Abstract
Accumulating evidence from human and rodent studies suggests that females are more sensitive to the motivating and rewarding properties of drugs of abuse. Numerous reports implicate estradiol in enhancing drug-related responses in females, yet the neurobiological mechanisms underlying this effect of estradiol are unknown. Because dendritic spine plasticity in the nucleus accumbens (NAc) is linked to the addictive effects of drugs, we examined the influence of estradiol on dendritic spines in this region. Previously our laboratory demonstrated that in female medium spiny neurons, estradiol activates metabotropic glutamate receptor subtype five (mGluR5), a G protein-coupled receptor already implicated in the etiology of drug addiction. Thus, we sought to determine whether mGluR5 is a part of the mechanism by which estradiol affects dendritic spine density in the NAc. To test this hypothesis, ovariectomized female rats were treated with the mGluR5 antagonist, MPEP, or vehicle prior to estradiol (or oil) treatment and 24 h later dendritic spine density was evaluated by DiI labeling and confocal microscopy. We found that estradiol decreased dendritic spine density in the NAc core and that pretreatment with MPEP blocked this effect. In contrast, MPEP had no effect on dendritic spine density in the NAc shell or CA1 region of the hippocampus, two regions in which estradiol increased the density of dendritic spines. As dendritic spine plasticity in the NAc core has behavioral consequences for drug addiction, these data provide a clue as to how estradiol acts in females to enhance behavioral responses to drugs of abuse.
Similar content being viewed by others
References
Anker JJ, Carroll ME (2011) Females are more vulnerable to drug abuse than males: evidence from preclinical studies and the role of ovarian hormones. Curr Top Behav Neurosci 8:73–96. doi:10.1007/7854_2010_93
Asrar S, Jia Z (2013) Molecular mechanisms coordinating functional and morphological plasticity at the synapse: role of GluA2/N-cadherin interaction-mediated actin signaling in mGluR-dependent LTD. Cell Signal 25:397–402. doi:10.1016/j.cellsig.2012.11.007
Becker JB, Hu M (2008) Sex differences in drug abuse. Front Neuroendocrinol 29:36–47. doi:10.1016/j.yfrne.2007.07.003
Boulware MI, Mermelstein PG (2009) Membrane estrogen receptors activate metabotropic glutamate receptors to influence nervous system physiology. Steroids 74:608–613. doi:10.1016/j.steroids.2008.11.013
Boulware MI, Weick JP, Becklund BR et al (2005) Estradiol activates group I and II metabotropic glutamate receptor signaling, leading to opposing influences on cAMP response element-binding protein. J Neurosci 25:5066–5078. doi:10.1523/JNEUROSCI.1427-05.2005
Carroll ME, Anker JJ (2010) Sex differences and ovarian hormones in animal models of drug dependence. Horm Behav 58:44–56. doi:10.1016/j.yhbeh.2009.10.001
Christensen A, Dewing P, Micevych P (2011) Membrane-initiated estradiol signaling induces spinogenesis required for female sexual receptivity. J Neurosci 31:17583–17589. doi:10.1523/JNEUROSCI.3030-11.2011
Dumitriu D, Laplant Q, Grossman YS et al (2012) Subregional, dendritic compartment, and spine subtype specificity in cocaine regulation of dendritic spines in the nucleus accumbens. J Neurosci 32:6957–6966. doi:10.1523/JNEUROSCI.5718-11.2012
Duncan JR, Lawrence AJ (2012) The role of metabotropic glutamate receptors in addiction: evidence from preclinical models. Pharmacol Biochem Behav 100:811–824. doi:10.1016/j.pbb.2011.03.015
Festa ED, Quinones-Jenab V (2004) Gonadal hormones provide the biological basis for sex differences in behavioral responses to cocaine. Horm Behav 46:509–519. doi:10.1016/j.yhbeh.2004.04.009
Fujii R, Okabe S, Urushido T et al (2005) The RNA binding protein TLS is translocated to dendritic spines by mGluR5 activation and regulates spine morphology. Curr Biol CB 15:587–593. doi:10.1016/j.cub.2005.01.058
Gasparini F, Lingenhöhl K, Stoehr N et al (1999) 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 38:1493–1503. doi:10.1016/S0028-3908(99)00082-9
Golden SA, Russo SJ (2012) Mechanisms of psychostimulant-induced structural plasticity. Cold Spring Harb Perspect Med. doi:10.1101/cshperspect.a011957
Grove-Strawser D, Boulware MI, Mermelstein PG (2010) Membrane estrogen receptors activate the metabotropic glutamate receptors mGluR5 and mGluR3 to bidirectionally regulate CREB phosphorylation in female rat striatal neurons. Neuroscience 170:1045–1055. doi:10.1016/j.neuroscience.2010.08.012
Hu M, Becker JB (2003) Effects of sex and estrogen on behavioral sensitization to cocaine in rats. J Neurosci 23:693–699
Huang GZ, Woolley CS (2012) Estradiol acutely suppresses inhibition in the hippocampus through a sex-specific endocannabinoid and mGluR-dependent mechanism. Neuron 74:801–808. doi:10.1016/j.neuron.2012.03.035
