Prenatal Stress and Prenatal Alcohol Alter the Adult Dopamine System and Alcohol Consumption: Dopamine Drives Drinking Behavior in a Prospective Twenty-Year Longitudinal Experiment with Rhesus Macaques

Given the prevalence of alcohol use and stress during pregnancy, we examined the effects in offspring of prenatal alcohol and stress on the dopamine system and drinking behavior in a primate model. In a twenty-year prospective longitudinal experiment, we studied alcohol-naive adult rhesus monkeys of both sexes bred from mothers randomly assigned during pregnancy to consume moderate alcohol, be exposed to mild stress, both, or neither. Positron emission tomography (PET) was used to measure dopamine D 2 -type receptor (D2) and transporter (DAT) availability in substantia nigra/ventral tegmental area (SN/VTA), striatum, and prefrontal cortex (PFC), at baseline and after chronic fixed-dose drinking in offspring. After the follow-up PET scans, monkeys were given ad libitum access to alcohol. Findings were: (1) Prenatal stress increased DAT in SN/VTA and striatum, while an interaction of prenatal stress and alcohol altered D2 in PFC; (2) prenatal alcohol alone increased the fixed-dose drinking rate; (3) in the three brain regions, low baseline D2 predicted faster fixed-dose drinking rate, and changes in DAT from baseline to follow-up predicted consumption in subsequent ad libitum drinking; and (4) no significant alteration of D2 or DAT due to drinking was observed. This experiment highlights the sensitivity of the primate dopamine system to prenatal perturbations, dopamine’s role in drinking, and an individual neuroadaptive response to chronic alcohol consumption. The results suggest that alcohol abuse may originate, in part, from prenatal alcohol exposure. Moreover, reports in AUD of lower D2 might reflect pre-existing dopamine receptor status rather than resulting entirely from alcohol consumption. Significance Statement This work addresses important questions related to stress and alcohol use in pregnancy, as well as brain mechanisms underlying alcoholism. In a prospective longitudinal study of rhesus monkeys, we found that prenatal alcohol and stress exposure altered the adult dopamine system and drinking behavior. We also found that the dopamine system influenced drinking. This experimental work, which closely models prenatal exposures and drinking in humans, is relevant to public health policy. These brain-behavior findings add to knowledge gained from human retrospective and rodent experimental studies, which suggests that pregnant women should be warned of the risks of prenatal alcohol and stress. Furthermore, these results provide insight into dopamine’s role in alcohol use disorders that may aid the search for therapies.