Further evidence on the anxiogenic-like effect of substance P evaluated in the elevated plus-maze in rats.

Substance P (SP) and its preferred NK1 receptor are widely expressed throughout the fear-processing pathways of the brain and its role in the modulation of experimental anxiety has been demonstrated. SP, like other peptides, are cleaved by peptidases in two fragments: C-terminal (SP 6-11) and N-terminal (SP 1-7) that could be responsible for its anxiogenic-like response. In this study we investigate the effects of i.c.v. micro-injections of SP free acid (SPfa), which is resistant to enzymatic cleavage, the influence of the pretreatment with peptidase inhibitors (PIs), thiorphan and/or phosphoramidon, as well as the effects of SP 6-11 and SP 1-7 and the participation of NK1 and NK2 receptors on their behavioral effects. Adult male Wistar rats were treated with 10 pmol solutions of SP 6-11, SP 1-7 or 1 and 10 pmol of SPfa and evaluated in the elevated plus maze (EPM) test. Other experimental groups received thiorphan 0.2 pmol, phosphoramidon 2 pmol or both PIs 30 min prior SP 1-11, 10 pmol i.c.v. The C-terminal fragment (SP 6-11, 10 pmol) and SPfa (1 pmol) promoted an anxiogenic-like profile of action similar to 10 pmol of SP 1-11, i.e., a decrease of entries and time spent on the open arms, whereas the N-terminal fragment (SP 1-7) was inactive at the EPM. The effect of SP 6-11 was inhibited by pretreatment (100 pmol) with NK1 (FK 888) and NK2 (SR 48968) antagonists. Moreover, both PIs enhanced the SP effect when used alone, but their combination produced an apparent reversion of anxiogenic-like effect produced by SP. Altogether, our results give further support to the SP role in the modulation of experimental anxiety in rats.