Estradiol impacts the endocannabinoid system in female rats to influence behavioral and structural responses to cocaine - PubMed (original) (raw)

Estradiol impacts the endocannabinoid system in female rats to influence behavioral and structural responses to cocaine

Brittni M Peterson et al. Neuropharmacology. 2016 Nov.

Abstract

Compared with men, women show enhanced responses to drugs of abuse, and consequently are thought to be more vulnerable to addiction. The ovarian hormone estradiol has emerged as a key facilitator in the heightened development of addiction in females. These actions of estradiol appear mediated by estrogen receptor (ER) activation of metabotropic glutamate receptor type 5 (mGluR5). However, the downstream effectors of this ER/mGluR5 signaling pathway are unknown. Here we investigate whether cannabinoid 1 receptor (CB1R) activation is a part of the mechanism whereby estradiol influences behavioral and synaptic correlates of addiction. Following repeated cocaine administration, estradiol-treated ovariectomized rats exhibited both sensitized locomotor responses and decreases in the dendritic spine density of nucleus accumbens core medium-spiny neurons in comparison to oil-treated controls. Both effects of estradiol were blocked by AM251, a CB1R inverse agonist. These results indicate that part of the signaling mechanism through which estradiol impacts behavioral and synaptic correlates of addiction in female rats requires activation of CB1Rs.

Keywords: Behavioral sensitization; Dendritic spine plasticity; Drug addiction; Estrogen; Nucleus accumbens core; Type 1 cannabinoid receptors.

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Figures

Fig. 1

Timeline of experimental manipulations. Ovariectomized female rats were injected with the cannabinoid type 1 receptor inverse agonist, AM251, or vehicle (veh) followed by estradiol (E) or oil, on days 1, 2, 5, and 6 (n = 14–19 per group). Cocaine (Coc) was injected on days 3–7 and locomotor activity was assessed on day of the first and fifth Coc injections (Test 1 and Test 5 respectively). 24 hrs after the final Coc injection a subset of females that were tested for behavior were sacrificed for DiI labeling.

Fig. 2

The estradiol-mediated increase in cocaine-induced ambulations depends on type 1 cannabinoid receptors. In estradiol (E) treated females, ambulations (mean + SEM) were higher in response to the fifth cocaine (Coc) vs. first Coc injection (Test 5 vs. Test 1). This effect of estradiol was not observed when females were treated with the cannabinoid type 1 receptor inverse agonist, AM251, 30 min prior to estradiol. Oil or AM251 treatment alone did not affect Coc-induced ambulations. The number inside of each bar represents the number of animals per treatment condition. * p < 0.0125 Veh+E Test 1 vs Veh+E Test 5

Fig. 3

Estradiol-mediated dendritic spine plasticity in the nucleus accumbens core depends on type 1 cannabinoid receptors. a Low power DiI-labeled nucleus accumbens medium spiny neuron, scale bar 50 μm. b High power dendritic segment from an NAc core medium spiny neuron, scale bar 5 μm. c In cocaine-treated females, estradiol treatment decreased dendritic spine density of medium spiny neurons in the NAc core, and this effect was attenuated by pretreatment with the cannabinoid type 1 receptor inverse agonist, AM251. Dendritic spine density in the NAc core of females treated with AM251 alone did not differ from estradiol or oil treatment alone. d Cumulative probability distribution plot of dendritic spine density within treatment groups for nucleus accumbens core highlights the effect of estradiol on dendritic spines. The number inside of each bar represents the number of animals per treatment condition. * p < 0.05 Veh+Oil vs Veh+E and Veh+E vs AM251+E

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Estradiol impacts the endocannabinoid system in female rats to influence behavioral and structural responses to cocaine - PubMed (original) (raw)