Intracerebral administration of antisense oligodeoxynucleotides to GAD65 and GAD67 mRNAs modulate reproductive behavior in the female rat

McCarthy, Margaret M.; Masters, David B.; Rimvall, Karin; Schwartz-Giblin, Susan; Pfaff, Donald W.

doi:10.1016/0006-8993(94)91019-7

Cited by 95 publications

(37 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another aspect of this experiment to consider is the timing of the effects. Based upon previous studies utilizing similar antisense oligonucleotides regimen, protein knockdown occurs between 12 and 48 h following antisense oligonucleotide administration (McCarthy et al, 1994(McCarthy et al, , 2000Ogawa et al, 1994). Although we cannot know that, at the initial time of conditioning of E 2 and ER antisense oligonucleotides (30 min after administration), expression of ERs was knocked down, knockdown of ERs at 24 h is consistent with the actions of E 2 at ERs being blocked by ER antisense oligonucleotides on the second day in the nonpreferred side of the CPP chamber and Western blot analyses.…”

Section: Neuropsychopharmacologymentioning

confidence: 99%

Estradiol-Induced Conditioned Place Preference may Require Actions at Estrogen Receptors in the Nucleus Accumbens

Walf

Rhodes

Meade

et al. 2006

Neuropsychopharmacol

View full text Add to dashboard Cite

Intrinsic rewarding effects of estradiol (E 2 ) may underlie some of the sex differences that emerge postpuberty for the prevalence of drug use and behavioral responses to drugs, but the effects and mechanisms of E 2 for reward have not been well characterized. Conditioned place preference (CPP), as measured by the time spent on the nonpreferred/drug-associated side of the chamber, was utilized as a functional assay to investigate the effects and mechanisms of E 2 in the nucleus accumbens for reward. To determine whether intracellular estrogen receptors (ERs) are important for E 2 -induced CPP, rats were administered E 2 (10 mg; subcutaneously (s.c.)), which produced CPP in each experiment, and/or ER blockers, such as tamoxifen (Experiment 1), ICI 182,780 (Experiment 2), or antisense oligonucleotides targeted to ERs (Experiment 3). Experiment 1: E 2 significantly increased the time spent on the originally nonpreferred side of the chamber. Coadministration of tamoxifen (10 mg/kg; s.c.) attenuated effects of E 2 to produce a CPP, but tamoxifen alone, increased time spent on the nonpreferred side. Experiment 2: coadministration of ICI 182,780 (10 mg/ml) to the nucleus accumbens attenuated effects of E 2 to enhance CPP and did not produce a CPP when administered alone. Experiment 3: coadministration of s.c. E 2 with ER antisense oligonucleotides to the nucleus accumbens significantly decreased time spent on the nonpreferred side and expression of ERs in the nucleus accumbens compared to scrambled antisense oligonucleotides or saline vehicle administration. Thus, E 2 's rewarding effects may involve actions at ERs in the nucleus accumbens.

show abstract

Section: Neuropsychopharmacologymentioning

confidence: 99%

Estradiol-Induced Conditioned Place Preference may Require Actions at Estrogen Receptors in the Nucleus Accumbens

Walf

Rhodes

Meade

et al. 2006

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…Regarding roles of VMN GABAergic neurotransmission in lordosis behavior in the adult, both positive (36, 37) and negative (38,39) effects can be observed. There may be interactions with other neurotransmission systems (40).…”

Section: Interactions Between E and Gabaergic Neurotransmission In Vmnmentioning

confidence: 99%

Sex differences in estrogenic regulation of neuronal activity in neonatal cultures of ventromedial nucleus of the hypothalamus

