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Electrophysiological characterization of chronic stress-induced sensitization of noradrenergic neurons of the locus coeruleus

Jedema, Hank Peter (2002) Electrophysiological characterization of chronic stress-induced sensitization of noradrenergic neurons of the locus coeruleus. Doctoral Dissertation, University of Pittsburgh.

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    Abstract

    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.


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    Item Type: University of Pittsburgh ETD
    ETD Committee:
    ETD Committee TypeCommittee MemberEmailORCID
    Committee ChairGrace, A.A
    Committee MemberSved, A.F
    Committee MemberAghajanian, G.K
    Committee MemberCard, J.P
    Committee MemberAustin, M.C
    Committee MemberSesack, S.R
    Committee MemberdeGroat, W.C
    Title: Electrophysiological characterization of chronic stress-induced sensitization of noradrenergic neurons of the locus coeruleus
    Status: Unpublished
    Abstract: 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.
    Date: 15 October 2002
    Date Type: Completion
    Defense Date: 31 July 2002
    Approval Date: 15 October 2002
    Submission Date: 26 August 2002
    Access Restriction: No restriction; The work is available for access worldwide immediately.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: PhD - Doctor of Philosophy
    URN: etd-08262002-163920
    Uncontrolled Keywords: chronic stress; cold exposure; corticotropin-releasing hormone; CRH; electrophysiology; locus coeruleus; norepinephrine
    Schools and Programs: Dietrich School of Arts and Sciences > Neuroscience
    Date Deposited: 10 Nov 2011 15:01
    Last Modified: 30 Apr 2012 13:59
    Other ID: http://etd.library.pitt.edu:80/ETD/available/etd-08262002-163920/, etd-08262002-163920

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