Estrogen receptor α and G-protein coupled estrogen receptor 1 are localized to GABAergic neurons in the dorsal striatum

Abstract

Estrogens affect dopamine transmission in the striatum, increasing dopamine availability, maintaining D2 receptor density, and reducing the availability of the dopamine transporter. Some of these effects of estrogens are rapid, suggesting that they are mediated by membrane associated receptors. Recently our group demonstrated that there is extra-nuclear labeling for ERα, ERβ, and GPER1 in the striatum, but that ERα and GPER1 are not localized to dopaminergic neurons in this region. GABAergic neurons are the most common type of neuron in the striatum, and changes in GABA transmission affect dopamine transmission. Thus, to determine whether ERα or GPER1 are localized to GABAergic neurons, we double labeled the striatum with antibodies for ERα or GPER1 and GABA and examined them using electron microscopy. Ultrastructural analysis revealed that ERα and GPER1 are localized exclusively to extranuclear sites in the striatum, and ~35% of the dendrites and axon terminals labeled for these receptors contain GABA immunoreactivity. Binding at membrane-associated ERα and GPER1 could account for rapid estrogen-induced decreases in GABA transmission in the striatum, which, in turn, could affect dopamine transmission in this region.

Sex differences in addiction

“…[77][78][79] However, estradiol receptors are not found on the striatal DA terminals, but are found on medium spiny GABA projection neurons that have reciprocal collaterals onto the presynaptic DA terminals. 80 These neuroanatomical results are consistent with patch-clamp electrophysiology showing that estradiol blocks L-type calcium channels in medium spiny striatal neurons and with in vivo microdialysis studies showing that estradiol attenuates potassium-stimulated striatal GABA release. 81,82 Thus, the rapid effects of estradiol on stimulated striatal DA release are apparently indirectly mediated by an attenuation of GABAergic inhibition.…”

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

“…Within the hippocampus, estradiol rapidly suppresses GABAergic signaling (Murphy et al, 1998), an effect that is dependent on both group I mGluR and endocannabinoid signaling and is specific to females (Huang and Woolley, 2012). Although similar effects of estradiol have not yet been demonstrated in the NAc, GABAergic medium spiny neurons (the principle output cell of the dorsal/ventral striatum) express ERα (Almey et al, 2016), and activation of cannabinoid receptor subtype 1 in the NAc rapidly induces dopamine release (Sperlágh et al, 2009). Recent work extends these findings by demonstrating that estradiol enhancement of behavioral sensitization to cocaine in females is prevented by blockade of cannabinoid receptor subtype 1 (Peterson et al, 2016).…”

Preventative treatment in an animal model of ADHD: Behavioral and biochemical effects of methylphenidate and its interactions with ovarian hormones in female rats

“…An additional possible mechanism could involve estrogenic effects on GABA neurons. Increases in estrogen produce a decrease in GABA transmission (Almey et al, 2016), which could also explain the findings hormones × treatment interaction in the Sham females. In the intact females, estrogen would decrease GABA, and treatment reverses the effects via the receptors as discussed above.…”