Methamphetamine-withdrawal stress activates PACAP-DBI pathway in rat salivary gland, resulting in inhibition of salivary secretion.

The purpose of this study was to investigate activation of inhibitory regulation pathways by methamphetamine (METH)-withdrawal stress in rat salivary gland. Our previous study showed that METH-withdrawal stress activated steroid biosynthesis and that pregnenolone produced during the early stage of this process inhibited salivary secretion. However, how this type of stress inhibits salivary secretion and the activation pathway of steroid biosynthesis in salivary gland remain to be clarified. In the present study, using an in vivo cannulation method, METH-withdrawal stress decreased salivary secretion and increased expression of diazepam-binding inhibitor (DBI), an endogenous peripheral-type benzodiazepine receptor (PBR) agonist; Western blot and RT-PCR also showed increased expression of DBI mRNA in parotid, submandibular, and sublingual gland. In addition, METH-withdrawal stress also elicited an increase in pituitary adenylate cyclase-activating polypeptide (PACAP) and PBR mRNA, which is associated with DBI activity. These results suggest that METH-withdrawal stress activates a PACAP-DBI pathway in salivary gland, enhancing steroid genesis and inhibiting secretion.