Estradiol facilitation of cocaine-induced locomotor sensitization in female rats requires activation of mGluR5

Abstract

In comparison to men, women exhibit enhanced responsiveness to the stimulating and addictive properties of cocaine. A growing body of evidence implicates the steroid hormone estradiol in mediating this sex difference, yet the mechanisms underlying estradiol enhancement of behavioral responses to cocaine in females are not known. Recently, we have found that estrogen receptor alpha (ERα) functionally couples with the metabotropic glutamate receptor 5 (mGluR5) to mediate the effects of estradiol on both cellular activation as well as dendritic spine plasticity in brain regions involved in cocaine-induced behavioral sensitization. Thus, we sought to determine whether mGluR5 activation is required for the facilitative effects of estradiol on locomotor responses to cocaine. To test this hypothesis, ovariectomized (OVX) female rats were tested for locomotor activity on the first and fifth days of daily systemic injections of cocaine. For the 2 days prior to each locomotor test, animals were injected with the mGluR5 antagonist MPEP (or vehicle) and estradiol (or oil). MPEP treatment blocked the facilitative effects of estradiol on cocaine-induced locomotor sensitization, without affecting acute responses to cocaine or the inhibitory actions of estradiol on weight gain. Considered together, these data indicate that mGluR5 activation is critical for the actions of estradiol on cocaine-induced behavioral sensitization.

Keywords: Behavioral sensitization; Drug addiction; Estrogen; Nucleus accumbens.

Figure 1

Timeline of experimental manipulations. OVX female rats were injected with MPEP or vehicle (Veh), followed by estradiol (E) or oil, on days 1, 2, 5, and 6 (n = 12-13 per group). Cocaine (Coc) was injected on days 3-7. Locomotor activity was assessed on the first and fifth Coc injection days.

Figure 2

Estradiol enhancement of cocaine-induced ambulations is dependent on mGluR5. In estradiol (E) treated females, ambulations (mean ± SEM) were higher in response to the fifth cocaine (Coc) vs. first Coc injection (Test 2 vs. Test 1, *p < .05 (paired-samples t-test)). This hormone effect was not observed when MPEP was administered 30 minutes prior to estradiol. In addition, MPEP alone did not affect Coc-induced ambulations.

Figure 3

Increase in fine motor movements following estradiol treatment and across test day. (A) Females exhibited more fine movements following the fifth cocaine (Coc) vs. the first Coc injection (Test 2 vs. Test 1), and more fine movements when injected with estradiol (E) vs. oil. (B) There were no differences within/across groups on rearing. *p < .05 (ANOVA main effect).

Figure 4

Estradiol attenuation of weight gain is unaffected by mGluR5 antagonism. In oil-treated OVX females, weight increased across the experimental time course, an effect that was not observed following estradiol (E) treatment. The inhibitory effects of E were not altered by MPEP treatment. *p < .05 (paired-samples t-tests with Bonferroni correction for multiple comparisons).