Sex-Dependent Effects of Stress on Immobility Behavior and VTA Dopamine Neuron Activity: Modulation by Ketamine.

Background: Stress constitutes a risk factor across several psychiatric disorders. Moreover, females are more susceptible to stress-related disorders, such as depression, than males. Although dopamine system underactivation is implicated in the pathophysiology of depression, little is known about the female dopamine system at baseline and post-stress. Methods: The effects of chronic mild stress were examined on ventral tegmental area dopamine neuron activity and forced swim test immobility by comparing male and female rats. The impact of a single dose of the rapid antidepressant ketamine (10 mg/kg, i.p.) on forced swim test immobility and ventral tegmental area function was then tested. Results: Baseline ventral tegmental area dopamine activity was comparable in both sexes. At baseline, females exhibited roughly double the forced swim test immobility duration than males, which corresponded to ~50% decrease in ventral tegmental area dopamine population activity compared with similarly treated (i.e., post-forced swim test) males. Following chronic mild stress, there was greater immobility duration in both sexes and reduced ventral tegmental area dopamine neuron activity by approximately 50% in males and nearly 75% in females. Ketamine restored behavior and post-forced swim test ventral tegmental area dopamine activity for up to 7 days in females as well as in both male and female chronic mild stress-exposed rats. Conclusions: These data suggest increased female susceptibility to depression-like phenotypes (i.e., greater immobility, ventral tegmental area hypofunction) is associated with higher dopamine system sensitivity to both acute and repeated stress relative to males. Understanding the neural underpinnings of sex differences in stress vulnerability will provide insight into mechanisms of disease and optimizing therapeutic approaches in both sexes.