Sex-based changes in rat brain serotonin and behavior in a model of altitude-related vulnerability to treatment-resistant depression

Kanekar, Shami; Sheth, Chandni; Ombach, Hendrick; Brown, Jadeda; Hoffman, Michael D.; Ettaro, Robert; Renshaw, Perry F.

doi:10.1007/s00213-021-05902-y

Cited by 7 publications

(16 citation statements)

References 72 publications

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“…Housing female rats at moderate altitude consistently reduces serotonin in the PFC, STR, HIP and BST [41], and CRMH treatment significantly improved serotonin levels in the PFC and STR (Figure 5). Male rats housed at 4500 ft exhibit a transient increase in serotonin in the HIP and BST at 2 weeks, but no change is seen with a longer duration of exposure [41]. In males at altitude, CRMH significantly reduced serotonin levels in the STR and HIP.…”

Section: Discussionmentioning

confidence: 94%

“…Changes in basal serotonin levels in the PFC, STR and BST are directly linked to MDD [53]. Housing female rats at moderate altitude consistently reduces serotonin in the PFC, STR, HIP and BST [41], and CRMH treatment significantly improved serotonin levels in the PFC and STR (Figure 5). Male rats housed at 4500 ft exhibit a transient increase in serotonin in the HIP and BST at 2 weeks, but no change is seen with a longer duration of exposure [41].…”

Section: Discussionmentioning

confidence: 99%

“…We established an animal model to study the impact of living at moderate altitude on depression-like behavior. We found that Sprague Dawley rats housed at moderate altitude (4500 ft, 10,000 ft) exhibit more depression-like behavior in the forced swim test (FST) and anhedonia in the sucrose preference test (SPT) vs. those at sea level, with sex-based differences [40,41]. Rats housed at moderate altitude also exhibit a sex-based disruption in brain serotonin [41], and forebrain deficits in brain energetic markers [27].…”

Section: Introductionmentioning

confidence: 95%

“…We found that Sprague Dawley rats housed at moderate altitude (4500 ft, 10,000 ft) exhibit more depression-like behavior in the forced swim test (FST) and anhedonia in the sucrose preference test (SPT) vs. those at sea level, with sex-based differences [40,41]. Rats housed at moderate altitude also exhibit a sex-based disruption in brain serotonin [41], and forebrain deficits in brain energetic markers [27]. In female rats, a sustained decrease in brain serotonin and increase in depression-like behavior is seen with housing at moderate altitude, while males exhibit a transient increase in both regional brain serotonin and depression-like behavior [41].…”

Section: Introductionmentioning

confidence: 99%

“…Rats housed at moderate altitude also exhibit a sex-based disruption in brain serotonin [41], and forebrain deficits in brain energetic markers [27]. In female rats, a sustained decrease in brain serotonin and increase in depression-like behavior is seen with housing at moderate altitude, while males exhibit a transient increase in both regional brain serotonin and depression-like behavior [41]. A serotonin deficiency is linked to SSRI lack of efficacy in the rodent and mouse FST.…”

Section: Introductionmentioning

confidence: 99%

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Sex-Based Impact of Creatine Supplementation on Depressive Symptoms, Brain Serotonin and SSRI Efficacy in an Animal Model of Treatment-Resistant Depression

Kanekar

Ettaro

Hoffman

et al. 2021

IJMS

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Background: Rates of major depressive disorder (MDD) increase with living at altitude. In our model, rats housed at moderate altitude (in hypobaric hypoxia) exhibit increased depression-like behavior, altered brain serotonin and a lack of antidepressant response to most selective serotonin reuptake inhibitors (SSRIs). A forebrain deficit in the bioenergetic marker creatine is noted in people living at altitude or with MDD. Methods: Rats housed at 4500 ft were given dietary creatine monohydrate (CRMH, 4% w/w, 5 weeks) vs. un-supplemented diet, and impact on depression-like behavior, brain bioenergetics, serotonin and SSRI efficacy assessed. Results: CRMH significantly improved brain creatine in a sex-based manner. At altitude, CRMH increased serotonin levels in the female prefrontal cortex and striatum but reduced male striatal and hippocampal serotonin. Dietary CRMH was antidepressant in the forced swim test and anti-anhedonic in the sucrose preference test in only females at altitude, with motor behavior unchanged. CRMH improved fluoxetine efficacy (20 mg/kg) in only males at altitude: CRMH + SSRI significantly improved male striatal creatine and serotonin vs. CRMH alone. Conclusions: Dietary CRMH exhibits sex-based efficacy in resolving altitude-related deficits in brain biomarkers, depression-like behavior and SSRI efficacy, and may be effective clinically for SSRI-resistant depression at altitude. This is the first study to link CRMH treatment to improving brain serotonin.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Sex-Based Impact of Creatine Supplementation on Depressive Symptoms, Brain Serotonin and SSRI Efficacy in an Animal Model of Treatment-Resistant Depression

