Interactions between estrogen receptors and metabotropic glutamate receptors and their impact on drug addiction in females

Abstract

Contribution to Special Issue on Fast effects of steroids. Estrogen receptors α and β (ERα and ERβ) have a unique relationship with metabotropic glutamate receptors (mGluRs) in the female rodent brain such that estradiol is able to recruit intracellular G-protein signaling cascades to influence neuronal physiology, structure, and ultimately behavior. While this association between ERs and mGluRs exists in many cell types and brain regions, its effects are perhaps most striking in the nucleus accumbens (NAc). This review will discuss the original characterization of ER/mGluR signaling and how estradiol activity in the NAc confers increased sensitivity to drugs of abuse in females through this mechanism.

Keywords: Brain; Drug addiction; Estrogen receptors; mGluR.

Figure 1

17β-Estradiol (17βE) binds to membrane-localized estrogen receptors (ER) to activate distinct signaling pathways via association with Group I or Group II mGluRs. Interaction with group I mGluRs activates Gq-mediated signaling through protein lipase C (PLC) and protein kinase C (PKC), leading to intracellular calcium release and activation of MAPK/ERK. Interaction with group II mGluRs activates Gi/o-mediated inhibition of adenylyl cyclase (AC), decreasing activity (indicated by gray dashed lines) of protein kinase A (PKA), resulting in reduced L-type calcium channel currents. CAV, caveolin. IP3, inositol triphosphate. IP3R, IP3 receptor. CaM, calmodulin. MEK, MAPK/ERK kinase. MAPK, mitogen-activated protein kinase. RSK, ribosomal S6 kinase. CaMKIV, calcium/calmodulin-dependent protein kinase type IV.

Figure 2

Overexpression of caveolin-1 (Cav1) in the nucleus accumbens (NAc) facilitates cocaine-mediated behavioral sensitization in female rats. (A) Immunohistochemistry confirmation of Cav1 overexpression (regulated under the synapsin (Syn) promoter) two weeks following AAV9-mediated delivery (left panel). Control animals overexpressed red fluorescent protein (RFP) (middle panels). Western blot confirmation of Cav1 overexpression in the NAc compared to caudate putamen (CPu) control region. GAPDH was used as a loading control (right panel). (B) Only animals overexpressing Cav1 exhibited behavioral sensitization between the first and seventh day of cocaine treatment (n = 9–10; *p = 0.01, paired-sample t-test between groups within day following main effect of two-way ANOVA). Dashed line indicates baseline ambulatory behavior one-day prior to cocaine administration. No differences were observed on these habituation days or in animals receiving repeated saline (data not shown).