resilience, male Sprague Dawley rats received intracerebroventricular (ICV) cannulation for drug delivery and frontocortical cannulation for microdialysis, and were housed with or without a running wheel for 21d. Rats were acutely injected with vehicle or the galanin receptor antagonist M40 and exposed to a single session of either footshock or no stress. Other groups received galanin, the galanin receptor antagonist M40, or vehicle chronically for 21d prior to the stress session. Microdialysis sampling occurred during stress exposure and anxiety-related behavior was measured on the following day in the elevated plus maze. Dendritic spines were visualized by Golgi impregnation in medial prefrontal cortex (mPFC) pyramidal neurons and quantified. Exercise increased galanin levels in the LC. Under non-stressed conditions, anxiety-related behavior and dopamine levels were comparable between exercised and sedentary rats. In contrast, exposure to stress reduced open arm exploration in sedentary rats but not in exercise rats or those treated chronically with ICV galanin, indicating improved resilience. Both exercise and chronic, ICV galanin prevented the increased dopamine overflow and loss of dendritic spines observed after stress in sedentary rats. Chronic, but not acute M40 administration blocked the resilience-promoting effects of exercise. The results indicate that increased galanin levels promote features of resilience at both behavioral and neural levels., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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22. Trophic Mechanisms for Exercise-Induced Stress Resilience: Potential Role of Interactions between BDNF and Galanin.
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Holmes PV
- Abstract
Current concepts of the neurobiology of stress-related disorders, such as anxiety and depression emphasize disruptions in neural plasticity and neurotrophins. The potent trophic actions of exercise, therefore, represent not only an effective means for prevention and treatment of these disorders, they also afford the opportunity to employ exercise paradigms as a basic research tool to uncover the neurobiological mechanisms underlying these disorders. Novel approaches to studying stress-related disorders focus increasingly on trophic factor signaling in corticolimbic circuits that both mediate and regulate cognitive, behavioral, and physiological responses to deleterious stress. Recent evidence demonstrates that the neural plasticity supported by these trophic mechanisms is vital for establishing and maintaining resilience to stress. Therapeutic interventions that promote these mechanisms, be they pharmacological, behavioral, or environmental, may therefore prevent or reverse stress-related mental illness by enhancing resilience. The present paper will provide an overview of trophic mechanisms responsible for the enhancement of resilience by voluntary exercise with an emphasis on brain-derived neurotrophic factor, galanin, and interactions between these two trophic factors.
- Published
- 2014
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23. Striatal enkephalinergic differences in rats selectively bred for intrinsic running capacity.
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Monroe DC, Holmes PV, Koch LG, Britton SL, and Dishman RK
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- Animals, Enkephalins genetics, Female, Male, Nucleus Accumbens metabolism, Olfactory Tubercle metabolism, RNA, Messenger metabolism, Rats, Running physiology, Enkephalins metabolism, Motor Activity, Ventral Striatum metabolism
- Abstract
Unlabelled: Rats selectively bred for high- and low-capacity for running on a treadmill (HCR; LCR) also differ in wheel-running behavior, but whether wheel-running can be explained by intrinsic or adaptive brain mechanisms is not as yet understood. It is established that motivation of locomotory behavior is driven by dopaminergic transmission in mesolimbic and mesostriatal systems. However, whether voluntary wheel running is associated with enkephalinergic activity in the ventral striatum is not known., Materials and Methods: 40 male (20 HCR and 20 LCR) and 40 female (20 HCR and 20 LCR) rats were randomly assigned to 3 weeks of activity wheel exposure or sedentary conditions without wheel access. After 3 weeks of activity-wheel running, rats were decapitated and brains were extracted. Coronal sections were analyzed utilizing in situ hybridization histochemistry for enkephalin (ENK) mRNA in the ventral striatum., Results: HCR rats expressed less ENK than LCR rats in the nucleus accumbens among females (p<0.01) and in the olfactory tubercle among both females (p<0.05) and males (p<0.05). There was no effect of wheel running on ENK mRNA expression., Conclusion: Line differences in ENK expression in the olfactory tubercle, and possibly the nucleus accumbens, partly explain divergent wheel-running behavior. The lower striatal ENK in the HCR line is consistent with enhanced dopaminergic tone, which may explain the increased motivation for wheel running observed in the HCR line., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
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24. Antidepressant and anticonvulsant effects of exercise in a rat model of epilepsy and depression comorbidity.
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Epps SA, Kahn AB, Holmes PV, Boss-Williams KA, Weiss JM, and Weinshenker D
- Subjects
- Animals, Disease Models, Animal, Disease Susceptibility psychology, Epilepsy chemically induced, Epilepsy physiopathology, Galanin genetics, Galanin metabolism, Gene Expression Regulation physiology, Locomotion physiology, Locus Coeruleus metabolism, Male, Muscarinic Agonists toxicity, Pilocarpine toxicity, RNA, Messenger metabolism, Rats, Statistics, Nonparametric, Depression physiopathology, Depression psychology, Depression rehabilitation, Epilepsy rehabilitation, Physical Conditioning, Animal physiology, Swimming physiology
- Abstract
The bidirectional comorbidity between epilepsy and depression is associated with severe challenges for treatment efficacy and safety, often resulting in poor prognosis and outcome for the patient. We showed previously that rats selectively bred for depression-like behaviors (SwLo rats) also have increased limbic seizure susceptibility compared with their depression-resistant counterparts (SwHi rats). In this study, we examined the therapeutic efficacy of voluntary exercise in our animal model of epilepsy and depression comorbidity. We found that chronic wheel running significantly increased both struggling duration in the forced swim test and latency to pilocarpine-induced limbic motor seizure in SwLo rats but not in SwHi rats. The antidepressant and anticonvulsant effects of exercise were associated with an increase in galanin mRNA specifically in the locus coeruleus of SwLo rats. These results demonstrate the beneficial effects of exercise in a rodent model of epilepsy and depression comorbidity and suggest a potential role for galanin., (© 2013.)
- Published
- 2013
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25. Exercise offers anxiolytic potential: a role for stress and brain noradrenergic-galaninergic mechanisms.
- Author
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Sciolino NR and Holmes PV
- Subjects
- Animals, Anxiety metabolism, Physical Conditioning, Animal physiology, Rats, Stress, Psychological metabolism, Anxiety psychology, Brain metabolism, Galanin metabolism, Norepinephrine metabolism, Physical Conditioning, Animal psychology, Stress, Psychological psychology
- Abstract
Although physical activity reduces anxiety in humans, the neural basis for this response is unclear. Rodent models are essential to understand the mechanisms that underlie the benefits of exercise. However, it is controversial whether exercise exerts anxiolytic-like potential in rodents. Evidence is reviewed to evaluate the effects of wheel running, an experimental mode of exercise in rodents, on behavior in tests of anxiety and on norepinephrine and galanin systems in neural circuits that regulate stress. Stress is proposed to account for mixed behavioral findings in this literature. Indeed, running promotes an adaptive response to stress and alters anxiety-like behaviors in a manner dependent on stress. Running amplifies galanin expression in noradrenergic locus coeruleus (LC) and suppresses stress-induced activity of the LC and norepinephrine output in LC-target regions. Thus, enhanced galanin-mediated suppression of brain norepinephrine in runners is supported by current literature as a mechanism that may contribute to the stress-protective effects of exercise. These data support the use of rodents to study the emotional and neurobiological consequences of exercise., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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26. Voluntary exercise offers anxiolytic potential and amplifies galanin gene expression in the locus coeruleus of the rat.
