PT - JOURNAL ARTICLE AU - Tristan J. Hynes AU - Kelly M. Hrelja AU - Brett. A. Hathaway AU - Celine D. Hounjet AU - Chloe S. Chernoff AU - Sophie A. Ebsary AU - Graeme D. Betts AU - Brittney Russell AU - Lawrence Ma AU - Sukhbir Kaur AU - Catharine A. Winstanley TI - Dopamine neurons gate the intersection of cocaine use, decision making, and impulsivity AID - 10.1101/2020.06.29.179069 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.06.29.179069 4099 - http://biorxiv.org/content/early/2020/06/30/2020.06.29.179069.short 4100 - http://biorxiv.org/content/early/2020/06/30/2020.06.29.179069.full AB - Gambling disorder and drug addiction are superficially similar, and highly comorbid. Both clinical populations are highly impulsive and exhibit risky decision-making. Drug-associated cues have long been known to facilitate habitual drug-seeking, and the salient audiovisual cues embedded within modern gambling products may likewise encourage problem gambling. The dopamine (DA) neurons of the ventral tegmental area (VTA) are exquisitely sensitive to drugs of abuse, uncertain rewards, and reward-paired cues, and may therefore be the common neural substrate mediating synergistic features of both disorders. To test this hypothesis, we first gained specific inhibitory control over VTA DA neurons by transducing a floxed inhibitory DREADD (AAV5-hSyn-DIO-hM4D(Gi)-mCherry) in rats expressing Cre recombinase in tyrosine hydroxylase neurons. We then trained rats in our cued rat gambling task (crGT), inhibiting DA neurons throughout task acquisition and performance, before allowing them to self-administer cocaine in the same diurnal period as crGT sessions. The trajectories of addiction differ in women and men, and the DA system may differ functionally across the sexes, therefore we used male and female rats here. We found that inhibition of VTA DA neurons improved decision making and impulse control in males, but surprisingly worsened decision making in females, yet prevented cocaine-induced deficits in decision making in both sexes. Inhibiting VTA DA neurons nevertheless drove both sexes to consume more cocaine. These findings show that chronic dampening of DA signalling can have both protective and deleterious effects on addiction-relevant behaviours, depending on biological sex and dependent variable of interest.Competing Interest StatementIn the last 3 years, CAW has been retained as an expert witness by Hogan Lovells LLP, and received due compensation. The authors confirm they have no other conflicts of interest or financial disclosures to make.