Abstract
Epidemiological studies report strong association between mood disorders and tobacco addiction. This high comorbidity requires adequate treatment but the underlying mechanisms are unknown. We demonstrate that nicotine exposure, independent of drug withdrawal effects, increases stress sensitivity, a major risk factor in mood disorders. Nicotine and stress concur to induce long-lasting cellular adaptations within the dopamine (DA) system. This interplay is underpinned by marked remodeling of nicotinic systems, causing increased ventral tegmental area (VTA) DA neurons’ activity and stress-related behaviors, such as social aversion. Blocking β2 or α7 nicotinic acetylcholine receptors (nAChRs) prevents, respectively, the development and the expression of social stress-induced neuroadaptations; conversely, facilitating α7 nAChRs activation specifically in the VTA promotes stress-induced cellular and behavioral maladaptations. Our work unravels a complex nicotine-stress bidirectional interplay and identifies α7 nAChRs as a promising therapeutic target for stress-related psychiatric disorders.
Highlights
Psychiatric disorders, including drug addiction and depression, impose an alarming burden on society.[1,2,3,4,5] Tobacco use is the leading cause of preventable death in developed countries
We demonstrate a bidirectional interplay between stress and nicotine exposure, which requires modulation of ventral tegmental area (VTA) DA neurons activity via α7 nicotinic acetylcholine receptors (nAChRs)
The ability of systemic nicotine to excite VTA DA neurons in naive conditions requires the activation of VTA nAChRs located on both GABA and DA neurons.[11]
Summary
Psychiatric disorders, including drug addiction and depression, impose an alarming burden on society.[1,2,3,4,5] Tobacco use is the leading cause of preventable death in developed countries. Depression is associated with increased risk for smoking initiation[8] and the appearance of early mental complications markedly increases the risk of later tobacco abuse.[9,10] In addition, more severe drug withdrawal episodes have been reported in people with a history of depression, which impedes smoking cessation. This indicates a link between nicotine exposure and stress-related mood disorders
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