Intranigral substance P modulation of striatal dopamine: interaction with N-terminal and C-terminal substance P fragments

Abstract

The effects of unilateral injections of two substance P fragments, the N-terminal substance P (1–7) (SP 1–7) and the C-terminal substance P (6–11) (SP 6–11) into the subtantia nigra, pars reticulata on dopamine (DA) release in the ipsilateral striatum of halothane-anaesthetized rats were studied using microdialysis. SP 1–7 and SP 6–11 were also tested for their ability to modify the DA stimulation produced by intranigral injections of SP or neurokinin A (NKA). In addition, the SP antagonist Spantide I was tested for its ability to modify the DA stimulation produced by an intranigral injection of SP 1–7. Intranigral injections of SP 1–7 (0.001–5.0 nmol) inhibited DA release after low doses (0.001–0.01 nmol), but stimulated DA release after high doses (0.1–5.0 nmol). Striatal dihydroxyphenylacetic acid (DOPAC) levels increased moderately after high doses of SP 1–7 (1.0–5.0 nmol). Intranigral injections of SP 1–6 (0.01–5.0 nmol) inhibited DA release, but enhanced striatal DOPAC levels, dose-dependently. SP 1–7 (0.01–0.1 nmol), but not SP 6–11 (0.1 nmol), blocked the stimulation of striatal DA release produced by intranigral SP (0.07 nmol). Neither SP 1–7 (0.1 nmol) nor SP 6–11 (0.1 nmol) could modify the stimulation of striatal DA release produced by intranigral NKA (0.09 nmol). The increase in DA release after a high dose of SP 1–7 (1.0 nmol) was not modified by co-administration with Spantide I (0.07 nmol). It is concluded that low doses of the N-terminal SP fragment, SP 1–7, decreased striatal DA release via an antagonistic action on SP receptor/mechanisms, while high doses of SP 1–7 stimulated striatal DA release via a non-SP receptor/mechanism. The C-terminal SP fragment, SP 6–11, decreased striatal DA release, however, this seemed to be independent of SP or NKA receptor/mechanisms. Since SP 1–7 so potently inhibits SP actions, it is suggested that the stimulatory effects of SP on nigrostriatal DA might be internally regulated by the inhibitory properties of its metabolite SP 1–7.