Control by tachykinin NK 2 receptors of CRF 1 receptor-mediated activation of hippocampal acetylcholine release in the rat and guinea-pig

Abstract

In vivo microdialysis was employed to explore the effects of different selective non-peptides NK 1,NK 2 and NK 3 receptor antagonists on the corticotropin releasing factor (CRF)-induced release of acetylcholine (ACh) in the hippocampus of rats and guinea-pigs. In both species, the intracerebroventricular (i.c.v.) administration of CRF produced a time- and dose-dependent increase in hippocampal ACh release that was totally suppressed by an intraperitoneally (i.p.) pretreatment with the selective non-peptide CRF 1 receptor antagonist antalarmin (30 mg/kg). Pretreatment with the selective NK 2 receptor antagonist SR48968 (1 mg/kg, i.p.) significantly reduced the increase of ACh induced by CRF. In contrast, its low-affinity enantiomer SR48965 (1 mg/kg, i.p.) or the NK 1 receptor antagonist, GR205171 (1 mg/kg, i.p.) did not exert any antagonist effect. Moreover, administration of the selective NK 3 receptor antagonist SR142801 (1 mg/kg, i.p.) did not significantly reduce the CRF-induced hippocampal ACh release in guinea-pigs (the only species studied). The selective activity of SR48968 versus GR205171 or SR142801 indicates that NK 2 receptors play a major role in the control of CRF-induced hippocampal ACh release. Moreover, in freely moving rats, two sessions of stroking of the neck and back of the rat for 30 min, at 90 min intervals, known to be a stressful stimulus, produced a marked and reproducible increase in hippocampal ACh release. This effect was prevented by the administration of the two selective non-peptide CRF1 and NK 2 receptor antagonists antalarmin (30 mg/kg, i.p.) and SR48968 (1 mg/kg, i.p.), respectively. This suggests that stress-induced activation of the hippocampal ACh system may be under the control of both endogenously released CRF and NKA, and opens the possibility of the existence of a functional interplay between the pathways containing these peptides as we observed in our experiments on anaesthetized animals.