Opposite Effects of mGluR1a and mGluR5 Activation on Nucleus Accumbens Medium Spiny Neuron Dendritic Spine Density

Gross, Kellie S.; Brandner, Dieter D.; Martínez, Luis A.; Olive, M. Foster; Meisel, Robert L.; Mermelstein, P.

doi:10.1371/journal.pone.0162755

Cited by 1,398 publications

(26 citation statements)

References 37 publications

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“…The effects of estradiol on plasticity in the NAc of OVX females are mediated by mGluR5 in the NAcC, but not in the shell subdivision; MPEP treatment alone has no effect in either subdivision (Peterson et al, 2014). In contrast, treatment of OVX females with CDPPB (in the absence of estradiol) induces plasticity in both regions (Gross et al, 2016). It is perhaps not surprising, then, that widespread activation of mGluR5 (via systemic CDPPB administration) did not mimic the effect of estradiol in the present study.…”

Section: Discussionmentioning

confidence: 98%

“…The mGluR5-positive allosteric modulator 3-cyano- N -(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB; 3235, Tocris) was dissolved in 10% Tween-80 (low CDPPB, 10 mg/ml/kg; high CDPPB, 25 mg/2 ml/kg) and injected i.p. The 10 mg/ml/kg dose of CDPPB mimics the effects of estradiol on dendritic spine density in the NAc in OVX females (Gross et al, 2016). Cocaine (cocaine hydrochloride; 0406-1520-53, Mallinckrodt, St. Louis, MO) was dissolved in sterile PBS (9.3 mg/ml) and infused i.v.…”

Section: Methodsmentioning

confidence: 99%

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Estradiol Facilitation of Cocaine Self-Administration in Female Rats Requires Activation of mGluR5

Martínez

Gross

Himmler

et al. 2016

eNeuro

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In comparison to men, women initiate drug use at earlier ages and progress from initial use to addiction more rapidly. This heightened intake and vulnerability to drugs of abuse is regulated in part by estradiol, although the signaling mechanisms by which this occurs are not well understood. Recent findings indicate that within the nucleus accumbens core, estradiol induces structural plasticity via membrane-localized estrogen receptor α, functionally coupled to metabotropic glutamate receptor subtype 5 (mGluR5). Hence, we sought to determine whether mGluR5 activation was essential for estradiol-mediated enhancement of cocaine self-administration. Ovariectomized (OVX) female rats were allowed to freely self-administer cocaine under extended access conditions (6 h/d) for 10 consecutive days. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) or vehicle was administered before estradiol (or oil), on a 2 d on/2 d off schedule throughout the extended access period. MPEP treatment prevented the estradiol-dependent enhancement of cocaine self-administration in OVX females. In a separate experiment, potentiation of mGluR5 function with the positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (in the absence of estradiol treatment) failed to increase cocaine self-administration. These data suggest that mGluR5 activation is necessary for estradiol-mediated enhancement of responses to cocaine, but that direct mGluR5 activation is insufficient to mimic the female response to estradiol. Building on previous studies in male animals, these findings further highlight the therapeutic potential of mGluR5 antagonism in the treatment of addiction and suggest that there may be added therapeutic benefit in females.

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Section: Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Estradiol Facilitation of Cocaine Self-Administration in Female Rats Requires Activation of mGluR5

Martínez

Gross

Himmler

et al. 2016

eNeuro

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“…Previously, we found that knocking down CAV‐1 protein levels reduced trafficking of full‐length ERα, and mediated coupling with mGluR1a, which activates excitatory actions of estradiol, including: intracellular calcium, PKC, MAPK, and ultimately CREB . In addition to the hypothalmus, the ER and mGluR interactions mediate estradiol suppression of GABAergic inhibition in female rats via an intracellular signaling pathway involving phospholipase C and inositol triphosphate, inhibition of internal free calcium in DRG cells, and striatal function …”

Section: Discussionmentioning

confidence: 98%

“…Initial experiments with cultured hippocampal neurons from males and females demonstrated that estradiol induces ERα trafficking to the membrane in association with caveolin (CAV) proteins . These observations have been confirmed in hypothalamic and striatal neurons and hypothalamic astrocytes and dorsal root ganglion cells from males and females . Knockdown of ARH caveolin‐1 (CAV‐1) prevented ERα trafficking to the membrane, but did not alter cytosolic levels of the receptor .…”

