Sex-specific effects of early neonatal progesterone treatment on dopamine and serotonin metabolism in rat striatum and frontal cortex

Muneoka, Katsumasa; Kuwagata, Makiko; Ogawa, Tetsuo; Shioda, Seiji

doi:10.1016/j.lfs.2010.10.016

Cited by 14 publications

(6 citation statements)

References 39 publications

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“…RU486 treatment neonatally decreased the density of THir fibers in the PL mPFC at P25, but not in adulthood, suggesting that PR activity earlier in development may set the stage for subsequent maturation that occurs in prefrontal cortex during adolescence, potentially permanently altering subsequent dopaminergic activity. Indeed, previous work shows that neonatal progesterone administration increased the dopamine metabolites DOPAC and HVA in the adult PFC [17], indicating an increase in dopamine turnover.…”

Section: Discussionmentioning

confidence: 99%

“…The timing of PR expression in VTA and PFC corresponds with periods of significant dendritic maturation of mPFC neurons and synaptogenesis for dopaminergic axons within the frontal cortex [13-15], suggesting that PR activity may be important for establishing functional connectivity. Consistent with this idea, progesterone treatment during postnatal life increased the number of midbrain neurons expressing tyrosine hydroxylase (TH), the rate limiting enzyme in the synthesis of dopamine [16] and altered levels of dopamine and its metabolites in the prefrontal cortex in adulthood [17]. …”

Section: Introductionmentioning

confidence: 99%

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Progesterone Receptor Expression in the Developing Mesocortical Dopamine Pathway: Importance for Complex Cognitive Behavior in Adulthood

Willing

Wagner²

2015

Neuroendocrinology

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Background: Numerous psychiatric and behavioral disorders such as autism, attention deficit disorder and schizophrenia may involve disruptions in the development of the mesocortical dopamine pathway, consisting of dopaminergic projections from the midbrain ventral tegmental area (VTA) to the medial prefrontal cortex (mPFC). Nuclear steroid hormone receptors are powerful transcription factors and can profoundly and permanently alter fundamental processes of neural development. Nuclear progesterone receptor (PR) is transiently expressed in both the VTA and the PFC of rodents during perinatal life, suggesting that PR may regulate the normal development of this important behavioral circuit. Methods and Results: Here, we demonstrate that virtually all PR-immunoreactive (PR-ir) cells in the VTA also express tyrosine hydroxylase immunoreactivity (TH-ir). In addition, retrograde tract tracing reveals that many PR-ir cells in the VTA project to the mPFC. Administration of a PR antagonist to rats during the neonatal period decreased TH-ir fiber density in the prelimbic mPFC of juveniles (postnatal day 25) and decreased levels of TH-ir in the VTA of adults. Neonatal treatment with a PR antagonist impaired adult performance on a passive inhibitory avoidance task and an attentional set-shifting task, measures of behavioral inhibition/impulsivity and cognitive flexibility, respectively. TH-ir levels in the VTA were reduced and cognitive flexibility was impaired in PR knockout mice as well. Conclusions: These findings provide novel insights into a potential role for PR in the developmental etiology of behavioral disorders that involve impairments in complex cognitive behaviors and have implications for the use of synthetic progestins in humans during critical neurodevelopmental periods.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Progesterone Receptor Expression in the Developing Mesocortical Dopamine Pathway: Importance for Complex Cognitive Behavior in Adulthood

Willing

Wagner²

2015

Neuroendocrinology

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“…However, there is recent information about amitraz’s toxic effects which was not taken into account in the previously published amitraz risk assessments by JMPR and by the EPA. ,, Thus, according to the recent data amitraz could be mutagenic and genotoxic by itself, it could induce multiple forms of P450, , endocrine disruption, ,,,,, cell death, ,− and oxidative stress, and produce immune, ,,, reproductive, − and developmental toxicity. − ,,− Moreover, the US EPA has started a re-evaluation of this compound, which will be finished in 2016 and includes many of the points mentioned above and which should also be taken into account by the rest of agencies to evaluate its risk assessment.…”

Section: Discussionmentioning

confidence: 99%

“…However, amitraz showed region-dependent effects that could be explained by regional kinetic differences which increase amitraz levels in the affected regions, but the gender-dependent effects suggest a sex hormone interaction on amitraz effects. In this sense, amitraz was reported to modulate serum concentrations of E2 and testosterone in rats, which play a role in the development of catecholamine systems − and mammalian sex differentiation . Moreover, it was described that sex steroid hormones modulated the expression of enzymes which regulate the metabolism and synthesis of monoaminergic neurotransmitters in a gender and region-dependent way. − This could possibly be another mechanism by which developmental exposure to amitraz may alter permanently the monoamine levels in prefrontal cortex, striatum, and hippocampus, and not only by MAO inhibition, suggesting that the sex differences observed in these neurotransmitter systems could be related to the endocrine disruption induced by amitraz.…”

Section: Reproductive and Developmental Toxicitymentioning

confidence: 99%

Molecular Mechanisms of Amitraz Mammalian Toxicity: A Comprehensive Review of Existing Data

Pino

Moyano-Cires

Anadón

et al. 2015

Chem. Res. Toxicol.

