Neuronal Substrates and Pathways underlying Nicotine and Stress interplay relevant for psychiatric disorders – nicostress

Nicotine dependence is the leading cause of illness and premature death in patients with psychiatric disorders. Smokers who successfully abstain are at increased risk of experiencing a depressive episode when compared to individuals who continue smoking. More severe drug withdrawal episodes have also been reported in people with a history of depression. Comorbidity which is here defined by the co-occurrence of mental and substance use disorders is much more common than expected. The prevalence of these problems and their complex underlying interactions question the strategy that consists to deal solely with each entity separately. It is now important to reckon these problems as a whole, where the two pathologies feed each other. In this context, we aim to dissect the sequence of events within the brain that underlie interaction between nicotine and stress.

Dopaminergic (DAergic) neurotransmission is widely recognized as being critical to the neurobiology of reward, motivation and mood. Nicotine’s reinforcing properties are mediated by neuronal nicotinic acetylcholine receptors that profoundly alter the firing patterns of dopamine (DA) neurons in the ventral tegmental area (VTA). Also, numerous studies have shown that chronic social defeat stress triggers pronounced increases in VTA DA neuron activity, which are causally associated with behavioral alterations such as anhedonia, increased anxiety and social aversion. Therefore DA neurons act as a hub that convey signals related to salient stimuli, either rewarding or aversive, to subsequently shape (mal)adaptive behaviors. This led us to conceive that DA neurons stand as a prominent candidate to sustain the co-morbidity between nicotine dependence and stress-mediated psychiatric-like conditions.

We thus aim at deciphering the role of DA neuron subpopulations and their cholinergic modulation in comorbidities associated with smoking and in particular in stress-related disorders. We will use mice as a model to dissect the complex and multifaceted interaction between nicotine and social stress by examining how social stress pre-exposure conditions subsequent responses to nicotine and reciprocally. This is at the heart of the complex mutual feeding between the two processes. While several studies have described depression as a consequence of nicotine withdrawal, we will here also identify nicotine exposure as a risk factor for the development of stress-related disorders, independent of the withdrawal. This is a new perspective. We will also address the outcomes of social stress and nicotine on DA neurons and assess whether these changes occur in specific pathways. An important aspect of our program is to demonstrate that interaction between both processes occur in the DAergic system, with an emphasis on the nicotinic pathway that strongly tunes the responsiveness of DA neurons. Finally, we will investigate the mechanisms by which nicotine and social stress shape decision-making processes. It is indeed critical to determine, within the set of modifications that occur in the DAergic system which of them are supportive of vulnerability to smoking behavior but also of a reduction of coping skills (i.e a strategy that helps reducing the effects of stress) such as modification of risk taking, decreased reward sensitivity or progressive loss of control.

Psychiatric disorders, and especially addiction, constitute an important burden on well-being and health systems. This project is thus clearly in adequacy with the aims of the “health and well-being” societal challenge and more particularly with the axis 7 "Exploration of the nervous system in its normal and pathological functions", an axis with special emphasis on psychiatry and addictive conditions. It builds on previous expertise and breakthroughs of the teams in order to achieve a further qualitative leap in understanding the mechanisms underlying the comorbidity between nicotine consumption and stress-related psychiatric disorders.