Research reportLocus coeruleus activation by colon distention: role of corticotropin-releasing factor and excitatory amino acids
Introduction
The nucleus locus coeruleus (LC) gives rise to a widespread projection system that provides the major source of norepinephrine in the forebrain [41]. Activation of LC neurons and subsequent norepinephrine release onto forebrain target neurons has been implicated in arousal and attention 4, 20. The LC-noradrenergic (LC-NE) system is activated by sensory stimuli of various modalities, as demonstrated in unanesthetized monkeys [19], rats [5], and cats [1]. Additionally, metabolic 16, 30, cardiovascular 14, 49and visceral stimuli 15, 34increase LC discharge rate and this is often associated with activation of forebrain electroencephalographic (EEG) activity 34, 35, 44, indicating that the magnitude of LC activation produced by these stimuli is sufficient to impact on forebrain targets (see also [40]for review). LC activation by physiological stimuli may be important in initiating the forebrain activation that occurs in parallel with autonomic responses to these physiological stimuli.
Of the physiological stimuli that have been demonstrated to activate the LC, hypotension 14, 35, 44, 49and pelvic visceral stimuli [34]have been studied with regard to the mechanism by which they increase LC discharge rate. The effects of hypotension, produced by nitroprusside infusion, have been demonstrated to be dependent on endogenous corticotropin-releasing factor (CRF) and pharmacological evidence suggests that CRF inputs to the LC are required for these effects 35, 44, 49. In contrast, LC responses to a pelvic visceral stimulus, bladder distention, appear to be independent of CRF, but require activation of excitatory amino acid receptors in the LC [34]. A similar role for excitatory amino acid neurotransmission in the LC has been proposed for LC activation by sciatic nerve stimulation [17]and opiate withdrawal.
Colon distention is another pelvic visceral stimulus that increases LC discharge rate [15]. However, the circuitry and neurotransmitters underlying this activation are unknown. The same neuronal pathways that mediate LC activation by bladder distention could also underlie LC activation by colon distention, as both are pelvic visceral stimuli. Alternatively, a role for CRF in this response is also possible. Recent anatomical studies identified neurons in Barrington's nucleus that were retrogradely labeled from both the LC and lumbosacral spinal cord, some of which were CRF-immunoreactive [45]. As Barrington's projections to the sacral parasympathetic nucleus could influence colon function, it is possible that CRF-Barrington's neurons that diverge to project to the LC and spinal cord could coactivate the brain noradrenergic system and colonic efferents in response to colon distention. Indeed, this would be consistent with the hypothesized role of CRF in irritable bowel syndrome [42], a disorder characterized by both psychiatric and colonic dysfunctions [26].
In the present study single unit LC activity was recorded from halothane-anesthetized rats during distention of the distal colon and the ability of antagonists of CRF or excitatory amino acids to prevent LC responses to colon distention was used to elucidate a role of these putative neurotransmitters in this response.
Section snippets
Surgery
The procedures used for recording LC discharge of halothane-anesthetized rats were similar to those previously reported [46]. Male Sprague-Dawley rats (Taconic Farms; approximately 300 g) were anesthetized with a 1–2% halothane-in-air mixture administered through a nose cone. Rats were positioned in a stereotaxic instrument using blunt ear bars, and the head was oriented at a 15° angle to the horizontal plane (nose down). Body temperature was constantly monitored and maintained at 37°C with a
Effects of colon distention on LC discharge rate and cortical EEG
The mean spontaneous discharge rate recorded from 94 LC neurons prior to colon distention was 1.7±0.1 Hz. Colon distention of 2 min duration resulted in a reversible, volume-dependent increase in LC discharge (F(2,36)=12.4, P<0.001) (Fig. 1). Distention with 0.5, 1.0 and 3.0 ml volumes increased LC discharge by 16.6±2.2%, 34.1±5.2%, and 59.1±6.6% above predistention rates, respectively. This increase was significant for all volumes (P<0.01, Student's t-test for matched pairs; Fig. 1B). Fig. 1,
Discussion
The present study confirms and extends the findings of Elam and coworkers [15], which demonstrated that colon distention increases LC spontaneous discharge rates of halothane-anesthetized rats, by characterizing the neuromediators of this response. The differential pharmacological sensitivity of LC activation elicited by different magnitudes of colon distention suggests that heterogeneous neural pathways are recruited depending on the magnitude of the stimulus. Sensitivity to intracoerulear
Acknowledgements
This work was supported by USPHS Grants MH40008, MH42796, MH00840 (RSDA award to R.J.V.) and MH11312 (an NRSA to S.M.L.). The authors acknowledge the generosity of Dr. Jean Rivier for the gift of DPheCRF12–41. The authors also wish to thank Mr. Bowen Kang for expert technical assistance.
References (51)
- Abercrombie, E.D. and Jacobs, B.L., Single unit response of noradrenergic neurons in locus coeruleus of freely moving...
- Akaoka, H. and Aston-Jones, G., Opiate withdrawal-induced hyperactivity of locus coeruleus neurons is substantially...
- Akaoka, H., Saunier, C.-F., Chergui, K., Charlety, P., Buda, M. and Chouvet, G., Combining in vivo volume-controlled...
- Aston-Jones, G., Behavioral functions of locus coeruleus derived from cellular attributes, Physiol. Psych., 13 (1985)...
- Aston-Jones, G. and Bloom, F.E., Norepinephrine-containing locus coeruleus neurons in behaving rats exhibit pronounced...
- Berridge, C.W. and Foote, S.L., Effects of locus coeruleus activation on electroencephalographic activity in the...
- Berridge, C.W., Page, M.E., Valentino, R.J. and Foote, S.L., Effects of locus coeruleus inactivation on...
- Curtis, A.L., Grigoradis, D., Page, M.E., Rivier, J. and Valentino, R.J., Pharmacological comparison of two...
- Curtis, A.L., Pavcovich, L.A. and Valentino, R.J., Previous stress alters corticotropin-releasing factor...
- de Groat, W.C. and Steers, W.D., Autonomic regulation of the urinary bladder and sexual organs, Central Regulation of...