Exploring sex differences in psychostimulant-induced activation of the tail of the ventral tegmental area

It is well established that women and men respond differently to drugs of abuse. Women begin use at an earlier age, progress through the stages of addiction more quickly, and are more vulnerable to relapse than men. Through the support of both human and animal literature, it is clear that one of the driving factors mediating this difference is ovarian hormones. Increases in the ovarian hormone estradiol have been linked to potentiated acquisition of cocaine administration, increased responding for cocaine in the maintenance of addiction, and increased cue-reactivity in female rats. Recent research has begun to characterize the primary reward circuit in female rats and women, but extended structures associated with the modulation of this circuit have not received as much attention. A newly characterized brain region, called the tail of the ventral tegmental area (tVTA), has been proposed to act as a "brake" on the dopamine system. While the unique function of this area has received attention in male rats, no such work has been conducted to investigate its function in female rats. The goal of the current project was to explore the recruitment of this area in a female population in response to cocaine administration and to determine the extent to which estradiol modulates this recruitment. Specifically, we wanted to determine the degree to which female rats express the same prominent cluster of FosB/DeltaFosB-expressing neurons that characterize the tVTA in male rats following cocaine administration, characterize the cytoarchitecture of these FosB/DeltaFosB-expressing neurons in female animals by identifying the distribution of FosB/DeltaFosB induction in both GABAergic and dopaminergic cells, and to identify any fluctuations in the degree of FosB/DeltaFosB expression in response to the presence or absence of estradiol replacement in ovariectomized female rats. Overall, we found that (1) female rats do express FosB/DeltaFosB in the tVTA following cocaine administration, (2) FosB/DeltaFosB expression in the tVTA is overwhelmingly expressed in GABAergic cells and almost completely absent in dopaminergic cells regardless of sex or treatment with estradiol, (3) acute pretreatment with estradiol does not meaningfully increase the recruitment of the tVTA when compared to acute peanut oil pretreated female animals, and (4) extended estradiol access significantly increases tVTA recruitment in response to cocaine administration when compared to both acute peanut oil and acute estradiol treated female animals. Taken all together, these data suggest that estradiol meaningfully regulates the recruitment of the tVTA in response to cocaine administration, and that this recruitment is more strongly regulated by the genomic effects of estradiol.