GPR55 in the bed nucleus of stria terminalis modulates anxiety-like behavior, amphetamine self-administration and inflammatory response.

The antireward system, which regulates fear and anxiety, includes several nuclei, such as the bed nucleus of the stria terminalis (BNST). The GPR55 receptor seems to play a critical role in BNST physiology and anxiety regulation, although our knowledge on this topic is still limited. This study aimed to investigate the effects of GPR55 activation in the BNST on anxiety, amphetamine (AMPH)-seeking and consumption behaviors, and the AMPH-induced inflammatory response. Adult male Wistar rats were subjected to an AMPH self-administration (AMPH-SA) protocol. Initially, rats were trained to press a lever under a fixed ratio 1 (FR1) schedule to obtain a 45 mg food pellet. Following the acquisition of lever-pressing behavior, rats were anesthetized for bilateral implantation of stainless-steel cannula into the BNST and catheterization of the jugular vein for AMPH delivery. The AMPH-induced breakpoint (AMPH-BP) was also evaluated. After completing the AMPH-SA protocol, interleukin expression in BNST samples was assessed using Western blot analysis. In a separate group of AMPH-naïve rats, anxiety-like behaviors under GPR55 activation were examined using the elevated plus maze (EPM) following administration of lysophosphatidylinositol (LPI), a GPR55 agonist or CID 16020046 (CID), an GPR55 antagonist. In a third experimental group, GPR55-siRNA was injected into the BNST for three consecutive days, followed by an evaluation of anxiety-like behavior and AMPH-SA. LPI infusion into the BNST reduced anxiety-like behavior, AMPH-SA, AMPH-BP, and AMPH-induced pro-inflammatory cytokine expression (IL-1β and IL-6) while increasing the expression of the anti-inflammatory cytokine IL-10. These effects were prevented by co-administration of CID. Conversely, GPR55-siRNA reduced GPR55 expression, which facilitated anxiety-like behavior and AMPH-SA. These findings suggest that GPR55 in the BNST modulates anxiety-like behaviors, reduces AMPH-induced inflammatory responses and decreases AMPH seeking.