- Author
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Sciolino NR, Dishman RK, and Holmes PV
- Subjects
- Analysis of Variance, Animals, Anxiety chemically induced, Anxiety rehabilitation, Body Weight drug effects, Carbolines toxicity, Defense Mechanisms, GABA Antagonists toxicity, Galanin genetics, Gene Expression Regulation drug effects, Immobility Response, Tonic drug effects, Immobility Response, Tonic physiology, Locomotion drug effects, Male, Maze Learning drug effects, Random Allocation, Rats, Rats, Sprague-Dawley, Anxiety pathology, Galanin metabolism, Gene Expression Regulation physiology, Locus Coeruleus metabolism, Physical Conditioning, Animal adverse effects
- Abstract
Although exercise improves anxiety in humans, it is controversial whether exercise is anxiolytic in rodents. We tested the hypothesis that stress influences the effect of exercise on anxiety-like and defensive behaviors. To explore the neurobiological mechanisms of exercise, we also examined whether exercise alters gene expression for the stress-related peptide galanin. Rats were housed in the presence or absence of a running wheel for 21 d. A subset of these rats were (1) not injected or received a single high, dose of the β-carboline FG7142 (inverse agonist at the benzodiazepine receptor site) immediately prior to testing or (2) were injected repeatedly with vehicle or FG7142 during the last 10d of exercise. On day 22, anxiety-like and defensive behaviors were measured in the elevated plus maze, shock probe defensive burying, and defensive withdrawal tests. Locus coeruleus prepro-galanin mRNA was measured by in situ hybridization. Exercise and sedentary rats that were not injected exhibited similar behavior in all tests, whereas FG7142 injected immediately prior to the test battery produced intense avoidance and immobility consistent with an anxiety-like response. However, exercise produced anxiolytic-like and active defensive behaviors in the test battery relative to the sedentary condition in rats injected repeatedly with vehicle or FG7142. Exercise also increased prepro-galanin mRNA in the locus coeruleus relative to sedentary controls. These data suggest that the emergence of enhanced adaptive behavior after chronic voluntary exercise is influenced by stress. Our data support a role for galanin in the beneficial consequences of wheel running., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2012
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27. Changes in mRNA levels for brain-derived neurotrophic factor after wheel running in rats selectively bred for high- and low-aerobic capacity.
- Author
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Groves-Chapman JL, Murray PS, Stevens KL, Monroe DC, Koch LG, Britton SL, Holmes PV, and Dishman RK
- Subjects
- Age Factors, Animals, Brain-Derived Neurotrophic Factor genetics, CA1 Region, Hippocampal metabolism, Exercise Tolerance genetics, Male, Physical Conditioning, Animal methods, RNA, Messenger biosynthesis, Rats, Rats, Sprague-Dawley, Brain-Derived Neurotrophic Factor metabolism, Breeding methods, Motor Activity genetics, Physical Conditioning, Animal physiology, RNA, Messenger metabolism, Running physiology
- Abstract
We evaluated levels of exercise-induced brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) within the hippocampal formation in rats selectively bred for 1) high intrinsic (i.e., untrained) aerobic capacity (High Capacity Runners, HCR), 2) low intrinsic aerobic capacity (Low Capacity Runners, LCR), and 3) unselected Sprague-Dawley (SD) rats with or without free access to running wheels for 3 weeks. The specific aim of the study was to determine whether a dose-response relationship exists between cumulative running distance and levels of BDNF mRNA. No additional treatments or behavioral manipulations were used. HCR, LCR, and SD rats were grouped by strain and randomly assigned to sedentary or activity (voluntary access to activity wheel) conditions. Animals were killed after 21 days of exposure to the assigned conditions. Daily running distances (mean ± standard deviation meters/day) during week three were: HCR (4726 ± 3220), SD (2293 ± 3461), LCR (672 ± 323). Regardless of strain, levels of BDNF mRNA in CA1 were elevated in wheel runners compared to sedentary rats and this difference persisted after adjustment for age (p=0.040). BDNF mRNA was not affected by intrinsic aerobic capacity and was not related to total running distance. The results support that BDNF mRNA expression is increased by unlimited access to activity wheel running for 3 weeks but is not dependent upon accumulated running distance., (Copyright © 2011 Elsevier B.V. All rights reserved.)
- Published
- 2011
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28. The importance of corticosterone in mediating restraint-induced weight loss in rats.
- Author
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Scherer IJ, Holmes PV, and Harris RB
- Subjects
- Adrenalectomy, Analysis of Variance, Animals, Corticosterone administration & dosage, Corticotropin-Releasing Hormone genetics, Corticotropin-Releasing Hormone metabolism, Gene Expression Regulation drug effects, Gene Expression Regulation physiology, Male, Paraventricular Hypothalamic Nucleus drug effects, Paraventricular Hypothalamic Nucleus metabolism, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Stress, Physiological physiology, Time Factors, Corticosterone metabolism, Restraint, Physical methods, Weight Loss physiology
- Abstract
I. J. Scherer, P. V. Holmes, R. B.S. Harris. The importance of corticosterone in mediating restraint-induced weight loss in rats. PHYSIOL BEHAV 00 (0) 000-000, 2010. Rats restrained for 3 h/day for 3d ays (RR) lose weight and do not return to the weight of non-restrained controls once restraint has ended. This study tested the importance of restraint-induced corticosterone release in mediating the change in body weight by injecting ADX rats with 2.0mg corticosterone/kg before each restraint to replicate the restraint-induced surge in circulating corticosterone. Restrained adrenalectomized (ADX) rats injected with corticosterone had the same initial weight loss as intact restrained rats, whereas corticosterone injection in non-restrained ADX rats and restraint of ADX rats injected with saline each produced only half as much initial weight loss. Sustained weight loss, measured for 14 days after the end of RR, was the same for restrained intact rats and restrained ADX rats injected with corticosterone whereas restrained ADX rats injected with saline achieved the same weight gain as their controls. Corticosterone injections had no effect on weight gain of non-restrained intact rats. In situ hybridization showed that corticotropin releasing factor (CRF) mRNA expression in the paraventricular nucleus of the hypothalamus (PVN) was increased by the same degree in ADX rats and restrained intact rats and was not modified by corticosterone injections. There was no significant effect of restraint, ADX or corticosterone injection on PVN arginine vasopressin (AVP) mRNA expression. These data indicate that a surge in corticosterone causes sustained weight loss in ADX rats through a mechanism that can be compensated for in intact rats and is independent of changes in PVN CRF or AVP mRNA expression., (Copyright © 2010 Elsevier Inc. All rights reserved.)
