The proposed studies are designed to examine if the transcription factor CREB (cAMP response element binding protein) in the nucleus accumbens shell (NASh) plays a role in depression. Although the NASh is involved in the hedonic (pleasurable) effects of food, sex, and addictive drugs, little is known about its involvement in mood disorders. We found previously that blockade of CREB function in the NASh increases cocaine reward in rats, whereas elevated CREB function in this region eliminates cocaine reward. Because anhedonia (a diminished ability to experience pleasure) is a hallmark symptom of depression, these data suggest that CREB (and genes regulated by CREB) in the NASh may be involved in depressive syndromes. To address this question, we have examined relationships between CREB function in the NASh and behavior in the Porsolt forced swim test (FST), a model of depression. In preliminary studies, we find that exposure to the FST causes immediate increases in phospho-CREB (P-CREB, an activated form of CREB) in the NASh. To examine the significance of this effect, we elevated CREB expression in the NASh by viral-mediated gene transfer. This treatment increases immobility in the FST (suggesting increased depression), whereas blockade of CREB function in the NASh (by overexpression of a dominant negative CREB) decreases immobility (suggesting an antidepressant effect). Together, our work suggests that CREB in the NASh is a molecular regulator of at least some symptoms of depression (anhedonia, despair). We propose to further examine the interaction of CREB (and CREB-regulated genes) in the NASh with two antidepressants (desipramine, fluoxetine) in the FST. First, we will determine if antidepressants block CREB-induced increases in immobility. Second, we will examine the time course of FST-induced P-CREB elevations in the NASh, and determine if they are blocked by antidepressants. Third, we will determine if the FST increases expression of dynorphin, a target gene of CREB. Fourth, we will determine if blockade of the brain receptors for dynorphin (k opioid receptors) has antidepressant actions. Finally, we will use intracranial self-stimulation (ICSS) to examine if elevated CREB expression in the NASh produces symptoms of depression in a second behavioral assay. These studies may establish that elevated CREB expression in the NASh is a """"""""molecular trigger"""""""" for depression, and identify novel targets for pharmacotherapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH063266-02
Application #
6539240
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Meinecke, Douglas L
Project Start
2001-07-01
Project End
2006-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$197,500
Indirect Cost
Name
Mc Lean Hospital (Belmont, MA)
Department
Type
DUNS #
City
Belmont
State
MA
Country
United States
Zip Code
02478
Lezak, Kimberly R; Missig, Galen; Carlezon Jr, William A (2017) Behavioral methods to study anxiety in rodents. Dialogues Clin Neurosci 19:181-191
Der-Avakian, Andre; D'Souza, Manoranjan S; Potter, David N et al. (2017) Social defeat disrupts reward learning and potentiates striatal nociceptin/orphanin FQ mRNA in rats. Psychopharmacology (Berl) 234:1603-1614
Wells, Audrey M; Ridener, Elysia; Bourbonais, Clinton A et al. (2017) Effects of Chronic Social Defeat Stress on Sleep and Circadian Rhythms Are Mitigated by Kappa-Opioid Receptor Antagonism. J Neurosci 37:7656-7668
Pizzagalli, Diego A; Carlezon, William A (2017) Error Processing in Depressive States: A Translational Opportunity? Neuropsychopharmacology 42:372
Tejeda, Hugo A; Wu, Jocelyn; Kornspun, Alana R et al. (2017) Pathway- and Cell-Specific Kappa-Opioid Receptor Modulation of Excitation-Inhibition Balance Differentially Gates D1 and D2 Accumbens Neuron Activity. Neuron 93:147-163
Nygard, Stephanie K; Hourguettes, Nicholas J; Sobczak, Gabe G et al. (2016) Stress-Induced Reinstatement of Nicotine Preference Requires Dynorphin/Kappa Opioid Activity in the Basolateral Amygdala. J Neurosci 36:9937-48
Van't Veer, Ashlee; Smith, Karen L; Cohen, Bruce M et al. (2016) Kappa-opioid receptors differentially regulate low and high levels of ethanol intake in female mice. Brain Behav 6:e00523
Carlezon Jr, William A; Krystal, Andrew D (2016) Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials. Depress Anxiety 33:895-906
Penrod, Rachel D; Wells, Audrey M; Carlezon Jr, William A et al. (2015) Use of Adeno-Associated and Herpes Simplex Viral Vectors for In Vivo Neuronal Expression in Mice. Curr Protoc Neurosci 73:4.37.1-31
Donahue, Rachel J; Landino, Samantha M; Golden, Sam A et al. (2015) Effects of acute and chronic social defeat stress are differentially mediated by the dynorphin/kappa-opioid receptor system. Behav Pharmacol 26:654-63

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