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
Lewis, Alan S; Olincy, Ann; Buchanan, Robert W et al. (2018) Effects of a nicotinic agonist on the Brief Psychiatric Rating Scale five-factor subscale model in schizophrenia. Schizophr Res 195:568-569
Lewis, Alan S; van Schalkwyk, Gerrit Ian; Lopez, Mayra Ortiz et al. (2018) An Exploratory Trial of Transdermal Nicotine for Aggression and Irritability in Adults with Autism Spectrum Disorder. J Autism Dev Disord 48:2748-2757
Mineur, Yann S; Cahuzac, Emma L; Mose, Tenna N et al. (2018) Interaction between noradrenergic and cholinergic signaling in amygdala regulates anxiety- and depression-related behaviors in mice. Neuropsychopharmacology 43:2118-2125
Mineur, Yann S; Mose, Tenna N; Blakeman, Sam et al. (2018) Hippocampal ?7 nicotinic ACh receptors contribute to modulation of depression-like behaviour in C57BL/6J mice. Br J Pharmacol 175:1903-1914
Roberts, Walter; Verplaetse, Terril L; Moore, Kelly E et al. (2018) A preliminary investigation into the effects of doxazosin on cognitive functioning in tobacco-deprived and -satiated smokers. Hum Psychopharmacol 33:e2660
Jung, Yonwoo; Lee, Angela M; McKee, Sherry A et al. (2017) Maternal smoking and autism spectrum disorder: meta-analysis with population smoking metrics as moderators. Sci Rep 7:4315
Verplaetse, Terril L; Weinberger, Andrea H; Oberleitner, Lindsay M et al. (2017) Effect of doxazosin on stress reactivity and the ability to resist smoking. J Psychopharmacol 31:830-840
Roberts, Walter; Verplaetse, Terril L; Moore, Kelly et al. (2017) Effects of varenicline on alcohol self-administration and craving in drinkers with depressive symptoms. J Psychopharmacol 31:906-914
Mineur, Yann S; Fote, Gianna M; Blakeman, Sam et al. (2016) Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviors and Response to Social Stress. Neuropsychopharmacology 41:1579-87
McClure-Begley, Tristan D; Esterlis, Irina; Stone, Kathryn L et al. (2016) Evaluation of the Nicotinic Acetylcholine Receptor-Associated Proteome at Baseline and Following Nicotine Exposure in Human and Mouse Cortex. eNeuro 3:

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