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Women are more susceptible than men to develop anxiety disorders, however, the mechanisms involved are still unclear. In this study, we investigated the role of group I metabotropic glutamate receptors (mGluRs), a target for anxiety disorders, and whether estradiol may modulate conflict-based anxiety in female rats by using the Vogel Conflict Test (VCT). We used ovariectomized female rats with high (OVX + EB) and low (OVX) estradiol levels and intact male rats to evaluate sex differences. Infusion of (S)-3,5-Dihydroxyphenylglycine (DHPG), a group I mGluR agonist, into the basolateral amygdala, a region involved in anxiety-responses, statistically increased the number of shocks in OVX, but not OVX + EB female rats at 0.1, nor at 1.0 μM. In contrast, DHPG statistically decreased the number of shocks in male rats at 1.0 μM only. DHPG (0.1 μM) increased the number of recoveries in OVX, but not OVX + EB or male rats. Sex differences were detected for the number of shocks, recoveries and punished licks, where female rats displayed more conflict than male rats. Western blot analyses showed that protein expression of mGluR1, but not mGluR5 was higher in OVX + EB > OVX > male rats in the amygdala, whereas no significant differences were detected in the hippocampus, olfactory bulb and/or the periaqueductal gray. Therefore, DHPG produced paradoxical effects that are sex dependent; producing anxiolytic-like effects in female rats, while anxiogenic-like effects in male rats according to the VCT. These results highlight the importance of including female experimental models to underpin the neural circuitry of anxiety according to sex and for the screening of novel anxiolytic compounds.

Anxiety is the most common psychiatric disorders affecting females twice more than males. In hippocampal cells, estradiol regulates group I/II metabotropic glutamate receptors (mGluR1a/5 and mGluR2/3, respectively) activation. Thus, estradiol might modulate female anxiety within the basolateral amygdala (BLA) through mGluRs. We hypothesized that: 1) BLA activation of mGluRs might produce anxiolytic‐like effects; and 2) mGluR protein expression will be up‐regulated, in an estradiol dependent manner. Ovariectomized female rats, with (OVX+EB) and without (OVX) estradiol treatment were compared to male rats. We infused (S)‐3,5‐dihydroxyphenylglycin (DHPG), a group I mGluR agonist into the BLA. Anxiety was analyzed with the elevated plus maze and risk assessment behaviors (RABs); and protein expression by western blots analysis. DHPG (1.0 μM) increased the time and entries in open arms; and reduced RABs in OVX+EB (p<0.05), but not OVX and/or male rats. In the amygdala, protein expression of mGluR1a and mGluR2/3 were up‐regulated in OVX+EB (p<0.05) than OVX and/or male rats. No differences were found for mGluR5. Thus, activation of group I mGluRs, within the BLA, depends upon estradiol to modulate female anxiety. This effect might be underlined by region‐specific estradiol genomic and nongenomic effects.Grant Funding Source: NIH‐EARDA 1G11H046326, MBRS‐RISE GM61838 and NSF DBI‐0932955

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