Sex Differences in Behavioral Responses to Rewarding and Aversive Stimuli
Authors: Sanders Christie M. , Kutlu Munir Gunes , Calipari Erin S. 
Published: June 2021

Drug addiction is a devastating condition involving cycles of withdrawal, drug seeking despite adverse consequences, and relapse. Clinical and preclinical models show that females are more vulnerable to drug addiction than males, taking more cocaine and relapsing more frequently. To better understand these sex differences, operant conditioning was used to compare reward and aversive learning between male and female mice (Figure 1). Males and females were tested in separate groups in operant boxes containing two spatially distinct nose pokes. Mice were trained to nose poke on one poke for sucrose delivery during the presentation of a discrete cue. The alternative poke was paired with shock avoidance during the presentation of a different and distinct discrete cue. The first phase compared male and female responses to sucrose (i.e. positive reinforcement). Females learned to obtain sucrose reward faster than males. Next, during a negative reinforcement phase, a mild footshock was administered during a tone. Mice were trained to nose poke, on operanda opposite from the sucrose paired poke, to avoid shock. Males learned to avoid shock faster than females. Following these training phases, animals learned that each distinct cue represented that a particular subsequent nose poke response was correct – either on the right or left lever ‐ to receive sucrose or avoid shock. The third phase involved 50% sucrose and 50% shock trials, and trained mice to distinguish between a cue that predicted lever pressing for sucrose and a different cue that predicted lever pressing on the opposite lever for shock avoidance. The fourth and final phase involved 40% sucrose, 40% shock, and 20% conflict trials. During conflict trials, mice were presented with tone and white noise simultaneously, and had three choices: 1) poke to obtain sucrose and receive a mild foot shock, 2) poke to avoid shock with no sucrose, and 3) no response to receive shock and no sucrose. Under these conditions, all females chose to avoid shock, but most males chose sucrose. Additional testing showed that these behavioral effects were independent from shock sensitivity between the groups, which was not significantly different. These results suggest that males have greater motivation to obtain reward despite punishment, and that females value avoiding footshock over sucrose. To understand the neural circuitry that drives these behaviors, future studies will use inhibitory DREADDs to identify the role of specific dopamine cell types in reward and aversive learning.Support or Funding InformationFunding for this project was provided by the ASPET Summer Undergraduate Research Fellowship and by startup funds from Vanderbilt University School of Medicine (E.S.C), as well as funding from the National Institutes of Health (NIH). Funds from the National Institute of Drug Abuse (NIDA) DA042111(E.S.C) and the Brain and Behavior Research Foundation (E.S.C) also supported this work.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.