Antisense Oligonucleotides in the Study of Neuroendocrine Systems

Morris, Mariana; Lucion, Aldo Bolten

doi:10.1111/j.1365-2826.1995.tb00787.x

Cited by 24 publications

(11 citation statements)

References 62 publications

(168 reference statements)

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“…This percent reduction is consistent with what we observed using SRC-1 antisense ODN, which completely blocked the defeminizing, but not the masculinizing, actions of testosterone (26). Typically antisense ODN treatments reduces protein levels by 10-40%, and the behavioral or physiological effects are more profound (44). It has been suggested that newly synthesized proteins may be functionally preferred over older proteins (44).…”

Section: Discussionsupporting

confidence: 78%

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Expression of the Nuclear Receptor Coactivator, cAMP Response Element-Binding Protein, Is Sexually Dimorphic and Modulates Sexual Differentiation of Neonatal Rat Brain

et al. 2002

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Recent studies indicate that the transcriptional activity of steroid receptors is governed by proteins called nuclear receptor coactivators. Using immunocytochemistry, we found that on the day of birth (postnatal d 0) males express higher levels of the nuclear receptor coactivator, cAMP response element binding protein-binding protein (CBP), within the ventromedial hypothalamus, medial preoptic area, and arcuate nucleus. Using Western immunoblots, we confirmed that males have higher levels of CBP on postnatal d 0, 1, and 5; however, there was no sex difference on postnatal d 11. To examine the functional role of CBP, we infused oligodeoxynucleotides that were antisense to CBP mRNA or a scrambled sequence as a control into the hypothalamus of female rats on postnatal d 0, 1, and 2. On postnatal d 1, all rats were injected with 100 μg testosterone propionate to both masculinize (increase male) and defeminize (decrease female) sexual behavior. Rats were ovariectomized in adulthood and tested for adult sexual behavior. Neonatal CBP antisense oligodeoxynucleotides treatment interfered with the defeminizing, but not the masculinizing, actions of testosterone. These results indicate that CBP expression in developing rat brain is sexually dimorphic and an important modulator for steroid hormone action.STEROID HORMONES ACT in the brain to influence a wide variety of behavioral and physiological processes, largely by binding to intracellular steroid receptors (1,2). It is well established that steroid receptors exert most of their effects in cells by binding to hormone response elements (HREs) on DNA and influencing gene transcription (3). Recent studies indicate that steroid receptors also interact with other regulatory proteins, nuclear receptor coactivators or corepressors, that increase or decrease, respectively, their binding and action at the HRE (4,5). The nuclear coactivator found to enhance transcriptional activity of progestin receptors when bound to its HRE was termed steroid receptor coactivator-1 (SRC-1) because it also enhances the transcriptional activity of receptors for estrogens, androgens, glucocorticoids, and thyroid hormone (6). Since SRC-1 was first characterized, other coactivators have been identified, such as the SRC-1-related proteins, TIF2 (SRC-2) and SRC-3, and unrelated coactivators such as ARA70, Trip1, and TIF1. The cAMP response element-binding protein (CREB)-binding protein (CBP), which was originally identified as a coactivator for CREB (7,8), appears to function as a nuclear receptor coactivator by interacting with SRC-1 (9) and synergistically enhance steroid receptor action at the HRE (4,10).Address all correspondence and requests for reprints to: Anthony P. Auger, Department of Physiology, University of Maryland, Baltimore, Maryland 21201. E-mail: E-mail: aauge001@umaryland.edu.. Nuclear receptor coactivators increase steroid receptor transcription via their intrinsic histone acetyltransferase activity. Acetylation of histones by coactivators removes a positive charge, leading...

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Section: Discussionsupporting

confidence: 78%

“…Typically antisense ODN treatments reduces protein levels by 10-40%, and the behavioral or physiological effects are more profound (44). It has been suggested that newly synthesized proteins may be functionally preferred over older proteins (44). The Western blot technique would detect both old and newly synthesized proteins.…”

Section: Discussionmentioning

confidence: 99%

Expression of the Nuclear Receptor Coactivator, cAMP Response Element-Binding Protein, Is Sexually Dimorphic and Modulates Sexual Differentiation of Neonatal Rat Brain

et al. 2002

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“…This suggests that where there is redundancy of function due to spare receptors, the behavioural output may remain unaltered (Wah!estedt, 1994;Morris and Lucion, 1995). The failure of reduced 5-HT7 receptor expression to alter the behavioural, neuroendocrine, and neurochemical parameters measured in this study could therefore be due to the presence of sufficient residual receptors, and does not conclusively rule out an involvement of this subtype in the responses investigated.…”

