Elsevier

Neuroscience

Volume 94, Issue 2, September 1999, Pages 663-673
Neuroscience

Distribution of Fos-like immunoreactivity in guinea-pig brain following administration of the neurokinin-1 receptor agonist, [Sar9,Met(O2)11]substance P

https://doi.org/10.1016/S0306-4522(99)00283-3Get rights and content

Abstract

The tachykinins are a family of peptides with putative neurotransmitter roles in the nervous system. They mediate their effects via neurokinin-1, neurokinin-2 and neurokinin-3 receptors. There has been increasing interest in the therapeutic application of the tachykinin neurokinin-1 receptor antagonists in the treatment of pain and emesis, and more recently in depression. However, the central role of neurokinin-1 receptors is not well understood. The aims of the present study were to determine the behavioural responses of guinea-pigs, and the distribution of Fos-like immunoreactivity in the guinea-pig brain, following intracerebroventricular administration of the neurokinin-1 receptor-selective agonist, [Sar9,Met(O2)11]substance P. The effects of pretreatment with the neurokinin-1 receptor antagonist, SR 140333, were also investigated.

Administration of [Sar9,Met(O2)11]substance P induced increased locomotor activity, as well as face washing, grooming and wet-dog shake behaviours, all of which were inhibited by the neurokinin-1 receptor antagonist, SR 140333, indicating the involvement of neurokinin-1 receptors. In order to localize the brain regions activated by [Sar9,Met(O2)11]substance P, the distribution of neurons expressing Fos-like immunoreactivity was examined. [Sar9,Met(O2)11]substance P induced increased Fos-like immunoreactivity in widespread areas, including the frontal cortex, hippocampus, amygdala, thalamus, hypothalamus, periaqueductal gray, area postrema and nucleus of the solitary tract. SR 140333 reduced Fos-like immunoreactivity induced by [Sar9,Met(O2)11]substance P in most areas. Thus, brain regions associated with emotion, sensation, learning and memory, autonomic regulation and emesis were activated by stimulation of neurokinin-1 receptors.

The present data have added a functional domain to previous neurokinin-1 receptor localization studies by describing the extensive regions of the CNS that may be activated by stimulation of these receptors, and the potential of neurokinin-1 receptor antagonists to inhibit activation of these regions.

Section snippets

Animal preparation

Adult tricolour guinea-pigs of either sex (from the Central Animal Facility, University of Newcastle) weighing 450–550 g were used. The guinea-pigs were housed in a room maintained at constant temperature (23°C) and on a 12-h/12-h light/dark cycle. Food (standard guinea-pig pellets) and water were available ad libitum, and vitamin C was added to the drinking water daily. Implantation of i.c.v. cannulae was carried out as described previously.14 Guinea-pigs were weighed and anaesthetized with

Effect of [Sar9,Met(O2)11]substance P on locomotor activity and behaviours

Locomotor activity was significantly increased in animals given [Sar9,Met(O2)11]SP (1 nmol each side, i.c.v.) compared with control animals (Fig. 1). The increase in locomotor activity reached significance at 30 min (0.05>P>0.01) and was sustained for the remainder of the 90-min period of observation. Administration of the NK1 receptor antagonist SR 140333 (total dose 12 μg, i.c.v.), but not its less active enantiomer SR 140603, significantly reduced the increase in locomotor activity at 40 min

Discussion

Administration of [Sar9,Met(O2)11]SP produced increased locomotor activity which was inhibited by SR 140333, confirming that this response to [Sar9,Met(O2)11]SP was mediated by NK1 receptors. [Sar9,Met(O2)11]SP produced a wide range of behavioural responses, including circling, turning, cage biting, face washing, grooming, wet-dog shakes, scratching, chewing and vocalization. The most marked increases occurred in circling, face washing and wet-dog shake behaviours, each of which were

Conclusion

The data obtained in the present study have added a functional domain to previous NK1 receptor localization studies by describing the extensive regions of the CNS that may be activated by stimulation of these receptors, and the potential of NK1 receptor antagonists to inhibit activation of these regions.

Acknowledgments

We wish to thank Dr Emonds-Alt of Sanofi Recherche, France, for generous donations of SR 140333 and SR 140603. The work was supported by a project grant to L.A.C. (970799) from the National Health and Medical Research Council of Australia.

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