Kanekar

Ettaro

Hoffman

et al. 2021

IJMS

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Postnatal depletion of serotonin affects the morphology of neurons and the function of the hippocampus in male rats

Ghaheri

Niapour

Sakhaie

et al. 2022

Intl J of Devlp Neuroscience

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Serotonin (5-HT) is an essential neurotransmitter for the refined organization of the cerebral cortex. Studies have suggested that altered serotonin signaling contributes to cognitive impairment and psychiatric disorders. However, the exact role of this neurotransmitter on the development of hippocampal neurons is not recognized. Here we aimed to examine the effects of the parachlorophenylalanine (PCPA; 100 mg/kg/daily, s.c. during the postnatal days 10-20), a reversible inhibitor of 5-HT synthesis, on the serotonin level of the hippocampal and prefrontal cortex. We also focused on the morphology of the neurons in the hippocampus and spatial learning and memory. Our results

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Effects of prenatal exposure to fluoxetine on circadian rhythmicity in the locomotor activity and neuropeptide Y and 5‐HT expression in male and female adult Wistar rats

Linhares

Meurer

Aquino

et al. 2022

Intl J of Devlp Neuroscience

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Serotonin (5-HT) reuptake inhibitors, such as fluoxetine, are the most prescribed antidepressant for maternal depression. In this sense, it exposes mothers and the brains of infants to increased modulatory and trophic effects of serotonergic neurotransmission. 5-HT promotes essential brain changes throughout its development, which include neuron migration, differentiation and organisation of neural circuitries related to emotional, cognitive and circadian behavior. Early exposure to the SSRIs induces long-term effects on behavioral and neural serotonergic signalisation. We have aimed to evaluate the circadian rhythm of locomotor activity and the neurochemical content, neuropeptide Y (NPY) and 5-HT in three brain areas: intergeniculate leaflet (IGL), suprachiasmatic nuclei (SCN) and raphe nuclei (RN), at two zeitgebers (ZT6 and ZT18), in male and female rat's offspring early exposed (developmental period GD13-GD21) to fluoxetine (20 mg/kg). First, we have conducted daily records of the locomotor activity rhythm using activity sensors coupled to individual cages over 4 weeks. We have lastly evaluated the immunoreactivity of NPY in both SCN and IGL, as well the 5-HT expression in the dorsal and medial RN. In summary, our results showed that (1) prenatal fluoxetine affects phase entrainment of the rest/activity rhythm at ZT6 and ZT18, more in male than female specimens, and (2) modulates the NPY and 5-HT expression. Here, we show male rats are more susceptible to phase entrainment and the NPY and 5-HT misexpression compared to female ones. The sex differences induced by early exposure to fluoxetine in both the circadian rhythm of locomotor activity and the neurochemical expression into SCN, IGL and midbrain

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Sex-based changes in rat brain serotonin and behavior in a model of altitude-related vulnerability to treatment-resistant depression

Cited by 7 publications

References 72 publications

Sex-Based Impact of Creatine Supplementation on Depressive Symptoms, Brain Serotonin and SSRI Efficacy in an Animal Model of Treatment-Resistant Depression

Sex-Based Impact of Creatine Supplementation on Depressive Symptoms, Brain Serotonin and SSRI Efficacy in an Animal Model of Treatment-Resistant Depression

Postnatal depletion of serotonin affects the morphology of neurons and the function of the hippocampus in male rats

Effects of prenatal exposure to fluoxetine on circadian rhythmicity in the locomotor activity and neuropeptide Y and 5‐HT expression in male and female adult Wistar rats

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