- Published
- 2011
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29. An overview of brain-derived neurotrophic factor and implications for excitotoxic vulnerability in the hippocampus.
- Author
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Murray PS and Holmes PV
- Abstract
The present paper examines the nature and function of brain-derived neurotrophic factor (BDNF) in the hippocampal formation and the consequences of changes in its expression. The paper focuses on literature describing the role of BDNF in hippocampal development and neuroplasticity. BDNF expression is highly sensitive to developmental and environmental factors, and increased BDNF signaling enhances neurogenesis, neurite sprouting, electrophysiological activity, and other processes reflective of a general enhancement of hippocampal function. Such increases in activity may mediate beneficial effects such as enhanced learning and memory. However, the increased activity also comes at a cost: BDNF plasticity renders the hippocampus more vulnerable to hyperexcitability and/or excitotoxic damage. Exercise dramatically increases hippocampal BDNF levels and produces behavioral effects consistent with this phenomenon. In analyzing the literature regarding exercise-induced regulation of BDNF, this paper provides a theoretical model for how the potentially deleterious consequences of BDNF plasticity may be modulated by other endogenous factors. The peptide galanin may play such a role by regulating hippocampal excitability.
- Published
- 2011
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30. Locus coeruleus galanin expression is enhanced after exercise in rats selectively bred for high capacity for aerobic activity.
- Author
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Murray PS, Groves JL, Pettett BJ, Britton SL, Koch LG, Dishman RK, and Holmes PV
- Subjects
- Animals, Female, In Situ Hybridization, Male, Rats, Rats, Sprague-Dawley, Running, Tyrosine 3-Monooxygenase genetics, Galanin genetics, Locus Coeruleus metabolism
- Abstract
The neuropeptide galanin extensively coexists with norepinephrine in locus coeruleus (LC) neurons. Previous research in this laboratory has demonstrated that unlimited access to activity wheels in the home cage increases mRNA for galanin (GAL) in the LC, and that GAL mediates some of the beneficial effects of exercise on brain function. To assess whether capacity for aerobic exercise modulates this upregulation in galanin mRNA, three heterogeneous rat models were tested: rats selectively bred for (1) high intrinsic (untrained) aerobic capacity (High Capacity Runners, HCR) and (2) low intrinsic aerobic capacity (Low Capacity Runners, LCR) and (3) unselected Sprague-Dawley (SD) rats with and without free access to running wheels for 3 weeks. Following this exercise protocol, mRNA for tyrosine hydroxylase (TH) and GAL was measured in the LC. The wheel running distances between the three models were significantly different, and age contributed as a significant covariate. Both selection and wheel access condition significantly affected GAL mRNA expression, but not TH mRNA expression. GAL was elevated in exercising HCR and SD rats compared to sedentary rats while LCR rats did not differ between conditions. Overall running distance significantly correlated with GAL mRNA expression, but not with TH mRNA expression. No strain differences in GAL or TH gene expression were observed in sedentary rats. Thus, intrinsic aerobic running capacity influences GAL gene expression in the LC only insofar as actual running behavior is concerned; aerobic capacity does not influence GAL expression in addition to changes associated with running., (Copyright © 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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31. Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine β-hydroxylase.
- Author
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Schroeder JP, Cooper DA, Schank JR, Lyle MA, Gaval-Cruz M, Ogbonmwan YE, Pozdeyev N, Freeman KG, Iuvone PM, Edwards GL, Holmes PV, and Weinshenker D
- Subjects
- Animals, Brain drug effects, Brain metabolism, Cocaine administration & dosage, Cocaine antagonists & inhibitors, Dopamine metabolism, Drug Interactions, Food, Imidazoles pharmacology, Male, Norepinephrine metabolism, Rats, Rats, Sprague-Dawley, Self Administration, Thiones pharmacology, Alcohol Deterrents pharmacology, Cocaine pharmacology, Conditioning, Operant drug effects, Disulfiram pharmacology, Dopamine beta-Hydroxylase antagonists & inhibitors, Extinction, Psychological drug effects
- Abstract
The antialcoholism medication disulfiram (Antabuse) inhibits aldehyde dehydrogenase (ALDH), which results in the accumulation of acetaldehyde upon ethanol ingestion and produces the aversive 'Antabuse reaction' that deters alcohol consumption. Disulfiram has also been shown to deter cocaine use, even in the absence of an interaction with alcohol, indicating the existence of an ALDH-independent therapeutic mechanism. We hypothesized that disulfiram's inhibition of dopamine β-hydroxylase (DBH), the catecholamine biosynthetic enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons, underlies the drug's ability to treat cocaine dependence. We tested the effects of disulfiram on cocaine and food self-administration behavior and drug-primed reinstatement of cocaine seeking in rats. We then compared the effects of disulfiram with those of the selective DBH inhibitor, nepicastat. Disulfiram, at a dose (100 mg/kg, i.p.) that reduced brain NE by ∼40%, did not alter the response for food or cocaine on a fixed ratio 1 schedule, whereas it completely blocked cocaine-primed (10 mg/kg, i.p.) reinstatement of drug seeking following extinction. A lower dose of disulfiram (10 mg/kg) that did not reduce NE had no effect on cocaine-primed reinstatement. Nepicastat recapitulated the behavioral effects of disulfiram (100 mg/kg) at a dose (50 mg/kg, i.p.) that produced a similar reduction in brain NE. Food-primed reinstatement of food seeking was not impaired by DBH inhibition. Our results suggest that disulfiram's efficacy in the treatment of cocaine addiction is associated with the inhibition of DBH and interference with the ability of environmental stimuli to trigger relapse.
- Published
- 2010
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32. A role for 2-arachidonoylglycerol and endocannabinoid signaling in the locomotor response to novelty induced by olfactory bulbectomy.
- Author
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Eisenstein SA, Clapper JR, Holmes PV, Piomelli D, and Hohmann AG
- Subjects
- Animals, Autoradiography, Chromatography, High Pressure Liquid, Cyclohexanols, Densitometry, Dopamine physiology, Environment, Limbic System physiology, Lipid Metabolism physiology, Male, Mass Spectrometry, Piperidines pharmacology, Pyrazoles pharmacology, Radiopharmaceuticals, Rats, Rats, Sprague-Dawley, Receptor, Cannabinoid, CB1 physiology, Rimonabant, Arachidonic Acids physiology, Cannabinoid Receptor Modulators physiology, Endocannabinoids, Glycerides physiology, Motor Activity physiology, Olfactory Bulb physiology, Signal Transduction physiology
- Abstract
Bilateral olfactory bulbectomy (OBX) in rodents produces behavioral and neurochemical changes associated clinically with depression and schizophrenia. Most notably, OBX induces hyperlocomotion in response to the stress of exposure to a novel environment. We examined the role of the endocannabinoid system in regulating this locomotor response in OBX and sham-operated rats. In our study, OBX-induced hyperactivity was restricted to the first 3 min of the open field test, demonstrating the presence of novelty (0-3 min) and habituation (3-30 min) phases of the open field locomotor response. Levels of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide were decreased in the ventral striatum, a brain region deafferented by OBX, whereas cannabinoid receptor densities were unaltered. In sham-operated rats, 2-AG levels in the ventral striatum were negatively correlated with distance traveled during the novelty phase. Thus, low levels of 2-AG are reflected in a hyperactive open field response. This correlation was not observed in OBX rats. Conversely, 2-AG levels in endocannabinoid-compromised OBX rats correlated with distance traveled during the habituation phase. In OBX rats, pharmacological blockade of cannabinoid CB(1) receptors with either AM251 (1 mg kg(-1) i.p.) or rimonabant (1 mg kg(-1) i.p.) increased distance traveled during the habituation phase. Thus, blockade of endocannabinoid signaling impairs habituation of the hyperlocomotor response in OBX, but not sham-operated, rats. By contrast, in sham-operated rats, effects of CB(1) antagonism were restricted to the novelty phase. These findings suggest that dysregulation in the endocannabinoid system, and 2-AG in particular, is implicated in the hyperactive locomotor response induced by OBX. Our studies suggest that drugs that enhance 2-AG signaling, such as 2-AG degradation inhibitors, might be useful in human brain disorders modeled by OBX., ((c) 2010. Published by Elsevier Ltd.)
