Rapid effects of ovarian hormones in dorsal striatum and nucleus accumbens

Abstract

Contribution to Special Issue on Fast effects of steroids. Estradiol and progesterone rapidly induce changes in dopaminergic signaling within the dorsal striatum and nucleus accumbens of female rats. In ovariectomized females, estradiol rapidly enhances dopamine release and modulates binding of dopamine receptors. Progesterone further potentiates the effect of estradiol on dopamine release. The effects of both estradiol and progesterone are time course dependent, with increases in dopamine release immediately after acute hormone administration followed by later inhibition of dopamine release. Importantly, these changes are also seen in naturally cycling females, indicating their importance for normal physiological states and relevant reproductive behaviors. Here, we summarize the literature establishing the rapid effects of estradiol and progesterone on dopamine release and receptor expression in dorsal striatum and nucleus accumbens of both males and females. Integrating this literature with the larger body of work focusing on dopamine regulated behaviors, we propose hypotheses for adaptive reasons (i.e., ultimate causes) as to why changes in ovarian hormones modulate dopamine release. Finally, we note the importance of these studies for understanding sex differences in vulnerability to drug addiction. Research on how dopaminergic systems regulate behavior in both males and females is crucial for developing a full appreciation of dopamine's role in both natural and drug-induced behaviors.

Copyright © 2018 Elsevier Inc. All rights reserved.

Figures

Figure 1

Proposed model of estradiol (E2) regulation of striatal dopamine (DA) circuitry in females. E2 increases DA release with dorsal striatum by acting directly on GABAergic neurons to decrease GABA release and disinhibit DA terminals. E2 enhances DA release in NAc by acting directly on NAc GABA (1) or DA neurons (2), or by acting on GABAergic neurons in the medial preoptic area (MPOA) to increase inhibitory transmission to GABA interneurons in the VTA (3). Increased inhibition of VTA GABA interneurons leads to decreased inhibitory tone within VTA, and increased DA transmission (4).

Figure 2

Distribution of dopamine (DA) receptors and dopamine transporter (DAT; ) varies by sex and reproductive state. Expression of DAT is higher in females (c; solid blue line) than males (c; dashed blue line) regardless of estrous cycle stage, and increases the morning of proestrus, when levels of estradiol (E2) are peaking and levels of progesterone (P) begin to rise (b). Males have greater expression of D1 DA receptors ( ) in females, and D1 DA receptor expression does not change across the estrous cycle in females (a). Expression of D2 DA receptors is constant across the estrous cycle (a), but the ratio of high to low D2 DA receptors is dependent on both sex and reproductive state (c). Diestrus females have a higher level of high ( ) vs low ( ) D2 DA receptors than males (dashed green line), but as E2 and P rise during proestrus, the ratio of high to low D2 DA receptors in females (solid green line) decreases to lower than observed in intact males.

Figure 3

Proposed mechanism for estradiol (E2) enhancement of dopamine (DA)release within dorsal striatum. Activation of estradiol receptors (ER) located on soma, dendrites, or axonal terminals of GABAergic medium spiny neurons (MSNs) leads to decreased Ca2+ release and disinhibition of DA release from nigrostriatal terminals. The expanded view of the plasma membrane depicts that ERs are anchored to the plasma membrane via caveolin proteins (CAV). This positioning allows functional coupling of ERs to metabotropic glutamate receptors (mGluR). Within striatum, ERα is coupled to both Group I (mGluR5) and Group II (mGluR3) mGluRs, whereas ERβ is coupled to only group II mGluRs. Activation of ERs coupled to Group I mGluRs results in activation of protein kinase A (PKA)/mitogen-activated protein kinase (MAPK) pathways, leading to increased activation of cAMP response binding proteins (CREB). Alternatively, activation of ERs coupled to Group II mGluRs inhibits CREB via inhibition of adenylate cyclase (AC)/PKA pathways and decreased Ca2+ influx, resulting in decreased activity of calmodulin (CaM) and calcium/calmodulin dependent kinase IV.

Figure 4

Proposed mechanism for estradiol (E2) enhancement of dopamine (DA) release within nucleus accumbens (NAc). Activation of estradiol receptors (ER) located on GABAergic medium spiny neurons leads to disinhibition of DA release. ER are also expressed on pre-synaptic DA terminals within NAc. The expanded view of the plasma membrane depicts how ERβ activation decreases activity of Regulator of G-protein signaling 9-2, which leads to decreased inhibition of GTPases involved in deactivation of D2 DA receptor subunits, and ultimately increased D2 DA receptor signaling. The localization of this process to specific neuron populations within the NAcc is unknown. Alternatively, E2 can activate GABAergic projections to the ventral tegmental area (VTA) from the medial preoptic area (MPOA), which leads to decreased inhibitory tone within the VTA and increased DA transmission.