Estradiol affects how ethanol influences dopamine neuron activity in the ventral tegmental area




Lambeth, Philip Stanhope

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Females can progress to alcohol and other substance use disorders more quickly than males. The ovarian hormone 17β-estradiol (E2) contributes to sex differences observed in drug use and abuse and may be a principal driver of these differences. However, it is not entirely clear how E2 acts to affect processing of ethanol reward, and several brain regions and mechanisms are implicated. We sought to clarify the role of E2 in modulating the response of ventral tegmental area dopamine neurons to ethanol. To this end, I recorded spontaneous action potentials and inhibitory postsynaptic currents from dopaminergic neurons in acute horizontal brain slices from ovariectomized (OVX) dopamine neuron reporter mice (Pitx3-eGFP) treated with either vehicle (VEH) or E2. My data confirmed that ethanol stimulation of the firing rate of dopamine neurons from OVX+E2 mice was greater than that of OVX+VEH animals. Further, we hypothesized that the firing rate increase would be accompanied by a concomitant decrease in ethanol stimulated inhibition onto those same neurons. I found that although ethanol caused the expected increase in the frequency of GABA [subscript A] receptor-mediated synaptic inhibition in both groups, there was no difference in this response between OVX+E2 and OVX+VEH animals. I also observed a small effect of ethanol to increase the amplitude of these currents in both groups. These findings lend additional support for the ability of E2 to enhance ventral tegmental area dopamine neuron responses to ethanol and suggest that this effect is not mediated by an E2-elicited suppression of synaptic inhibition, although future studies are needed to conclusively determine the mechanism. The experiments and research surveyed in this document help to strengthen the field of addiction generally, as well as alcohol research specifically. As although alcohol has some very specific effects, the information that we learn about dopaminergic transmission as it relates to drug use can be used well outside of the alcohol field. Furthermore, this research has led to new insights into the underlying causes and subsequent consequences of sex differences, both physiological and behavioral.


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