- Published
- 2010
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33. Endocannabinoid modulation of amphetamine sensitization is disrupted in a rodent model of lesion-induced dopamine dysregulation.
- Author
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Eisenstein SA, Holmes PV, and Hohmann AG
- Subjects
- Amidohydrolases drug effects, Amidohydrolases metabolism, Animals, Benzamides pharmacology, Carbamates pharmacology, Dopamine metabolism, Enzyme Inhibitors pharmacology, Exploratory Behavior drug effects, Male, Motor Activity drug effects, Motor Activity physiology, Olfactory Bulb metabolism, Rats, Rats, Sprague-Dawley, Receptor, Cannabinoid, CB1 metabolism, Amphetamine pharmacology, Cannabinoid Receptor Modulators metabolism, Central Nervous System Stimulants pharmacology, Endocannabinoids, Olfactory Bulb surgery
- Abstract
We tested the hypothesis that increased dopaminergic sensitivity induced by olfactory bulbectomy is mediated by dysregulation of endocannabinoid signaling. Bilateral olfactory bulbectomy induces behavioral and neurobiological symptomatology related to increased dopaminergic sensitivity. Rats underwent olfactory bulbectomy or sham operations and were assessed 2 weeks later in two tests of hyperdopaminergic responsivity: locomotor response to novelty and locomotor sensitization to amphetamine. Amphetamine (1 mg/kg i.p.) was administered to rats once daily for 8 consecutive days to induce locomotor sensitization. URB597, an inhibitor of the anandamide hydrolyzing enzyme fatty-acid amide hydrolase (FAAH), was administered daily (0.3 mg/kg i.p.) to sham and olfactory bulbectomized (OBX) rats to investigate the impact of FAAH inhibition on locomotor sensitization to amphetamine. Pharmacological specificity was evaluated with the CB(1) antagonist/inverse agonist rimonabant (1 mg/kg i.p). OBX rats exhibited heightened locomotor activity in response to exposure either to a novel open field or to amphetamine administration relative to sham-operated rats. URB597 produced a CB(1)-mediated attenuation of amphetamine-induced locomotor sensitization in sham-operated rats. By contrast, URB597 failed to inhibit amphetamine sensitization in OBX rats. The present results demonstrate that enhanced endocannabinoid transmission attenuates development of amphetamine sensitization in intact animals but not in animals with OBX-induced dopaminergic dysfunction. Our data collectively suggest that the endocannabinoid system is compromised in olfactory bulbectomized rats.
- Published
- 2009
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34. Effects of exercise on male copulatory behavior after beta-adrenoreceptor blockade.
- Author
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Thom NJ, Holmes PV, and Dishman RK
- Subjects
- Analysis of Variance, Animals, Body Weight, Catheterization, Ejaculation drug effects, Ejaculation physiology, Galanin metabolism, In Situ Hybridization, Male, Propranolol pharmacology, RNA, Messenger metabolism, Random Allocation, Rats, Rats, Long-Evans, Receptors, Adrenergic, beta metabolism, Sexual Behavior, Animal drug effects, Sexual Behavior, Animal physiology, Time Factors, Adrenergic beta-Antagonists pharmacology, Copulation drug effects, Copulation physiology, Physical Conditioning, Animal physiology, Preoptic Area drug effects, Preoptic Area physiology
- Abstract
Unlabelled: Chronic activity-wheel running enhances male copulation and is associated with brain noradrenergic adaptations that may be modulated by the neuropeptide galanin (GAL). When injected into the medial pre-optic area (MPOA) of the hypothalamus, norepinephrine facilitates, and the beta-adrenoreceptor antagonist propranolol inhibits, male copulation. The present experiment tested whether chronic exercise mitigates copulatory decrements induced by adrenergic blockade in the MPOA. It was hypothesized that 3 weeks of activity-wheel running would (1) reverse deficits in male copulatory performance and (2) increase GAL mRNA in the MPOA after beta-adrenoreceptor blockade with propranolol., Materials and Methods: Long-Evans male rats were randomly assigned to three experimental groups: sedentary/propranolol, activity-wheel/propranolol, and home-cage control. Animals were chronically administered propranolol in saline vehicle (6 microm/day) via an osmotic mini-pump connected to a cannula implanted into the third ventricle. After 3 weeks of activity-wheel running, rats underwent copulatory testing. After rapid decapitation 24h later, rat brains were analyzed utilizing in situ hybridization histochemistry for GAL mRNA in the MPOA., Results: Chronic exercise mitigated reductions in the percentage of males that intromitted and ejaculated after propranolol treatment, but there was no effect of exercise on GAL mRNA., Conclusion: The findings are consistent with noradrenergic adaptations in the MPOA that facilitate male copulation after wheel running independently of GAL mRNA expression.
- Published
- 2009
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35. Chronic activity wheel running reduces the severity of kainic acid-induced seizures in the rat: possible role of galanin.
