The Role of Ventral Tegmental Area Estrogen Receptors in Neuronal Responses to Dopamine and Ethanol

Understanding the underlying biology of gender differences in drug addiction is important for developing effective new therapies to treat addiction. The ventral tegmental area (VTA) is a midbrain region enriched in dopamine (DA) neurons that regulate the rewarding and reinforcing effects of drugs of abuse. 17β-estradiol (E2) has profound effects on the midbrain DA system and enhances alcohol (ethanol) drinking in female rodents. Increased drinking by females may be due to E2 altering the physiology of VTA DA neurons. I hypothesized that E2 regulates the response of VTA DA neurons to ethanol and DA in female mice through activation of estrogen receptors. The aims of my project were therefore to (1) characterize the effect of E2 on the responses of VTA DA neurons to ethanol and DA, (2) determine which estrogen receptors mediate E2 effects on the sensitivity of VTA DA neurons to ethanol and DA, and (3) begin to investigate possible downstream signaling pathways activated by E2 that would alter the sensitivity of VTA DA neurons to ethanol and DA. I found that both excitation by ethanol and inhibition by DA of VTA DA neurons is enhanced when levels of E2 are elevated. E2-mediated enhancement of ethanol excitation occurs via activation of ER and a metabotropic glutamate receptor, whereas E2-mediated enhancement of DA inhibition requires both ER and ER. E2 also promotes the desensitization of the dopamine D2 receptor in the VTA. These changes in VTA function when E2 levels are high may promote binge drinking and increase drug reward in females.