Section: -Nt 7 Receptor Antisense Treatment In the Rat 1277mentioning

confidence: 47%

“…(1997) reported behavioural changes following intranigral injection of dopamine D2 or D3 receptor antisense oligonucleotides, associated with decreases in binding similar to those found in the present study. Alternatively, it has been suggested that antisense effects are most evident when the system is challenged by drug treatment (Morris and Lucion, 1995), as demonstrated by Shimizu et al (1996) who reported that the mianserin-induced enhancement of 5-HT-stimulated cyclic AMP in rat frontocortica! astrocytes was altered significantly by 5-HI7 receptor antisense oligonucleotides.…”

Section: -Nt 7 Receptor Antisense Treatment In the Rat 1277mentioning

confidence: 88%

Antisense Oligonucleotide‐Induced Reduction in 5‐Hydroxytryptamine₇ Receptors in the Rat Hypothalamus Without Alteration in Exploratory Behaviour or Neuroendocrine Function

Clemett

Cockett²,

Marsden

et al. 1998

Journal of Neurochemistry

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Abstract:The effect of a 5-hydroxytryptamine7 (5-HT7) receptor-directed antisense oligonucleotide on rat behaviour and neuroendocrine function was investigated. Six days of intracerebroventricular 5-HT7 antisense oligonucleotide treatment significantly reduced [ 3H]5-HT binding to hypothalamic 5-HT 7 receptors, whereas cortical 5-HT2~density remained unchanged. In rats on a foodrestricted diet, both antisense and mismatch oligonucleotides reduced food intake and body weight compared with that in vehicle-treated controls by day 4 of administration. 5-HT7 antisense oligonucleotide administration did not affect exploratory or locomotor activity in photocell activity monitors on day 4 or elevated plus-maze behaviour on day 6 of intracerebroventricular treatment. 5-HT7 antisense oligonucleotide did not affect plasma corticosterone or prolactin levels or 5-HT turnover in either 5-HT cell body or terminal areas. These data demonstrate that intracerebroventricular 5-HT7 antisense oligonucleotide administration selectively reduced rat hypothalamic 5-HT7 receptor density without affecting any of the biochemical or behavioural measures. The results suggest that this antisense protocol could be a valuable tool to investigate central 5-HT7 receptor functions, and that this receptor is not critical for the control of neuroendocrine function or food intake. Key Words: 5-Hydroxytryptamine7 receptor-Serotonin-Antisense-Oligonucleotide-Hypothalamic function -Aversive behaviour.

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“…Although a detailed methodological discussion is beyond the scope of this article and the methodology has already been reviewed by others (1)(2)(3)(4)(5)(6)(7)(8), some of the problems we are facing in the actual application of antisense ODN to the brain of conscious rats are briefly discussed in terms of administration, chemical modification, proper controls, mechanisms of antisense action and specificity in vivo. Furthermore, this review will highlight the literature on antisense effects on neuroendocrine systems and behavioral performance, with emphasis on those studies that include both neuroendocrine and behavioral parameters as well as our own attempts in this direction.…”

Section: Introductionmentioning

confidence: 99%

Neuroendocrine and behavioral effects of antisense oligonucleotides

Landgraf

Naruo

Vecsernyés

et al. 1997

European Journal of Endocrinology

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Antisense Oligonucleotides in the Study of Neuroendocrine Systems

Cited by 24 publications

References 62 publications

Expression of the Nuclear Receptor Coactivator, cAMP Response Element-Binding Protein, Is Sexually Dimorphic and Modulates Sexual Differentiation of Neonatal Rat Brain

Expression of the Nuclear Receptor Coactivator, cAMP Response Element-Binding Protein, Is Sexually Dimorphic and Modulates Sexual Differentiation of Neonatal Rat Brain

Antisense Oligonucleotide‐Induced Reduction in 5‐Hydroxytryptamine₇ Receptors in the Rat Hypothalamus Without Alteration in Exploratory Behaviour or Neuroendocrine Function

Neuroendocrine and behavioral effects of antisense oligonucleotides

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Antisense Oligonucleotides in the Study of Neuroendocrine Systems

Cited by 24 publications

References 62 publications

Expression of the Nuclear Receptor Coactivator, cAMP Response Element-Binding Protein, Is Sexually Dimorphic and Modulates Sexual Differentiation of Neonatal Rat Brain

Expression of the Nuclear Receptor Coactivator, cAMP Response Element-Binding Protein, Is Sexually Dimorphic and Modulates Sexual Differentiation of Neonatal Rat Brain

Antisense Oligonucleotide‐Induced Reduction in 5‐Hydroxytryptamine7 Receptors in the Rat Hypothalamus Without Alteration in Exploratory Behaviour or Neuroendocrine Function

Neuroendocrine and behavioral effects of antisense oligonucleotides

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Antisense Oligonucleotide‐Induced Reduction in 5‐Hydroxytryptamine₇ Receptors in the Rat Hypothalamus Without Alteration in Exploratory Behaviour or Neuroendocrine Function