A critical issue in substance abuse research is why some individuals can actively use addictive drugs and quit with relative ease, while others may only try a small dose before becoming life-long dependent (Fitzpatrick et al., 2016). The use of designer receptors exclusively activated by designer drugs (DREADDs) may shed light on individual differences in learning behaviors and why some individuals seem to be more prone to addiction and relapse than others. Using stereotaxic surgery on rats, an in vivo dual-vector approach was used to bilaterally inject Cre recombinase into the nucleus accumbens (NAc) and an excitatory Cre-dependent, G protein-coupled DREADD into the ventral hippocampus (vHPC). Five weeks after surgery, clozapine-N-oxide (CNO) was injected intraperitoneally to selectively activate this pathway for six days. Rats were then given one day of cross treatment followed by conditioned reinforcement. These procedures allowed determination of whether activation of the vHPC– NAc projection affects acquisition and/or expression of Pavlovian conditioned approach (PCA) behavior. There were no statistically significant differences amongst treatment groups. However, trends in data support a differential role of the vHPC—NAc pathway in sign- and goal-tracking behaviors, suggesting a need for further investigation using larger sample sizes to determine the importance of this pathway. Although this study found no statistically significant evidence for the role of the vHPC-NAc pathway in PCA behaviors, current and future findings may add to an understanding of how learning and neurological activity may play a role in behaviors associated with addiction in human beings.