In this application we will examine the interaction between chronic stress and nicotine by studying behavior, autonomic responses, and hormone and neurotransmitter levels in several mouse models. This proposal arises from the finding that smokers often report an anxiolytic effect of cigarettes, and stress-related disorders such as depression, posttraumatic stress syndrome, and anxiety are often associated with chronic nicotine use. The influence of nicotine might depend on its ability to both activate and desensitize nicotinic acetylcholine receptors (nAChRs) in stress-related neural circuits. That basic action of nicotine, in turn, depends on the subunit composition of nAChRs that modulate those neural circuits. A related phenomenon is that chronic exposure to stress produces neural adaptations in brain regions that are associated with the rewarding effects of nicotine. To determine which nAChR subtypes are important for the interaction between stress and nicotine's actions, we will expose nAChR mutant mice lacking one or combinations of nAChR subunits to chronic stress. Our experiments will capitalize on the anxiety-related phenotypes that we and others have reported in nAChR mutant mice. The application also will address gender differences in the stress/nicotine interaction. Gender plays a major role in stress integration and stress-related affective disease states. We will investigate gender-related mechanisms by performing our experiments in ovariectomized and orchiectomized animals. Particular attention will be paid to the role of progesterone in the physiological mechanisms underlying stress by analyzing mice lacking the progesterone receptors A and B alone or in combination. The proposal will begin by examining the effects of chronic stress on nAChR mutant mice and their wild-type littermates. The other two main aims will examine the interaction between stress and nicotine.
The second aim will examine how chronic stress affects the response to acute doses of nicotine.
The third aim will examine the behavioral and physiological manifestations produced by chronic nicotine with and without concomitant exposure to stress. Our in vivo studies will combine behavioral testing with telemetry and the measurement of plasma levels of stress hormones. The in vitro studies will use in situ hybridization, autoradiography, and immunohistochemistry techniques.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
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Volman, Susan
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Baylor College of Medicine
Schools of Medicine
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McLaughlin, Ian; Dani, John A; De Biasi, Mariella (2017) The medial habenula and interpeduncular nucleus circuitry is critical in addiction, anxiety, and mood regulation. J Neurochem 142 Suppl 2:130-143
Broussard, John I; Yang, Kechun; Levine, Amber T et al. (2016) Dopamine Regulates Aversive Contextual Learning and Associated In Vivo Synaptic Plasticity in the Hippocampus. Cell Rep 14:1930-9
Perez, Erika; Quijano-Cardé, Natalia; De Biasi, Mariella (2015) Nicotinic Mechanisms Modulate Ethanol Withdrawal and Modify Time Course and Symptoms Severity of Simultaneous Withdrawal from Alcohol and Nicotine. Neuropsychopharmacology 40:2327-36
Teng, Yanfen; Rezvani, Khosrow; De Biasi, Mariella (2015) UBXN2A regulates nicotinic receptor degradation by modulating the E3 ligase activity of CHIP. Biochem Pharmacol 97:518-530
Perez, E E; De Biasi, M (2015) Assessment of affective and somatic signs of ethanol withdrawal in C57BL/6J mice using a short-term ethanol treatment. Alcohol 49:237-43
De Biasi, M; McLaughlin, I; Perez, E E et al. (2014) Scientific overview: 2013 BBC plenary symposium on tobacco addiction. Drug Alcohol Depend 141:107-17
Muldoon, P P; Jackson, K J; Perez, E et al. (2014) The ?3?4* nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies. Br J Pharmacol 171:3845-57
Dao, Dang Q; Perez, Erika E; Teng, Yanfen et al. (2014) Nicotine enhances excitability of medial habenular neurons via facilitation of neurokinin signaling. J Neurosci 34:4273-84
Salas, Ramiro; Fung, Beryl; Sturm, Renea et al. (2013) Abnormal social behavior in nicotinic acetylcholine receptor ?4 subunit-null mice. Nicotine Tob Res 15:983-6
Dani, John A; De Biasi, Mariella (2013) Mesolimbic dopamine and habenulo-interpeduncular pathways in nicotine withdrawal. Cold Spring Harb Perspect Med 3:

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