Chronic stress exposure can produce sensitization of norepinephrine release in the terminal fields of locus coeruleus (LC) neurons. The present studies explore the potential localization and mechanism underlying the sensitized response of LC neurons in rats following chronic exposure to cold (2 weeks; 5*C).
Single unit recordings of LC neurons in halothane-anesthetized rats were used to compare the effect of intraventricular administration of corticotropin releasing hormone (CRH; 0.3-3.0µg) in control and previously cold-exposed rats. The CRH-evoked increase in LC neuron activity was enhanced following chronic cold exposure, without alteration in basal activity. The enhanced activation was only apparent at higher doses of CRH, resulting in an increased slope of the dose-response relationship for CRH in previously cold-exposed rats. It is concluded that the sensitization of CRH-evoked norepinephrine release in cold-exposed rats is accompanied by sensitization of LC neuron activity. We hypothesized that the response of LC neurons to multiple excitatory inputs is enhanced.
Using in vitro intracellular recordings, we subsequently examined whether CRH exerts a direct effect on LC neurons, and which ionic currents and second messenger systems are likely affected by CRH. It was demonstrated that CRH dose-dependently increases the firing rate of LC neurons through a direct (TTX-insensitive) mechanism by decreasing a potassium conductance via adenylate cyclase and protein kinase A. The CRH-evoked activation of LC neurons is, at least in part, mediated by CRH1 receptors.
In subsequent in vitro experiments using intracellular recordings, the electrophysiological properties of LC neurons were compared between control and cold-exposed rats. We observed that the excitability and input resistance of LC neurons was enhanced in slices from cold-exposed rats. In addition, the accommodation of spike firing was reduced and there was a strong trend toward a reduction of the post-activation inhibitory period. These data demonstrate that the stress-induced sensitization of LC neurons is, at least in part, maintained in vitro and suggest that alterations in electrophysiological properties of LC neurons contribute to the chronic stress-induced sensitization of central noradrenergic function observed in vivo. Furthermore, these data suggest that an alteration in auto-inhibitory control of LC activity is involved in chronic stress-induced alterations.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08262002-163920 |
| Date | 15 October 2002 |
| Creators | Jedema, Hank Peter |
| Contributors | M.C. Austin, J.P. Card, W.C. deGroat, S.R. Sesack, A.F. Sved, A.A. Grace, G.K. Aghajanian |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu:80/ETD/available/etd-08262002-163920/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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