Effects of Central Administration of Tachykinin Receptor Agonists and Antagonists on Plus-maze Behavior in Mice

This study assessed the effects of intracerebroventricular administration of selective agonists and antagonists for tachykinin NK1 and NK2 receptors on performance of mice in the elevated plus-maze, an ethological model of anxiety. Mice were treated with either vehicle (5 microliters) or 1, 10, 100 or 500 pmol of substance P, neurokinin A, the selective NK1 receptor agonist substance P methyl ester, or the selective NK2 receptor agonist, [beta-Ala8]neurokinin A-(4-10). Other mice received similar doses of FK 888, i.e., N2-[(4R)-4-hydroxy-1-(1-methyl-1 H-indol-3-y)carbonyl-L-prolyl]-N-methyl-N-phenylmethyl-3-(2-naphthyl)-L- alaninamide, or SR 48968, i.e., (S)-N-methyl-(N-[4-acetylamine-4-phenylpiperidine)-2-(3, 4-dichlorophenyl)buthyl]benzamide, selective antagonists of tachykinin NK1 and NK2 receptors, respectively. Injections of substance P, neurokinin A, substance P methyl ester or [beta-Ala8]neurokinin A-(4-10) significantly reduced the frequency of open arm entries, and [beta-Ala8]neurokinin A-(4-10) also enhanced the percentage of entries into enclosed arms. Conversely, the NK1 antagonist FK 888 and the NK2 antagonist SR 48968 each increased the time spent in the open arms, and SR 48968 also increased the frequency of entries into the open arms. None of the tachykinin receptor agonists or antagonists modified motor performance and coordination on the rotarod apparatus or ambulation in an activity cage. Together, these results suggest that centrally administered NK1 and NK2 receptor agonists and antagonists can modulate anxiety, as evaluated in the elevated plus-maze test in mice. Stimulation of either tachykinin NK1 or NK2 receptors induces anxiogenic-like responses, whereas the reverse occurs following their blockade. The anxiolytic-like profiles of action of both tachykinin NK1 and NK2 receptor antagonists suggest that central tachykinin mechanisms are tonically involved in the modulation of anxiety.