Expression and presence of septal neurokinin‐2 receptors controlling hippocampal acetylcholine release during sensory stimulation in rat

Abstract

We examined the expression and presence of NK2 receptors in the septal area of rat brain, and investigated their functional role in the regulation of the septohippocampal cholinergic system. Using reverse transcription-polymerase chain reaction (RT-PCR) analysis, we showed the presence of NK2 receptor mRNA expression in the septal area, and detected septal NK2 binding sites by using a fluorescent-tagged neurokinin A (NKA) derivative. In vivo microdialysis was employed to explore the functional role of NK2 receptors in the release of hippocampal acetylcholine evoked by tactile stimulation in freely moving rats. Two sessions of stroking of the neck and back of the rat for 30 min, at 90 min intervals, produced a marked and reproducible increase in hippocampal acetylcholine release. This effect was dose-dependently prevented by intraperitoneal administration of the two selective non-peptide tachykinin NK2 receptor antagonists SR144190 (0.03-0.3 mg/kg, i.p.) and SR48968 (0.3 and 1 mg/kg, i.p.), but not by the inactive enantiomer of SR48968 (SR48965, 1 mg/kg) nor by the two non-peptide NK1 receptor antagonists SR140333 (3 mg/kg, i.p.) and GR205171 (1 mg/kg, i.p.). Furthermore, the intraseptal application of SR144190 (10(-8) M) reduced the sensory response. Finally, intraseptal perfusion of neurokinin A (0.01-10 microM) in anaesthetized rats produced a concentration-dependent increase in hippocampal acetylcholine release. The response to neurokinin A (0.1 microM) was prevented by SR144190 (0.03-0.3 mg/kg, i.p.) and SR48968 (0.3-1 mg/kg, i.p.). In conclusion, this study provides direct evidence for the role of endogenous NKA/substance P, through the activation of NK2 receptors, in regulating the septohippocampal cholinergic function.

Receptor-mediated internalization of somatostatin in rat cortical and hippocampal neurons

“…The punctate distribution of internalized fluo-SRIF further supports an endosomal sequestration of the endocytosed ligand and is congruent with the vesicular localization of somatostatin reported for internalized 125 I-SRIF (Morel et al, 1985) and colloidal gold-labeled SRIF (Draznin et al, 1985) in pituitary cells. Other neuropeptides, such as neurotensin (Nouel et al, 1997a) and substance P (Steinberg et al, 1998) were previously found to internalize in neurons in a receptor-dependent manner. Several G-protein-coupled receptors were also shown to undergo ligand-induced internalization in nerve cells (Mantyh et al, 1995a,b;Bernard et al, 1998;Dumartin et al, 1998;Marvizón et al, 1999), but in these cases it was unclear whether the ligand was endocytosed together with the receptor or not.…”

Neurokinin3 receptor as a target to predict and improve learning and memory in the aged organism

“…Substance P was also found to increase ACh neurotransmission (27,28). However, it is possible that the memory-facilitating effect of SP is not solely modulated by NK1-Rs on cholinergic neurons, but also by NK3-Rs, because SP, although with highest affinity to NK1-Rs, can also bind to NK3-Rs (9,29).…”

“…Aged humans and animals show considerable individual differences in performance in cognitive tasks (21,22,26,27). Ageassociated differences in sensitivity to NK3-R agonism most likely reflect differences in cholinergic degeneration (35).…”

Are biological actions of neurokinin A in the adult brain mediated by a cross-talk between the NK1 and NK2 receptors?

“…4D). NK 2 receptors have been detected in discrete brain regions including the hippocampus, the septum the thalamus and the cortex (Steinberg et al, 1998;Saffroy et al, 2001Saffroy et al, , 2003. Nevertheless, the proposed concept of NK 1 /NK 2 receptor dimerization conforms to all principle findings reported in the present study: i) the essential role of the NK 1 receptor in the mediating central NKA responses, ii) the high potency of SR 48968 to inhibit these responses and, iii) the inability of selective peptide NK 2 receptor agonists to trigger biological effects in the brain.…”