- Author
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Reiss JI, Dishman RK, Boyd HE, Robinson JK, and Holmes PV
- Subjects
- Analysis of Variance, Animals, Autoradiography, Catheterization, Dose-Response Relationship, Drug, Galanin administration & dosage, Galanin antagonists & inhibitors, Hippocampus drug effects, Hippocampus physiopathology, In Situ Hybridization, Injections, Intraperitoneal, Injections, Intraventricular, Kainic Acid, Male, Peptide Fragments administration & dosage, Proto-Oncogene Proteins c-fos metabolism, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Seizures chemically induced, Galanin metabolism, Motor Activity, Physical Conditioning, Animal physiology, Seizures physiopathology
- Abstract
Studies in both humans and rodents suggest that exercise can be neuroprotective, but the mechanisms by which this occurs are still poorly understood. Three weeks of voluntary, physical activity in rats upregulates prepro-galanin messenger RNA levels in the locus coeruleus. Galanin is a neuropeptide extensively coexisting with norepinephrine that decreases neuronal hyperexcitability both in vivo and in vitro. Thus, exercise may diminish neural hyperexcitability through a galaninergic mechanism. The current experiments tested whether voluntary activity wheel running would protect against kainic acid-evoked seizures and whether galaninergic signaling is a necessary factor in this protection. In experiment 1, rats were given access to running wheels or remained sedentary for three weeks. After this period, rats received an intraperitoneal (i.p.) injection of 0, 7, 10 or 14 mg/kg kainic acid. Exercise decreased the severity of or eliminated seizure behaviors and hippocampal c-fos expression induced by kainic acid. In experiment 2, exercising or sedentary rats were injected intracerebroventricularly (i.c.v.) with 0.2 or 0.4 microg of kainic acid following either an injection of M-40 (a galanin receptor antagonist) or saline. Exercise decreased kainic acid-induced seizures at the 0.2 microg dose, and M-40 (6 nmol) decreased this effect. In contrast, there were no detectable differences between exercising and sedentary rats in behavior at the 0.4 microg dose. The results suggest that the protective effects of exercise against seizures are at least partially mediated by regulation of neural excitability through a process involving galanin.
- Published
- 2009
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36. Intracerebroventricular administration of galanin or galanin receptor subtype 1 agonist M617 induces c-Fos activation in central amygdala and dorsomedial hypothalamus.
- Author
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Blackshear A, Yamamoto M, Anderson BJ, Holmes PV, Lundström L, Langel U, and Robinson JK
- Subjects
- Amygdala metabolism, Analysis of Variance, Animals, Dorsomedial Hypothalamic Nucleus metabolism, Galanin administration & dosage, Immunohistochemistry, Injections, Intraventricular, Male, Rats, Rats, Sprague-Dawley, Amygdala drug effects, Dorsomedial Hypothalamic Nucleus drug effects, Galanin pharmacology, Proto-Oncogene Proteins c-fos metabolism, Receptor, Galanin, Type 1 agonists
- Abstract
The neuropeptide galanin and galanin receptors are widespread throughout cortical, limbic and midbrain areas implicated in reward, learning/memory, pain, drinking and feeding. While many studies have shown that galanin produces a variety of presynaptic and post-synaptic responses, work studying the effects of galanin on neural activation is limited. The present study examined patterns of c-Fos immunoreactivity resulting from intracerebroventricular administration of galanin versus saline injection in awake rats. An initial comprehensive qualitative survey was conducted to identify regions of high c-Fos expression followed up with quantitative analysis. Galanin induced a significant increase in c-Fos levels relative to saline-treated controls in dorsomedial hypothalamus and in the central nucleus of the amygdala. This pattern of activation was also produced by galanin receptor type 1 agonist M617. The present findings confirm that galanin upregulates c-Fos activation in hypothalamic nuclei, and supports roles for galanin in central amygdala-mediated regulation of stress-responses, food intake, and Pavlovian conditioning.
- Published
- 2007
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37. Chronic and voluntary exercise enhances learning of conditioned place preference to morphine in rats.
- Author
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Eisenstein SA and Holmes PV
- Subjects
- Animals, Brain-Derived Neurotrophic Factor genetics, Dose-Response Relationship, Drug, Drug Tolerance, Galanin genetics, Hippocampus drug effects, Hippocampus metabolism, Locus Coeruleus drug effects, Locus Coeruleus metabolism, Male, Morphine administration & dosage, Protein Precursors genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Sucrose administration & dosage, Conditioning, Psychological drug effects, Conditioning, Psychological physiology, Morphine pharmacology, Motor Activity physiology
- Abstract
Previous research has shown that brief and intermittent activity wheel running attenuates conditioned place preference (CPP) to morphine in rats, which suggests that exercise may produce a cross-tolerance to opiates. On the other hand, a different exercise paradigm, chronic and voluntary wheel running, enhances learning in contextual conditioning tasks. The present experiments tested CPP to 2.5, 5, and 7.5 mg/kg morphine in sedentary rats and rats provided free access to running wheels for three weeks. Sucrose preference was also tested to determine exercise's influence on appetitive processes. Levels of mRNA encoding brain-derived neurotrophic factor and preprogalanin mRNA were quantified using in situ hybridization. In rats that exhibited CPP to morphine, exercising rats spent significantly more time per entry in the morphine-paired chamber during the CPP test. CPP to morphine was dose-dependent. The expression of hippocampal brain-derived neurotrophic factor (BDNF) was greater in exercising rats compared to the sedentary group. Preprogalanin (GAL) mRNA expression in the locus coeruleus (LC) was positively correlated with mean distance run. These results suggest that while chronic exercise may produce cross-tolerance to opioids, exercise-induced enhancement of associative learning caused by exercise may override this effect in the conditioned place preference procedure.
- Published
- 2007
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38. Voluntary exercise and clomipramine treatment elevate prepro-galanin mRNA levels in the locus coeruleus in rats.
- Author
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Holmes PV, Yoo HS, and Dishman RK
- Subjects
- Animals, Antidepressive Agents, Tricyclic administration & dosage, Clomipramine administration & dosage, Galanin genetics, Humans, Male, Protein Precursors genetics, Rats, Rats, Sprague-Dawley, Antidepressive Agents, Tricyclic metabolism, Clomipramine metabolism, Galanin metabolism, Locus Coeruleus metabolism, Physical Conditioning, Animal, Protein Precursors metabolism, RNA, Messenger metabolism
- Abstract
Exercise exerts antidepressant effects in humans and rodent models of affective disorders. These effects may be mediated by the upregulation of endogenous factors that exert antidepressant actions. The physiological functions and behavioral actions of the neuropeptide galanin (GAL) suggest antidepressant activity. Previous studies have shown that various modes of exercise elevate GAL gene expression in the locus coeruleus (LC) in rats. The present experiments examined the interaction between voluntary exercise and antidepressant pharmacotherapy. Male Sprague-Dawley rats were provided access to activity wheels (exercise condition) or inoperative wheels (sedentary condition) for 28 days. Rats in each group were injected with clomipramine (10mg/kg/day) or vehicle throughout this period (for 3 weeks). Prepro-GAL mRNA in the LC was measured by in situ hybridization histochemistry. Exercise and clomipramine treatment significantly elevated GAL gene expression, though prepro-GAL mRNA levels in rats receiving both interventions did not differ from sedentary controls that received vehicle. Prepro-GAL mRNA levels were significantly correlated with running distance. The results further implicate a role for GAL in the antidepressant effects of exercise and pharmacotherapy, though the mechanisms through which these treatments influence GAL gene expression appear to differ significantly.
- Published
- 2006
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39. An endocannabinoid mechanism for stress-induced analgesia.
