The purpose of the present proposal is to conduct basic research on the neurobiology and pharmacology of the central noradrenergic system, a brain system thought to play an important role in central responses to stress and in mechanisms of antidepressant drug action. Research on the behavioral functions of this system has been hampered by the lack of a suitable means to study the activity of its receptors in the brains of conscious, freely moving animals. Recent studies in our laboratory however have indicated that a new technique involving the detection by implanted microdialysis probes of increases in the level of the second messenger, cyclic AMP (cAMP), in the brain in vivo in response to infusion of catecholamines now makes possible the study of these receptors in the intact brain. The purpose of the proposed research is to further develop this technique and to use it to study the in vivo regulation of central noradrenergic receptor function by pharmacological processes which are related to various aspects of stress and depression.
The first aim of the project is to determine the sensitivity of the microdialysis-cAMP method in detecting experimental alterations in brain receptor function and in detecting ongoing neurotransmission at these receptors. This will be accomplished a) by determining if the technique can detect the chronic desensitization and sensitization of cAMP responses to catecholamines caused by chronic administration of an antidepressant drug or a central noradrenergic lesion, and b) by determining if it can detect cAMP responses to endogenous norepinephrine released by various procedures including stress, amphetamine infusion and stimulation of the locus coeruleus.
The second aim of the project is to utilize the microdialysis method to investigate physiological factors that modulate the output of noradrenergic receptors in vivo. The studies will focus on the adrenocortical system, a system known to be active during stress and thought to have regulatory effects on noradrenergic receptors and will determine if corticosterone alters the action of catecholamines on these receptors or protects them from desensitization during prolonged catecholamine exposure. The above research therefore has the potential for providing a new tool that will facilitate investigations of the role of the noradrenergic system in stress and antidepressant drug actions and of providing insight into the physiological regulation of noradrenergic receptors during stress and during psychopathological conditions in which the level of adrenocortical function is increased (e.g., endogenous depression).

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Method to Extend Research in Time (MERIT) Award (R37)
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Neurosciences Research Review Committee (BPN)
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New York University
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Lin, Yan; Quartermain, David; Dunn, Adrian J et al. (2008) Possible dopaminergic stimulation of locus coeruleus alpha1-adrenoceptors involved in behavioral activation. Synapse 62:516-23
Stone, Eric A; Lin, Yan (2008) An anti-immobility effect of exogenous corticosterone in mice. Eur J Pharmacol 580:135-42
Lin, Yan; de Vaca, Soledad Cabeza; Carr, Kenneth D et al. (2007) Role of alpha(1)-adrenoceptors of the locus coeruleus in self-stimulation of the medial forebrain bundle. Neuropsychopharmacology 32:835-41
Stone, Eric A; Quartermain, David; Lin, Yan et al. (2007) Central alpha1-adrenergic system in behavioral activity and depression. Biochem Pharmacol 73:1063-75
Stone, Eric A (2007) A final common pathway for depression: implications for therapy. Expert Opin Ther Targets 11:1019-32
Stone, Eric A; Lehmann, Michael L; Lin, Yan et al. (2006) Depressive behavior in mice due to immune stimulation is accompanied by reduced neural activity in brain regions involved in positively motivated behavior. Biol Psychiatry 60:803-11
Stone, Eric A; Yan, Lin; Ahsan, Mohammed R et al. (2006) Role of CNS alpha1-adrenoceptor activity in central fos responses to novelty. Synapse 59:299-307
Stone, Eric A; Lin, Yan; Ahsan, Mohammad R et al. (2005) Evidence of roles of central alpha1-adrenoceptors and epinephrine in orexin A-induced hyperactivity in mice. Neurosci Lett 381:325-8
Stone, Eric A; Lin, Yan; Ahsan, Mohammad R et al. (2005) Alpha(1)-adrenergic and alpha(2)-adrenergic balance in the dorsal pons and gross behavioral activity of mice in a novel environment. Psychopharmacology (Berl) 183:127-32
Stone, Eric A; Quartermain, David (2005) Rate-dependent behavioral effects of stimulation of central motoric alpha(1)-adrenoceptors: hypothesized relation to depolarization blockade. Psychopharmacology (Berl) 178:109-14

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