The pituitary adenylate cyclase-activating polypeptide receptor and its splice variants: Unique roles in affective...

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide with established roles in stress, affective behavior, and motivated behavior. Its primary receptor in the brain, the PACAP type I receptor (PAC1), has multiple variants due to alternative splicing of the gene, and these variants have been found to have different relationships with the stress response. In the field of motivated behavior, however, there has been much more limited research on these variants. This review focuses on the PAC1 and its splice variants, to propose that they should be thoroughly characterized in the context of motivated behavior. It develops the hypothesis that, for the motivated behavior of drug use, upregulation of a specific receptor variant during repeated episodes of drug use and withdrawal serves to reverse the early relationship between PACAP and drug use, switching from negative feedback in a non-dependent state to positive feedback in a dependent state. The review will first examine the known brain distribution and receptor dynamics of the PAC1 variants. Next, it will examine the known roles of PACAP and its receptor variants in stress, anxiety, and depression. Then, it will describe the known role of the PACAP system in alcohol use, as an example of drug use. Finally, the review will consider these known relationships in order to advance the proposal about how the PAC1 receptor variants may interact with drug use and dependence. Further research on this relationship could allow for the development of novel and effective medications for the treatment of drug use disorders.