The interaction of membrane estradiol receptors and metabotropic glutamate receptors in adaptive and maladaptive estradiol-mediated motivated behaviors in females

Estrogen receptors were initially identified as intracellular, ligand-regulated transcription factors that result in genomic change upon ligand binding. However, rapid estrogen receptor signaling initiated outside of the nucleus was also known to occur via mechanisms that were less clear. Recent studies indicate that these traditional receptors, estrogen receptor α and estrogen receptor β, can also be trafficked to act at the surface membrane. Signaling cascades from these membrane-bound estrogen receptors (mERs) can rapidly alter cellular excitability and gene expression, particularly through the phosphorylation of CREB. A principal mechanism of neuronal mER action has been shown to occur through glutamate-independent transactivation of metabotropic glutamate receptors (mGlu), which elicits multiple signaling outcomes. The interaction of mERs with mGlu has been shown to be important in many diverse functions in females, including driving motivated behaviors. Experimental evidence suggests that a large part of estradiol-induced neuroplasticity and motivated behaviors, both adaptive and maladaptive, occurs through estradiol-dependent mER activation of mGlu. Herein we will review signaling through estrogen receptors, both “classical” nuclear receptors and membrane-bound receptors, as well as estradiol signaling through mGlu. We will focus on how the interactions of these receptors and their downstream signaling cascades are involved in driving motivated behaviors in females, discussing a representative adaptive motivated behavior (reproduction) and maladaptive motivated behavior (addiction).