Section: Introductionmentioning

confidence: 93%

ERαΔ4, an ERα splice variant missing exon4, interacts with caveolin‐3 and mGluR2/3

Wong

Scott

Johnson

et al. 2019

J Neuroendocrinology

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The two isoforms of the nuclear estrogen receptor, ERα and ERβ are widely expressed in the central nervous system. Although they were first described as nuclear receptors, both isoforms have also been found at the cell membrane where they mediate cell signaling. Surface biotinylation studies using neuronal and glial primary cultures label an alternatively spliced form of ERα. The 52 kDa protein, ERαΔ4, is missing exon 4 and is highly expressed in membrane fractions derived from cultured cells. In vivo, both full‐length (66 kDa) ERα and ERαΔ4 are present in membrane fractions. In response to estradiol, full‐length ERα and ERαΔ4 are initially trafficked to the membrane, and then internalized in parallel. Previous studies determined that only the full‐length ERα associates with metabotropic glutamate receptor‐1a (mGluR1a), initiating cellular signaling. The role of ERαΔ4, remained to be elucidated. Here, we report ERαΔ4 trafficking, association with mGluR2/3, and downstream signaling in female rat arcuate nucleus (ARH). Caveolin (CAV) proteins are needed for ER transport to the cell membrane, and using co‐immunoprecipitation CAV‐3 was shown to associate with ERαΔ4. CAV‐3 was necessary for ERαΔ4 trafficking to the membrane: in the ARH, microinjection of CAV‐3 siRNA reduced CAV‐3 and ERαΔ4a in membrane fractions by 50%, and 60%, respectively. Moreover, co‐immunoprecipitation revealed that ERαΔ4 associated with inhibitory mGluRs, mGluR2/3. Estrogen benzoate (EB) treatment (5 μg; s.c.; every 4 days; three cycles) reduced levels of cAMP, an effect attenuated by antagonizing mGluR2/3. Following EB treatment, membrane levels of ERαΔ4 and mGluR2/3 were reduced implying ligand‐induced internalization. These results implicate ERαΔ4 in an estradiol‐induced inhibitory cell signaling in the ARH.

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“…In male cultures, estradiol does not induce pCREB, while mGluR activation does. In addition, activation of mGluR5 mediates spine plasticity in male NAcC and NAcSh (Gross et al, 2016), suggesting that mGluRs possibly couple to membrane bound androgen receptor in males. The androgen receptor has indeed also been shown to migrate to the membrane (Tabori et al, 2005), using the same intracellular processes as estrogen receptors (Pedram et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Effects of gonadectomy and androgen on neuronal plasticity in motivation and reward related brain regions in the male rat

Huijgens

Snoeren

Meisel

et al. 2020

Preprint

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Gonadal hormones affect neuronal morphology to ultimately regulate behavior. Here, we investigated the effect of both castration and androgen replacement on spine plasticity in the nucleus accumbens shell and core (NAcSh and NAcC), caudate putamen (CPu), medial amygdala (MeA), and medial preoptic nucleus (MPN). Intact and castrated (GDX) male rats were treated with dihydrotestosterone (DHT, 1.5mg) or vehicle (oil) in 3 experimental groups: intact-oil, GDX-oil and GDX-DHT. Spine density and morphology, measured 24 hours after injection, were determined through 3D reconstruction of DiI-labeled dendritic segments. GDX decreased spine density in the MPN, which was rescued by DHT treatment. MeA spine density increased in GDX-DHT animals compared to intact-oil animals. In the NAcSh, DHT decreased spine density, and also rapidly increased the number of pCREB+ cell bodies.These findings indicate that androgen signaling plays a role in the regulation of spine plasticity within neurocircuits involved in motivated behaviors.

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Opposite Effects of mGluR1a and mGluR5 Activation on Nucleus Accumbens Medium Spiny Neuron Dendritic Spine Density

Cited by 1,398 publications

References 37 publications

Estradiol Facilitation of Cocaine Self-Administration in Female Rats Requires Activation of mGluR5

Estradiol Facilitation of Cocaine Self-Administration in Female Rats Requires Activation of mGluR5

ERαΔ4, an ERα splice variant missing exon4, interacts with caveolin‐3 and mGluR2/3

Effects of gonadectomy and androgen on neuronal plasticity in motivation and reward related brain regions in the male rat

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