Zhang

Pfaff

Chen

2005

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Estrogenic effects have been implicated in sexual differentiation of brain and behavior, in part by affecting neuronal activity in the ventromedial nucleus of the hypothalamus (VMN). We report here a remarkable sex difference in estrogenic regulation of neuronal activity in male vs. female neural networks. Spontaneous synaptic currents originating from a population of neurons were recorded in primary VMN cultures using the whole-cell patch-clamp technique. Treatment with 17␤-estradiol (E2, 10 nM) for 24 h induced opposite effects in the two sexes: the frequency of spontaneous synaptic events decreased significantly in neurons derived from males but increased in those from females. Interestingly, the 24-hour E2 effect was partially reversed by an acute application (5 min) of a second dose of E2 (10 nM), suggesting an interaction between extended (24-hr) and acute (5-min) effects of E2 in VMN neurons. To understand the underlying mechanism of this sexually dimorphic action of E2, we analyzed the E2 effect on GABAergic neurotransmission by recording miniature inhibitory postsynaptic currents. After 24-hour E2 treatment, both the amplitude and frequency of miniature inhibitory postsynaptic currents increased in neurons derived from males but decreased in those from females. These results suggest that E2-induced changes in GABAergic inhibition could at least partially explain E2 effects on neuronal activity. We conclude that E2 may have sexually dimorphic effects on the synaptic output of VMN neurons by modulating GABAergic neurotransmission.GABA ͉ sexual dimorphism ͉ steroid hormone E strogens (E) play important roles in a variety of neurobiological processes, including neural development and adult behaviors (1). The functional outcomes of these processes are coordinated with physiological events that are fundamentally different in males (() and females (&). These physiological events involve E interactions with nuclear E receptors (ERs), as well as interactions at several cellular levels, including signal transduction systems. One focus of these interactions is on hypothalamic neuronal activity. During a perinatal sensitive period, E exposure enhances neuronal excitability in the ( hypothalamus by affecting amino acid neurotransmitters, which might be a crucial mechanism in the process of masculinization of the ( brain (2). E plays a fundamental role in lordosis via actions in the ventromedial nucleus of the hypothalamus (VMN) (3, 4). Previous studies (5, 6) have demonstrated that an increase in VMN neuronal activity is a mechanism by which E acts through VMN to induce lordosis. However, the questions of exactly how E increases VMN neuronal activity and how sex differences might arise here remain to be elucidated.GABA plays an important role in VMN development (7), and GABAergic neurotransmission has been implicated in E's effects on several important functions, such as sexual differentiation during neural development (8) and lordosis behavior (9). E has been shown to affect many aspects of GABAergic transmission, ...

show abstract

“…In cell free and single cell systems, RNase H activity is thought to be the primary mediator of antisense effects (1,2,15). However, in the CNS, antisense actions may be independent of mRNase activity with evidence for effects on message translation and even neuronal excitability (16)(17)(18).…”

Section: Basic Considerationsmentioning

confidence: 99%

“…For example, PS oligomers inhibited human RNase H and DNA polymerase activity, effects which were independent of sequence, but dependent on the number of phosphorothioate linkages (23). In brain tissue culture or cerebral infusion studies, the PS form was reported to be more neurotoxic than the unmodified form (24)(25)(26)(27) and neurological deficits (28,29) and neuronal loss (17) were observed after in vivo administration. Thus, the possible disadvantages of the modified oligomers may overcome their important advantage, that is, resistance to nucleolytic degradation ( 2 ) .…”

Section: Basic Considerationsmentioning

confidence: 99%

“…However, the few investigations which have directly compared the biochemical forms have reported that the phosphothiorate derivative is more effective than the naturally occurring phosphodiester. The dose of a PS oligomer to glutamic acid decarboxylase (GAD) required to inhibit lordosis was twofold lower than the 'natural' PO form (17). Comparison of various antisense oligomers to c-fos demonstrated that a PS oligomer was effective while a PO or partially substituted form was inactive or partially active, respectively (49).…”

Section: Basic Considerationsmentioning

confidence: 99%

See 1 more Smart Citation

Antisense Oligonucleotides in the Study of Neuroendocrine Systems

Morris¹,

Lucion²

1995

J Neuroendocrinology

View full text Add to dashboard Cite

Intracerebral administration of antisense oligodeoxynucleotides to GAD65 and GAD67 mRNAs modulate reproductive behavior in the female rat

Cited by 95 publications

References 48 publications

Estradiol-Induced Conditioned Place Preference may Require Actions at Estrogen Receptors in the Nucleus Accumbens

Estradiol-Induced Conditioned Place Preference may Require Actions at Estrogen Receptors in the Nucleus Accumbens

Sex differences in estrogenic regulation of neuronal activity in neonatal cultures of ventromedial nucleus of the hypothalamus

Antisense Oligonucleotides in the Study of Neuroendocrine Systems

Contact Info

Product

Resources

About