Cortical induction of c-fos by intrastriatal endothelin-1 is mediated via NMDA receptors

Abstract

Intracerebral administration of endothelins (ETs) to rats induces a distinct and unusual behavioural syndrome which includes barrel-rolling and other seizures. 1,2 The mechanisms by which ETs produce these behaviours are not known, although it is generally considered that the action of ET in the CNS is mediated via a vasoconstrictor action on the cerebral vasculature. 3 ET receptors are not restricted to the vasculature, but are widely expressed throughout the brain. 4,5 Further, while the action of ETs on blood vessels is undisputed, there is growing evidence for a direct action of ETs on neurones, most of which comes from in vitro studies where neurones and glia are grown in the absence of vascular elements. [6][7][8] We tried to determine whether ETs act directly on neurones in vivo, using the expression of the immediate early gene c-fos as a marker of neuronal activation. 9 Transcription of c-fos is known to be induced in neuronal pathways in response to intrastriatal injection of excitotoxins, with different agonists inducing patterns of Fos expression different from each other. 9-12 and also distinct from those induced by ischaemia. 10,13 The pattern of c-fos expression induced by intrastriatal injection of ET-1 was examined, and compared with that reported after excitotoxin administration and forebrain ischaemia. The possible involvement in ET action of Nmethyl-D-aspartate (NMDA) receptors and of nitric oxide (NO) synthesis were also examined. Materials and MethodsIntrastriatal stereotaxic injection of ET-1: Adult male Sprague-Dawley rats were anaesthetized with halothane in nitrous oxide/oxygen. Halothane was used to induce anaesthesia, as recovery is rapid, and observation of the behaviour of the rats within the first 30 min after treatment was required. Twelve rats were given stereotaxic intrastriatal injections of ET-1 (0.1 nmol in 0.9% saline, injected in a volume of 1 l over a period of 2 min 3 ). Three additional rats were given control injections of saline alone. The coordinates used for all injections were 1 mm anterior and 2.5 mm lateral from bregma and 5 mm ventral from the dura mater, with the incisor bar at the interaural line. Pre-treatment with MK-801 (dizocilpine) or L-NNA (N -nitro-L-arginine):Three rats were treated with the NMDA receptor antagonist MK-801 (5 mg kg -1 , i.p.) 1 h before injection of ET-1. A further three rats were treated with the NOS inhibitor L-NNA (3 mg kg -1 , i.p.) 1 h before ET-1 injection. The behaviour of all rats was observed from the time of ET injection until sacrifice. Nine rats (three from ET-1 alone group, two from MK-801 group, two from L-NNA group and two from control group) were sacrificed 30 min after injection, and the brains were processed for in situ hybridization. The remaining five rats were sacrificed 1 h after the injection, by which time seizure activity had ceased. Seizures were scored using a modification of the Racine classification. 14 Neuropharmacology and Neurotoxicology 1 11 11 11 11 11 1p © Rapid Science Publishers Vol 8 No 1 20 December ...

Endothelin-1 Facilitates Synaptic Transmission in the Nucleus Tractus Solitarii in Normotensive Rats but Not in Spontaneously Hypertensive Rats.

“…These results are consistent with those of a receptor binding study in the NTS of both strains (15). There may thus be some association between ET receptor activation and Glu receptor activation, perhaps related to an increase in [Ca2] + ; (29,30). In support of this idea, it has been shown that the hypotensive effect of intracerebroventricular ET-1 is attenuated by excitatory amino acid receptor antagonists (8).…”