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Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini A, Mor M, Tarzia G, and Piomelli D
- Subjects
- Animals, Arachidonic Acids biosynthesis, Arachidonic Acids metabolism, Biological Transport drug effects, Biphenyl Compounds pharmacology, Cannabinoid Receptor Modulators biosynthesis, Glycerides biosynthesis, Glycerides metabolism, Hydrolysis drug effects, In Vitro Techniques, Male, Mesencephalon drug effects, Mesencephalon metabolism, Monoacylglycerol Lipases antagonists & inhibitors, Monoacylglycerol Lipases metabolism, Polyunsaturated Alkamides, Rats, Rats, Sprague-Dawley, Rats, Wistar, Receptor, Cannabinoid, CB1 antagonists & inhibitors, Receptor, Cannabinoid, CB1 metabolism, Analgesia, Cannabinoid Receptor Modulators metabolism, Endocannabinoids, Stress, Physiological physiopathology
- Abstract
Acute stress suppresses pain by activating brain pathways that engage opioid or non-opioid mechanisms. Here we show that an opioid-independent form of this phenomenon, termed stress-induced analgesia, is mediated by the release of endogenous marijuana-like (cannabinoid) compounds in the brain. Blockade of cannabinoid CB(1) receptors in the periaqueductal grey matter of the midbrain prevents non-opioid stress-induced analgesia. In this region, stress elicits the rapid formation of two endogenous cannabinoids, the lipids 2-arachidonoylglycerol (2-AG) and anandamide. A newly developed inhibitor of the 2-AG-deactivating enzyme, monoacylglycerol lipase, selectively increases 2-AG concentrations and, when injected into the periaqueductal grey matter, enhances stress-induced analgesia in a CB1-dependent manner. Inhibitors of the anandamide-deactivating enzyme fatty-acid amide hydrolase, which selectively elevate anandamide concentrations, exert similar effects. Our results indicate that the coordinated release of 2-AG and anandamide in the periaqueductal grey matter might mediate opioid-independent stress-induced analgesia. These studies also identify monoacylglycerol lipase as a previously unrecognized therapeutic target.
- Published
- 2005
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40. Area postrema-lesions increase operant responding to sucrose in rats.
- Author
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Miller CC, Holmes PV, Garrett JL, and Edwards GL
- Subjects
- Administration, Oral, Animals, Male, Rats, Rats, Sprague-Dawley, Area Postrema physiopathology, Area Postrema surgery, Conditioning, Operant, Drinking Behavior, Eating, Sucrose administration & dosage
- Abstract
Rats with lesions of the area postrema (APX) are known to exhibit an enhanced intake of highly palatable foods such as sweetened condensed milk and cookies. These observations suggest the possibility that APX rats find these foods more rewarding and will work harder to obtain these foods. Sham and APX rats were tested on fixed ratio (FR) and progressive ratio (PR) schedules. APX rats consistently pressed more times to receive sucrose solution and attained both FR 3 and FR 5 criteria significantly faster than sham-lesioned control rats. Furthermore, rats with APX had significantly higher break points than sham-lesioned control rats on a progressive ratio schedule. These results support the hypothesis that rats with lesions of the area postrema will consistently work harder to obtain a highly palatable food reward.
- Published
- 2005
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41. Effects of beta-adrenoreceptor blockade during chronic exercise on contextual fear conditioning and mRNA for galanin and brain-derived neurotrophic factor.
- Author
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Van Hoomissen JD, Holmes PV, Zellner AS, Poudevigne A, and Dishman RK
- Subjects
- Analysis of Variance, Animals, Autoradiography methods, Behavior, Animal, Brain-Derived Neurotrophic Factor genetics, Corticosterone blood, Electroshock adverse effects, Freezing Reaction, Cataleptic drug effects, Galanin genetics, Gene Expression Regulation drug effects, In Situ Hybridization methods, Male, Motor Activity drug effects, RNA, Messenger metabolism, Radioimmunoassay methods, Rats, Rats, Long-Evans, Running, Time Factors, Adrenergic beta-Antagonists pharmacology, Brain-Derived Neurotrophic Factor metabolism, Conditioning, Psychological drug effects, Fear, Galanin metabolism, Propranolol pharmacology
- Abstract
The authors examined the effects of activity wheel running (AWR) and propranolol on contextual fear conditioning (CFC) and messenger RNA (mRNA) for galanin (GAL) in the locus coeruleus (LC) and brain-derived neurotrophic factor (BDNF) in the hippocampal formation (HF) in rats. Freezing behavior during the testing session of the CFC protocol was elevated in the AWR-placebo group compared to sedentary-placebo and AWR-propranolol groups. AWR increased GAL mRNA in the LC. CFC increased BDNF mRNA in the HF. These results suggest that exercise enhances CFC and that antagonism of the beta-adrenoreceptors attenuates this effect. The exercise-related induction of GAL gene expression in the LC may influence noradrenergic transmission to facilitate CFC.
- Published
- 2004
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42. Effects of chronic activity wheel running and imipramine on masculine copulatory behavior after olfactory bulbectomy.
- Author
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Chambliss HO, Van Hoomissen JD, Holmes PV, Bunnell BN, and Dishman RK
- Subjects
- Animals, Copulation drug effects, Food Preferences drug effects, Food Preferences physiology, Male, Rats, Rats, Long-Evans, Sexual Behavior, Animal drug effects, Sucrose pharmacology, Antidepressive Agents, Tricyclic pharmacology, Copulation physiology, Imipramine pharmacology, Motor Activity physiology, Olfactory Bulb physiology, Sexual Behavior, Animal physiology
- Abstract
We examined the effects of chronic activity wheel running and imipramine administration on appetitive behavior after olfactory bulbectomy (OBX). Male Long-Evans rats were randomly assigned to the following conditions using a 2 x 2 x 2 design: (1) bilateral OBX or sham surgery, (2) voluntary activity wheel running or sedentary home cage, and (3) daily imipramine or saline injections. After 21 days of treatment, animals underwent behavioral testing for copulatory activity and sucrose preference. Bulbectomized animals exhibited decrements in copulatory performance and reductions in sucrose intake compared to sham animals. Within the bulbectomized groups, imipramine-treated rats either did not copulate or had reduced ejaculation frequencies. However, activity wheel running attenuated the copulatory deficits induced by OBX. The findings encourage studies of physical activity and male sexual dysfunction among depressed men being treated by pharmacotherapy., (Copyright 2004 Elsevier Inc.)
- Published
- 2004
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43. Reduced senescence and retained nuclear DNA integrity in human spermatozoa prepared by density gradient centrifugation.
- Author
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Morrell JM, Moffatt O, Sakkas D, Manicardi GC, Bizzaro D, Tomlinson M, Nilsson H, and Holmes PV
- Subjects
- Adult, Cell Separation methods, Cell Survival, Centrifugation, Density Gradient methods, Humans, Male, Semen Preservation, Sperm Motility, Spermatozoa cytology, Cell Nucleus ultrastructure, Cellular Senescence physiology, DNA analysis, Spermatozoa physiology
- Abstract
Purpose: To investigate whether removal of extraneous cells and immotile spermatozoa from a sperm preparation by density gradient centrifugation could help to maintain normal spermatozoa in a viable state and retain their deoxyribonucleic acid integrity., Methods: Sperm motility was assessed on a daily basis in aliquots of neat semen, extended semen, and spermatozoa prepared on a PureSperm density gradient. At the same time, aliquots of each sperm sample were preserved for TUNEL assay and nick translation., Results: Spermatozoa prepared using density gradient centrifugation survived three times as long as spermatozoa in neat semen or in extended semen. Both deoxyribonucleic acid integrity and sperm motility were retained in the gradient preparations., Conclusions: Preparing spermatozoa by density gradient centrifugation is advantageous in prolonging sperm survival and maintaining deoxyribonucleic acid integrity, presumably by removing sources of reactive oxygen species. Stored spermatozoa could be used for a second attempt at fertilization if oocyte immaturity was suspected.
