The present proposal is a revision of a previous grant, MH45265, whose aim was to elucidate the neurobiology of positively motivated behaviors that are deficient in depressive illness. The goal of the project is to identify more precisely how these behaviors are disrupted during this disorder. Previous work on this grant has shown that brain epinephrine (EPI) and central alpha-1 adrenoceptors, both of which have been neglected in prior research on depression, play key roles in positively motivated behaviors in animals and are altered by stressors that are known to induce depressive behavior. Specifically these studies have suggested the hypotheses that brain EPI is the endogenous neurotransmitter for behaviorally activating alpha-1 receptors and that this """"""""EPI/alpha-1 system"""""""" is specifically involved in positively- rather than negatively-motivated behaviors. These hypotheses will be tested in the present proposal by a combination of neuropharmacological, behavioral, immunohistochemical and neurochemical experiments that will assess the role of brain EPI as the endogenous stimulant of this system and the role of the system in various positively-motivated activities including self-stimulation of the lateral hypothalamus, conditioned approach and avoidance of positive and negative reinforcers, and effortful operant behavior. The research will likely identify the EPI/alpha-1 system as a new and important target for antidepressant and antistress medications ? ?

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Winsky, Lois M
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New York University
Schools of Medicine
New York
United States
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Lin, Yan; Sarfraz, Yasmeen; Jensen, Ashley et al. (2011) Participation of brainstem monoaminergic nuclei in behavioral depression. Pharmacol Biochem Behav 100:330-9
Lin, Yan; Suckow, Raymond F; Sarfraz, Yasmeen et al. (2011) Further evidence for an immediate antidepressant action of intracerebral drug administration in a model of chronic depression. Int J Neuropsychopharmacol 14:691-6
Stone, Eric A; Lin, Yan; Sarfraz, Yasmeen et al. (2011) The role of the central noradrenergic system in behavioral inhibition. Brain Res Rev 67:193-208
Stone, Eric A; Lin, Yan; Sarfraz, Yasmeen et al. (2011) Antidepressant-like action of intracerebral 6-fluoronorepinephrine, a selective full ?-adrenoceptor agonist. Int J Neuropsychopharmacol 14:319-31
Stone, Eric A; Lin, Yan (2011) Open-space forced swim model of depression for mice. Curr Protoc Neurosci Chapter 9:Unit9.36
(2010) Erratum: Corrigendum to ""Marked behavioral activation from inhibitory stimulation oflocus coeruleus alpha1-adrenoceptors by a full agonist"" Brain Res 1326:193
Stone, Eric A; Lin, Yan; Sarfraz, Yasmeen et al. (2009) Marked behavioral activation from inhibitory stimulation of locus coeruleus alpha1-adrenoceptors by a full agonist. Brain Res 1291:21-31
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
Stone, Eric A; Lin, Yan; Quartermain, David (2008) A final common pathway for depression? Progress toward a general conceptual framework. Neurosci Biobehav Rev 32:508-24

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