63 Sex-Dependent Effects in Dopaminergic Modulation of Risky Decision-Making in Rats
Authors: Ayoub Samantha M. , Libster Avraham M. , Dulawa Stephanie , Young Jared W. 
Published: December 2023

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<0.01], with pramipexole increasing %RC. When analyzed across each testing day, a main effect of session [F(6,108)=3.6, p<0.005] was observed, as was a session*sex*drug interaction [F(6,108)=2.2, p<0.05]. Post hoc analyses revealed females differed from males in the timing of their response to pramipexole based on dose. Experiment 2: there was a main effect of drug on %RC change from baseline [F(1,6)=20, p<0.01], with sulpiride decreasing %RC. There was also evidence for a drug*sex interaction [F(1,6)=3.6, p=0.11], with more pronounced attenuation by sulpiride in females. A similar pattern was observed when analyzed across testing days. Experiment 3: there was a main effect of drug on %RC change from baseline [F(2,26)=4.0, p<0.05], with the high dose of GBR-12909 (16-mg/kg) increasing %RC compared to VEH (p<0.05) and low dose (5-mg/kg).Conclusions:Together these data indicate a sex-specific modulation of baseline risk preferences as measured explicitly via reward seeking behaviors. Additionally, female rats may be more sensitive to D2R manipulations on such risky decision-making behavior, highlighting the necessity of tracking sex-based differences in such tasks. Ongoing studies will determine whether D2R activity reveal a similar sex-specific change during such reward-seeking risk-preference. Furthermore, ongoing studies will determine the link of such behavior to effortful decision making and more traditional measures of risk-taking behavior, such as the Iowa Gambling Task used both in rodents and humans.