- Published
- 2004
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44. Dopamine overflow is increased in olfactory bulbectomized rats: an in vivo microdialysis study.
- Author
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Masini CV, Holmes PV, Freeman KG, Maki AC, and Edwards GL
- Subjects
- 3,4-Dihydroxyphenylacetic Acid analysis, 3,4-Dihydroxyphenylacetic Acid metabolism, Animals, Basal Ganglia metabolism, Disease Models, Animal, Exploratory Behavior physiology, Homovanillic Acid analysis, Homovanillic Acid metabolism, Hydroxyindoleacetic Acid analysis, Hydroxyindoleacetic Acid metabolism, Male, Microdialysis, Motor Activity physiology, Norepinephrine metabolism, Olfactory Bulb surgery, Psychomotor Agitation physiopathology, Rats, Rats, Sprague-Dawley, Stress, Psychological metabolism, Basal Ganglia chemistry, Dopamine analysis, Dopamine metabolism, Norepinephrine analysis, Olfactory Bulb physiology, Psychomotor Agitation metabolism
- Abstract
Olfactory bulbectomy (OBX) in rats produces behavioral, physiological, and neurochemical changes that resemble symptoms of depression in humans. The procedure thus serves as a rodent model of affective disorder. Many of the behavioral effects of OBX resemble psychomotor agitation. The possible role of dysregulation of ventral striatal dopamine (DA) systems in this phenomenon was investigated. Basal levels of DA, norepinephrine (NE), homovanillic acid, dihydroxyphenylacetic acid, and 5-hydroxyindoleacetic acid were examined in the striatum of OBX and sham-operated controls using in vivo microdialysis. OBX rats exhibited significantly higher basal DA levels (192%) and lower NE levels (12%) than sham-operated controls. Locomotor activity in response to novelty and footshock stress was elevated in OBX rats. The finding of higher DA levels in striatum may explain this "agitation-like" behavior, a commonly observed phenomenon in the OBX model.
- Published
- 2004
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45. Herpes virus-mediated preproenkephalin gene transfer in the ventral striatum mimics behavioral changes produced by olfactory bulbectomy in rats.
- Author
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Primeaux SD, Wilson MA, Wilson SP, Guth AN, Lelutiu NB, and Holmes PV
- Subjects
- Animals, Basal Ganglia metabolism, DNA, Complementary, Enkephalins metabolism, Male, Naltrexone pharmacology, Narcotic Antagonists pharmacology, Protein Precursors metabolism, Psychomotor Agitation drug therapy, Rats, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction, Up-Regulation drug effects, Behavior, Animal, Enkephalins genetics, Gene Transfer Techniques, Herpesviridae, Olfactory Bulb surgery, Olfactory Pathways metabolism, Protein Precursors genetics, Psychomotor Agitation metabolism
- Abstract
The syndrome of behavioral, physiological, and neurochemical changes caused by ablation of the olfactory bulbs (OBX) in rats serves as a reliable and well-validated model of depression. Previous experiments have demonstrated that OBX leads to increased expression of the preproenkephalin (ENK) gene in the olfactory tubercle (OT) portion of the ventral striatum in rats. The aim of the present experiments was to investigate the role of OBX-induced ENK overexpression in the OT in the behavioral abnormalities exhibited by bulbectomized rats. A recombinant herpes virus carrying human preproENK cDNA was used to manipulate ENK gene expression in the OT of bulbectomized and sham-operated rats. Motivational deficits were assessed by the sucrose preference test, and 'agitation-like' behaviors were measured with the novel open field and footshock-induced freezing tests. ENK gene transfer in sham-operated rats mimicked some of the effects of OBX; it decreased freezing behavior in response to mild footshock and produced behavioral activation in the open field. In another experiment, virally mediated ENK gene transfer into the OT of intact rats decreased footshock-induced freezing, and this effect was reversed by naltrexone administration. PreproENK gene transfer into the OT did not produce analgesic effects in the tail-flick test. No effects on freezing behavior were observed following preproENK gene transfer into the frontal cortex. An additional experiment revealed that naltrexone administration attenuated the OBX-induced abnormality in freezing behavior. The results indicate that overexpression of the preproENK gene in the ventral striatum may mediate the 'agitation-like' behavior exhibited by bulbectomized rats.
- Published
- 2003
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46. An alternative to PVP for slowing sperm prior to ICSI.
- Author
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Balaban B, Lundin K, Morrell JM, Tjellström H, Urman B, and Holmes PV
- Subjects
- Cleavage Stage, Ovum drug effects, Electronic Data Processing, Embryonic and Fetal Development drug effects, Female, Humans, Male, Povidone pharmacology, Pregnancy, Pregnancy Rate, Hyaluronic Acid pharmacology, Sperm Injections, Intracytoplasmic, Sperm Motility drug effects, Tissue and Organ Harvesting methods
- Abstract
Background: There is a growing awareness of potential problems in exposing sperm to polyvinylpyrrolidone (PVP) to slow their motility, a procedure commonly used prior to ICSI. The study presented here evaluates an alternative product for slowing sperm motility, which contains hyaluronate, a substance found naturally in the reproductive tract., Methods: Computerized sperm motility analysis was used to compare the motilities of sperm exposed to either a PVP-containing product (ICSI-100), or a hyaluronate-containing product (SpermCatch), or control sperm resuspended in a sperm maintenance medium. A subjective assessment was made of the ease with which sperm could be isolated and be drawn into, and expelled from, an injection pipette after having their tails nicked. Sperm exposed to either ICSI-100 or SpermCatch were used for ICSI. Fertilization rate, zygote development, grading, and outcome of transfer were recorded for the two treatment groups., Results: The hyaluronate-containing product slowed sperm motility sufficiently for the sperm to be captured in an injection pipette, was easy to draw into and expel from the pipette, prevented sperm sticking to plastic or glassware, and did not affect post-injection zygote development. Clinical pregnancy rates were similar for the two groups., Conclusions: This product represents an alternative to PVP for slowing sperm motility prior to ICSI.
- Published
- 2003
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47. Effects of chronic exercise and imipramine on mRNA for BDNF after olfactory bulbectomy in rat.
