The primary pharmacological treatment for depression over the past several decades has been drugs that inhibit synaptic reuptake of monoamine neurotransmitters. Although the importance of monoamine neurotransmission in antidepressant efficacy cannot be discounted, recent evidence indicates other neurotransmitter systems certainly play a role in the mechanism of action of antidepressants. Furthermore, the limitations of current antidepressant treatments, including a large group of non-responders, necessitate the development of novel compounds to treat depression. A growing body of evidence suggests that cholinergic systems may be potential targets for the development of novel antidepressant compounds, and in particular, that excessive activation of cholinergic systems may contribute to the pathophysiology of depression. Studies at the cellular, physiological and behavioral levels have shown that a wide range of antidepressants, including tricyclics, selective serotonin (5HT) reuptake inhibitors, and atypical antidepressants, all act as non-competitive antagonists of nicotinic acetylcholine receptors. More recently, clinical trials have shown that the nicotinic antagonist mecamylamine has antidepressant effects when added to a selective 5HT reuptake inhibitor (SSRI) in human depressed patients non-responsive to the SSRI alone. In the last funding period we showed that interfering with endogenous ACh signaling using both nicotinic antagonists and low efficacy partial agonists of high affinity nAChRs had antidepressant-like effects in mice. We have also found that human depressed subjects show decreased occupancy of high affinity nAChRs with no change in nAChR number, suggesting that increased ACh levels may contribute to human depression. We have hypothesized that antagonism of high affinity neuronal nAChRs is an important component of the therapeutic mechanism of action of classical antidepressant compounds, and further, that nicotinic receptor antagonists may be novel therapeutic agents that could be useful in patients who are not responsive to current pharmacological treatments. Our current hypothesis based on data obtained in the last funding period is that blockade of ACh signaling in the basolateral amygdala along with activity of 5HT-1A receptors in the hippocampus mediate the antidepressant- like effects of nicotinic compounds. We propose the to follow up on this hypothesis and to investigate further the molecular and neuronal mechanisms underlying the antidepressant-like effect of nicotinic drugs by determining whether the antidepressant-like effects of nicotinic antagonists and partial agonists depend on nAChR function in specific neuronal subtypes in the amygdala, identifying pre- and post-synaptic 5HT receptor subtypes necessary for nicotinic-mediated antidepressant effects and determining whether calcineurin activity is essential for the antidepressant-like effects of nicotinic compounds.

Public Health Relevance

Up to 50% of patients with depression are non-responsive to existing antidepressant therapies so it is essential that new medications are developed to treat this crippling psychiatric illness. Emerging reports show that limiting the activity of nicotine receptors in the brain can result in an antidepressant response in patients who were not responsive to a classical antidepressant like Prozac and we have found that nicotine receptor blockers are antidepressant-like in mouse models of antidepressant effects. We propose to identify the brain regions and molecular changes that are responsible for this effect to enlarge our understanding of the brain circuits that are dysfunctional in patients with depression and to find new ways to treat patients who do not respond to existing treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH077681-08
Application #
8418773
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Winsky, Lois M
Project Start
2006-08-01
Project End
2016-02-29
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
8
Fiscal Year
2013
Total Cost
$399,200
Indirect Cost
$159,200
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Mineur, Yann S; Einstein, Emily B; Bentham, Matthew P et al. (2015) Expression of the 5-HT1A serotonin receptor in the hippocampus is required for social stress resilience and the antidepressant-like effects induced by the nicotinic partial agonist cytisine. Neuropsychopharmacology 40:938-46
McClure-Begley, T D; Papke, R L; Stone, K L et al. (2014) Rare human nicotinic acetylcholine receptor ?4 subunit (CHRNA4) variants affect expression and function of high-affinity nicotinic acetylcholine receptors. J Pharmacol Exp Ther 348:410-20
Higley, Michael J; Picciotto, Marina R (2014) Neuromodulation by acetylcholine: examples from schizophrenia and depression. Curr Opin Neurobiol 29:88-95
Park, Aesoon; O'Malley, Stephanie S; King, Sarah L et al. (2014) Mediating role of stress reactivity in the effects of prenatal tobacco exposure on childhood mental health outcomes. Nicotine Tob Res 16:174-85
Mineur, Yann S; Taylor, Seth R; Picciotto, Marina R (2014) Calcineurin downregulation in the amygdala is sufficient to induce anxiety-like and depression-like behaviors in C57BL/6J male mice. Biol Psychiatry 75:991-8
Picciotto, Marina R; Mineur, Yann S (2014) Molecules and circuits involved in nicotine addiction: The many faces of smoking. Neuropharmacology 76 Pt B:545-53
Hannestad, Jonas O; Cosgrove, Kelly P; DellaGioia, Nicole F et al. (2013) Changes in the cholinergic system between bipolar depression and euthymia as measured with [123I]5IA single photon emission computed tomography. Biol Psychiatry 74:768-76
Esterlis, Irina; Hannestad, Jonas O; Bois, Frederic et al. (2013) Imaging changes in synaptic acetylcholine availability in living human subjects. J Nucl Med 54:78-82
Neugebauer, Nichole M; Einstein, Emily B; Lopez, Maria B et al. (2013) Morphine dependence and withdrawal induced changes in cholinergic signaling. Pharmacol Biochem Behav 109:77-83
Mineur, Yann S; Obayemi, Adetokunbo; Wigestrand, Mattis B et al. (2013) Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior. Proc Natl Acad Sci U S A 110:3573-8

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