A dose-response analysis of intra-raphe tachykinin-induced hyperactivity

The nonmammalian (eledoisin, kassinin and physalaemin) and mammalian tachykinins (substance P and neurokinin (NK) A), as well as the metabolically stable neurokinin analogs, DiMe-C7 [( pGlu5, MePhe8, Sar9]substance P (5-11)] and senktide, were infused into the median raphe nucleus of rats via chronically implanted cannulas, and their effects on locomotor activity analyzed. The NK-3 receptor agonists, senktide and DiMe-C7, as well as the endogenous NK-2 receptor ligand, NKA, produced dose-dependent increases in locomotor activity. Substance P, eledoisin, kassinin and physalaemin elevated activity but not dose-dependently. Regression analyses demonstrated that senktide and DiMe-C7 were the most potent and efficacious of the peptides tested. The slopes of the senktide and DiMe-C7 dose-response curves were parallel and differed significantly from the slope of the NKA dose-response curve. Infusions of the endogenous NK-3 ligand, NKB (3.0 pmol in 1.0 microliter), also elicited hyperactivity equivalent to that produced by an equimolar dose of senktide. These and previous findings suggest that activation of NK-2 and NK-3 receptors in the midbrain raphe leads to behavioral arousal through their influence on serotonin neurons.