- Author
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Van Hoomissen JD, Chambliss HO, Holmes PV, and Dishman RK
- Subjects
- Animals, Autoradiography, Behavior, Animal physiology, Brain Chemistry drug effects, Brain Chemistry physiology, In Situ Hybridization, Male, Rats, Rats, Long-Evans, Running physiology, Antidepressive Agents, Tricyclic pharmacology, Brain-Derived Neurotrophic Factor biosynthesis, Imipramine pharmacology, Olfactory Bulb physiology, Physical Conditioning, Animal physiology, Physical Exertion physiology, RNA, Messenger biosynthesis
- Abstract
We examined the effects of chronic activity wheel running and antidepressant treatment on brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) in multiple brain regions-hippocampal formation (HF), ventral tegmental area/substantia nigra (VTA/SN), nucleus accumbens (NAc), and piriform cortex (PFx)-after bilateral olfactory bulbectomy (OBX). Male, Long-Evans rats (n=72) underwent either sham or OBX surgery and were randomly divided into eight experimental groups in a 2 (sham vs. OBX) x 2 (sedentary vs. activity wheel)x2 (saline vs. imipramine) factorial design. Animals were killed after 21 days of treatment. Drug x exercise interaction effects were observed for HF (P=0.006-0.023) and VTA/SN (P=0.021); exercise increased BDNF mRNA in the saline treated animals but not in the imipramine treated animals. OBX did not affect BDNF mRNA in the HF or VTA/SN (P>0.05). BDNF mRNA levels in the PFx were not altered by exercise, drug, or OBX (P>0.05). These results suggest that the effect of exercise on BDNF mRNA extends beyond the HF to the mesolimbic ventral tegmental area and that the potentiation of BDNF mRNA by exercise and antidepressant pharmacotherapy, reported by other investigators, is time limited.
- Published
- 2003
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48. Rodent models of depression: reexamining validity without anthropomorphic inference.
- Author
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Holmes PV
- Subjects
- Animals, Behavior, Animal physiology, Depressive Disorder etiology, Depressive Disorder psychology, Drug Evaluation, Preclinical, Humans, Motor Activity physiology, Neuropsychology methods, Neuropsychology standards, Reproducibility of Results, Rodentia psychology, Stress, Physiological complications, Depressive Disorder physiopathology, Disease Models, Animal, Rodentia physiology
- Abstract
This review aims to stimulate new ways of thinking about how to model depression in rats and mice. The article is founded on the premise that anthropomorphic inferences should be removed entirely from research involving rodents. The application of animal models to study depression over the past 30 years has been based largely on nonempirical and hence nonscientific assumptions about psychological states that probably do not exist and certainly cannot be measured in rodents. Such assumptions may have led to the misinterpretation of some behaviors, such as decreased locomotor activity or decreased sucrose consumption, as symptoms of depression in rats. Previous research has also overemphasized the causal role of stress in depression. After reviewing major features of several commonly employed models, this article challenges traditional concepts about validity. Models are first evaluated based on the goals of the research. Screening for potential antidepressant compounds requires little or no consideration of the validity of the model. Issues of validity become more critical when attempting to study the neurobiological basis of depression. The primary importance of face validity is emphasized, and the value of various behavioral measures is assessed based on how directly they resemble discrete behavioral symptoms seen in depressed humans. A "neurobehaviorally mechanistic" approach is described. This approach relies on formulating discrete, neurobiological hypotheses to explain individual symptoms rather than to explain collections of symptoms or the entire disorder. The approach thus relies on pragmatic measures of operationally well-defined behavioral variables. The review concludes with the proposal that understanding the neurobiological basis for individual symptoms will ultimately yield a better understanding of depression.
- Published
- 2003
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49. Olfactory bulbectomy attenuates cardiovascular sympathoexcitatory reflexes in rats.
- Author
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Moffitt JA, Grippo AJ, Holmes PV, and Johnson AK
- Subjects
- Animals, Baroreflex physiology, Blood Pressure drug effects, Blood Pressure physiology, Catheterization, Electrodes, Implanted, Ganglionic Blockers pharmacology, Heart Rate physiology, Lumbosacral Region, Male, Neurosurgical Procedures, Olfactory Bulb surgery, Rats, Rats, Sprague-Dawley, Smoke adverse effects, Stress, Physiological, Synaptic Transmission physiology, Cardiovascular System innervation, Olfactory Bulb physiology, Reflex, Abnormal physiology, Sympathetic Nervous System physiology
- Abstract
Bilateral removal of the olfactory lobes in rats produces a number of behavioral, endocrine, and neurochemical alterations in the brain. Little is known, however, regarding the effects of this treatment on cardiovascular function and autonomic reflexes. Male Sprague-Dawley rats underwent bilateral surgical ablation of the olfactory bulbs (n = 10) or were sham operated (n = 8). After 3 wk of recovery, animals were instrumented with femoral catheters and a lumbar sympathetic nerve recording electrode. After 24 h of recovery, cardiovascular responses to arterial baroreflex manipulation, air jet stress, and smoke exposure were recorded. Olfactory bulbectomized rats demonstrated attenuated sympathoexcitatory responses to hypotension, air jet stress, and smoke exposure, as well as elevated basal blood pressure, compared with sham-operated rats. These data indicate that the integrity of the olfactory bulbs in rats is important for the elicitation of normal cardiovascular and autonomic responses to a number of evocative stimuli.
- Published
- 2002
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50. Intravenous self-administration of amphetamine is increased in a rat model of depression.
- Author
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Holmes PV, Masini CV, Primeaux SD, Garrett JL, Zellner A, Stogner KS, Duncan AA, and Crystal JD
- Subjects
- Analysis of Variance, Animals, Behavior, Animal drug effects, Denervation, Disease Models, Animal, Male, Olfactory Bulb surgery, Rats, Rats, Sprague-Dawley, Self Administration, Amphetamine pharmacology, Amphetamine-Related Disorders physiopathology, Central Nervous System Stimulants pharmacology, Depression physiopathology
- Abstract
Affective disorders and substance abuse frequently coexist, yet few previous studies have examined drug self-administration using animal models of depression. The olfactory-bulbectomized rat is a well-established model that exhibits a high degree of neurochemical similarity to depression. Olfactory bulbectomy (OBX) increases dopamine receptor densities in the ventral striatum, which may increase the reinforcing effects of drugs of abuse. Experiments were designed to test the hypotheses that acquisition and stable self-administration of amphetamine would be increased in bulbectomized rats. In the first experiment, rats underwent bilateral OBX or sham surgery and intravenous jugular catheters were implanted 12-14 days later. Acquisition was examined using a standard operant paradigm involving a nose-poke response for a very low dose of D-amphetamine sulfate (12 microg/infusion, IV). A separate group of rats received coinfusions of sulpiride. In a second experiment designed to minimize differences in acquisition and examine stable self-administration, lever pressing for a low (0.10 mg/kg, IV) or high (0.25 mg/kg, IV) dose of D-amphetamine sulfate was measured in rats pretrained to lever press for food. Bulbectomized rats acquired the self-administration of very low dose amphetamine faster than sham-operated rats and this effect was reversed by sulpiride coinfusion. Stable self-administration of the low dose of amphetamine was also markedly increased in bulbectomized rats. The findings reveal the utility of the OBX model for studying the neurobiological basis of depression and drug abuse comorbidity and support the hypothesis that neurochemical abnormalities associated with depression may enhance the addictive properties of some drugs of abuse., (Copyright 2002 Wiley-Liss, Inc.)
- Published
- 2002
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