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Amitraz is a formamidine pesticide widely used as an insecticide and acaricide. Amitraz poisoning cases in humans and animals are still being described to date, which is a cause of concern for health authorities. Amitraz was reported not to pose unreasonable risks or adverse effects to humans or the environment unlike the other commercialized member of the formamidine family, chlordimeform, which was removed from the market because of carcinogenic effects in animal studies. Amitraz was classified as a nonquantifiable "Suggestive Evidence of Carcinogenicity" and not genotoxic, but recently, it has been reported that it could induce genotoxic effects. Moreover, ever since the previously published evaluations made by the Environmental Protection Agency (EPA) and the Joint Meeting of Pesticide Residues (JMPR) there have been new reported data on amitraz toxicity related to genotoxicity, oxidative stress, cell death, immunotoxicty, endocrine disruption, and developmental toxicity which indicate that the risk of this compound could be underestimated. Furthermore, there is missing information about the dose-response relationship for some mechanisms and toxic effects described for amitraz and its metabolites, the mechanism of action by which several toxic effects are produced, and amitraz pharmacokinetics on different species. According to this, the new information reported should be taken into account, and more studies should be performed to fill in the gaps of missing information for a complete hazard identification and therefore an exhaustive risk assessment of amitraz. This review is aimed at updating the current knowledge on molecular mechanisms of amitraz mammalian toxicity, pointing out the missing information, providing some possible explanation of the mechanism by which some toxic effects observed are produced, and suggesting future direction of its research. To our knowledge, this is the first review on the molecular mechanisms of amitraz toxicity.

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“…and therefore, regulation of DRN neuronal function by 17‐OHPC may be specific to the perinatal period. Consistent with this idea, progesterone administration during neonatal life decreased 5HT levels and decreased 5‐HIAA/5HT ratios in the frontal cortex of adult rats (Muneoka et al., 2010), suggesting reduced availability of serotonin for release within DRN neuron terminals.…”

Section: Discussionmentioning

confidence: 76%

Developmental exposure to the synthetic progestin, 17α‐hydroxyprogesterone caproate, disrupts the mesocortical serotonin pathway and alters impulsive decision‐making in rats

Fahrenkopf

Wood

et al. 2021

Developmental Neurobiology

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The synthetic progestin, 17α‐hydroxyprogesterone caproate (17‐OHPC), is administered to women at risk for preterm birth during a critical period of fetal development for mesocortical pathways. Yet, little information is available regarding the potential effects of 17‐OHPC on the developing fetal brain. In rat models, the mesocortical serotonin pathway is sensitive to progestins. Progesterone receptor (PR) is expressed in layer 3 pyramidal neurons of medial prefrontal cortex (mPFC) and in serotonergic neurons of the dorsal raphe. The present study tested the hypothesis that exposure to 17‐OHPC during development disrupts serotonergic innervation of the mPFC in adolescence and impairs behavior mediated by this pathway in adulthood. Administration of 17‐OHPC from postnatal days 1–14 decreased the density of SERT‐ir fibers within superficial and deep layers and decreased the density of synaptophysin‐ir boutons in all layers of prelimbic mPFC at postnatal day 28. In addition, rats exposed to 17‐OHPC during development were less likely to make impulsive choices in the Delay Discounting task, choosing the larger, delayed reward more often than controls at moderate delay times. Interestingly, 17‐OHPC exposed rats were more likely to fail to make any choice (i.e., increased omissions) compared to controls at longer delays, suggesting disruptions in decision‐making. These results suggest that further investigation is warranted in the clinical use of 17‐OHPC to better inform a risk/benefit analysis of progestin use in pregnancy.

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Sex-specific effects of early neonatal progesterone treatment on dopamine and serotonin metabolism in rat striatum and frontal cortex

Cited by 14 publications

References 39 publications

Progesterone Receptor Expression in the Developing Mesocortical Dopamine Pathway: Importance for Complex Cognitive Behavior in Adulthood

Progesterone Receptor Expression in the Developing Mesocortical Dopamine Pathway: Importance for Complex Cognitive Behavior in Adulthood

Molecular Mechanisms of Amitraz Mammalian Toxicity: A Comprehensive Review of Existing Data

Developmental exposure to the synthetic progestin, 17α‐hydroxyprogesterone caproate, disrupts the mesocortical serotonin pathway and alters impulsive decision‐making in rats

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