Ito R, Robbins TW, Everitt BJ (2004) Differential control over cocaine-seeking behavior by nucleus accumbens core and shell. Nat Neurosci 7:389–397. doi:10.1038/nn1217
Justice AJ, de Wit H (1999) Acute effects of d-amphetamine during the follicular and luteal phases of the menstrual cycle in women. Psychopharmacology 145:67–75
Lavreysen H, Wouters R, Bischoff F et al (2004) JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist. Neuropharmacology 47:961–972. doi:10.1016/j.neuropharm.2004.08.007
Loweth JA, Tseng KY, Wolf ME (2013) Using metabotropic glutamate receptors to modulate cocaine’s synaptic and behavioral effects: mGluR1 finds a niche. Curr Opin Neurobiol 23:500–506. doi:10.1016/j.conb.2013.01.009
Mccance-katz EF, Hart CL, Boyarsky B et al (2005) Gender effects following repeated administration of cocaine and alcohol in humans. Subst Use Misuse 40:511–528
McEwen BS (2001) Invited review: estrogens effects on the brain: multiple sites and molecular mechanisms. J Appl Physiol 91:2785–2801
Meitzen J, Mermelstein PG (2011) Estrogen receptors stimulate brain region specific metabotropic glutamate receptors to rapidly initiate signal transduction pathways. J Chem Neuroanat 42:236–241. doi:10.1016/j.jchemneu.2011.02.002
Meredith GE, Baldo BA, Andrezjewski ME, Kelley AE (2008) The structural basis for mapping behavior onto the ventral striatum and its subdivisions. Brain Struct Funct 213:17–27. doi:10.1007/s00429-008-0175-3
Milner TA, McEwen BS, Hayashi S et al (2001) Ultrastructural evidence that hippocampal alpha estrogen receptors are located at extranuclear sites. J Comp Neurol 429:355–371
Mitrano DA, Smith Y (2007) Comparative analysis of the subcellular and subsynaptic localization of mGluR1a and mGluR5 metabotropic glutamate receptors in the shell and core of the nucleus accumbens in rat and monkey. J Comp Neurol 500:788–806. doi:10.1002/cne.21214
Olive MF (2010) Cognitive effects of Group I metabotropic glutamate receptor ligands in the context of drug addiction. Eur J Pharmacol 639:47–58. doi:10.1016/j.ejphar.2010.01.029
Olive MF, Cleva RM, Kalivas PW, Malcolm RJ (2012) Glutamatergic medications for the treatment of drug and behavioral addictions. Pharmacol Biochem Behav 100:801–810. doi:10.1016/j.pbb.2011.04.015
Ridenour TA, Maldonado-Molina M, Compton WM et al (2005) Factors associated with the transition from abuse to dependence among substance abusers: implications for a measure of addictive liability. Drug Alcohol Depend 80:1–14. doi:10.1016/j.drugalcdep.2005.02.005
Robinson TE, Kolb B (2004) Structural plasticity associated with exposure to drugs of abuse. Neuropharmacology 47(Suppl 1):33–46. doi:10.1016/j.neuropharm.2004.06.025
Roth ME, Cosgrove KP, Carroll ME (2004) Sex differences in the vulnerability to drug abuse: a review of preclinical studies. Neurosci Biobehav Rev 28:533–546. doi:10.1016/j.neubiorev.2004.08.001
Russo SJ, Dietz DM, Dumitriu D et al (2010) The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci 33:267–276. doi:10.1016/j.tins.2010.02.002
Segarra AC, Agosto-Rivera JL, Febo M et al (2010) Estradiol: a key biological substrate mediating the response to cocaine in female rats. Horm Behav 58:33–43. doi:10.1016/j.yhbeh.2009.12.003
Sircar R, Kim D (1999) Female gonadal hormones differentially modulate cocaine-induced behavioral sensitization in fischer, lewis, and Sprague–Dawley rats. J Pharmacol Exp Ther 289:54–65
Staffend NA, Loftus CM, Meisel RL (2011) Estradiol reduces dendritic spine density in the ventral striatum of female Syrian hamsters. Brain Struct Funct 215:187–194. doi:10.1007/s00429-010-0284-7
Wang X, Moussawi K, Knackstedt L et al (2013) Role of mGluR5 neurotransmission in reinstated cocaine-seeking. Addict Biol 18:40–49. doi:10.1111/j.1369-1600.2011.00432.x
Waselus M, Flagel SB, Jedynak JP et al (2013) Long-term effects of cocaine experience on neuroplasticity in the nucleus accumbens core of addiction-prone rats. Neuroscience 248C:571–584. doi:10.1016/j.neuroscience.2013.06.042
Woolley CS (1998) Estrogen-mediated structural and functional synaptic plasticity in the female rat hippocampus. Horm Behav 34:140–148. doi:10.1006/hbeh.1998.1466
Acknowledgments
This material is based upon work supported by the National Institutes of Health DA035008 and National Science Foundation IOS-114616 and Grant No. 00006595. We would like to thank Dr. Luis Martinez for advice and technical assistance.
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical standard
This manuscript does not contain clinical studies or patient data.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Peterson, B.M., Mermelstein, P.G. & Meisel, R.L. Estradiol mediates dendritic spine plasticity in the nucleus accumbens core through activation of mGluR5. Brain Struct Funct 220, 2415–2422 (2015). https://doi.org/10.1007/s00429-014-0794-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00429-014-0794-9