63 Sex-Dependent Effects in Dopaminergic Modulation of Risky Decision-Making in Rats

Objective:Determining neurobiological mechanisms underlying risk-taking behavior is paramount toward developing targeted therapeutics for psychiatric conditions with such behavioral deficits. Therapies are urgently needed given risk-taking is strongly linked to suicidal behavior. Risk-taking is often assessed in tasks of varied rewards and losses, complicating the interpretation of chasing rewards vs. avoiding punishments. A novel task in rats was designed which utilizes varying rewards only, so as to determine mechanisms contributing to ‘chasing’ higher rewards. This task was used to determine that the high reward (risk) preference of male rats was increased by pramipexole treatment [a dopamine D2 receptor-(D2R) family agonist] and decreased by optogenetic inhibition of D2R expressing neurons. The impact of D2R antagonists and sex-dependent differences were not examined however and remains unclear. Here, we trained female and male rats in the task to determine sex-differences in risk preference at baseline and in response to pharmacological challenges of pramipexole, the D2R antagonist sulpiride, and the dopamine transporter inhibitor GBR-12909.Participants and Methods:In operant boxes animals could choose from one of two nose-pokes, one that delivered a 50 μl strawberry milkshake reward (safe-option), and the other a 10 μl reward with 75% probability and 170 μl reward with 25% probability (risky-option). Once trained to a stable baseline of risk preference, rats were treated with pramipexole (0.15- or 0.3-mg/kg; Experiment 1) or sulpiride (30-mg/kg; Experiment 2) for 3 days, each separated by a saline washout. Animals were once again trained to a stable baseline, then injected with GBR-12909 (5- or 16-mg/kg; Experiment 3).Results:Baseline: females were less risk-adverse/more risk-prone than males. Experiment 1: there was a main effect of drug on percent risk choice (%RC) change from baseline [F(1,18)=10.5, p