Developmental Nicotine Exposure and Addiction

Institution:	University of California, Irvine
Investigator(s):	Shahrdad Lotfipour, Ph.D.
Award Cycle:	2013 (Cycle 22)	Grant #: 22RT-0103A	Award: $102,816
Subject Area:	Disparities /Prevention/ Cessation/ Nicotine Dependence
Award Type:	Research Project Awards

Abstracts

Initial Award Abstract

While smoking is known to be harmful to both the mother and the unborn child, women continue to smoke during pregnancy. A number of negative consequences have been attributed to children who are exposed to maternal cigarette smoking during pregnancy. The most severe effects occur early in development or at birth, including low birth weight, sudden infant death syndrome and placenta previa. Late onset deficits also appear as these children mature, including emotional psychological deficits, attention deficit hyperactivity disorder, and substance use problems. Recent findings have shown that maternal cigarette smoking during pregnancy increases the likelihood of adolescent offspring to experiment with drugs of abuse, with associated changes in brain structures related to reward and emotional processing. Studies performed in animals have demonstrated that the harmful effects of developmental cigarette exposure can be attributed to nicotine, a major pharmacological agent in cigarettes. Nicotine is known to bind to brain nicotinic receptors to influence cigarette reward through changes in the mechanisms of learning and memory, which contribute to continued use. Recent evidence highlights the role of a genetic polymorphism in the nicotinic receptor subunits in predicting tobacco addiction. However, it is not known which nicotinic receptors subunits contribute to long-term psychopathologies associated with children whose mother's smoked during pregnancy. Our preliminary results suggest that alpha2-containing nicotinic receptors contribute to developmental nicotine induce-psychopathology related to emotional learning and memory. Therefore, the goal of this project is to use a mouse model that has a genetic deletion as well as a hypersensitive genetic polymorphism in the alpha2 nicotinic receptor subunit to identify the chemicals and brain regions modified by this gene product in offspring mice exposed to developmental nicotine exposure. Using innovative molecular, genetic, brain imaging, learning and memory behavioral techniques coupled with light activation of alpha2-containing neurons (through optogenetics), we predict that developmental exposure to nicotine influences emotional memory deficits in the offspring through alpha2-containing nicotinic receptors in selective brain regions, including the hippocampus. Our findings could have a significant impact in the scientific and public health communities by revealing novel mechanisms of how developmental nicotine exposure may contribute to emotional psychological deficits and the addictive properties of tobacco use in exposed offspring.

Publications

Optogenetic excitation of cholinergic inputs to hippocampus primes future contextual fear associations
Periodical: Scientific Reports			Index Medicus:
Authors: Hersman S, Cushman J, Lemelson N, Wassum K, Lotfipour S, Fanselow MS				ART
Yr: 2017	Vol: 7	Nbr: 1	Abs:	Pg: 2333

*a2 Nicotinic acetylcholine receptors influence hippocampus-dependent learning and memory in adolescent mice**
Periodical: Learning & Memory			Index Medicus:
Authors: Lotfipour S, Mojica C, Nakauchi S, Lipovsek M, Silverstein S, Cushman J, Tirtorahardjo J,				ART
Yr: 2017	Vol: 15	Nbr: 24	Abs:	Pg: 231-244

Mechanisms and genetic factors underlying co-use of nicotine and alcohol or_x000D_ other drugs of abuse
Periodical: American Journal of Drug and Alcohol Abuse			Index Medicus:
Authors: Cross SJ, Lotfipour S, Leslie FM				ART
Yr: 2017	Vol: 43	Nbr: 2	Abs:	Pg: 171-185

*a2-Null mutant mice have altered levels of neuronal activity in restricted midbrain and limbic brain regions during nicotine withdrawal as demonstrated by cfos expression**
Periodical: Biochemical Pharmacology			Index Medicus:
Authors: Upton M, Lotfipour S				ART
Yr: 2015	Vol: 97	Nbr: 4	Abs:	Pg: 558-565

Maternal cigarette smoking during pregnancy predicts drug use via externalizing behavior in two community-based samples of adolescents
Periodical: Addiction			Index Medicus:
Authors: Lotfipour S, Ferguson E, Leonard G, Miettunen J, Perron M, Pike GB, Richer L, Séguin JR, V				ART
Yr: 2014	Vol: 109	Nbr: 10	Abs:	Pg: 1718-29

Targeted deletion of the mouse a2 nicotinic acetylcholine receptor subunit gene (Chrna2) potentiates nicotine-modulated behaviors
Periodical: Journal of Neuroscience			Index Medicus:
Authors: Lotfipour S, Byun JS, Leach P, Fowler CD, Murphy NP, Kenny PJ, Gould TJ, Boulter J				ART
Yr: 2013	Vol: 1	Nbr: 33	Abs:	Pg: 7728-41

*Deletion of alpha 2 nicotinic acetylcholine receptors ablates learning and memory in maternal nicotine treated adolescent offspring**
Periodical: Journal of Neurochemistry			Index Medicus:
Authors: S Lotfipour				ABS
Yr:	Vol:	Nbr: 142	Abs:	Pg: 215-215

Gestational nicotine sex-dependently alters adolescent dopamine system development
Periodical: Neurotoxicology and Teratology			Index Medicus:
Authors: F Leslie, J Dwyer, S Lotfipour, J Belluzzi				ABS
Yr:	Vol:	Nbr: 61	Abs:	Pg: 150-150

Optogenetic excitation of cholinergic inputs to hippocampus primes future contextual fear associations
Periodical: Scientific Reports			Index Medicus:
Authors: Hersman S, Cushman J, Lemelson N, Wassum K, Lotfipour S, Fanselow MS				ART
Yr: 2017	Vol: 7	Nbr: 1	Abs:	Pg: 2333

*a2 Nicotinic acetylcholine receptors influence hippocampus-dependent learning and memory in adolescent mice**
Periodical: Learning & Memory			Index Medicus:
Authors: Lotfipour S, Mojica C, Nakauchi S, Lipovsek M, Silverstein S, Cushman J, Tirtorahardjo J,				ART
Yr: 2017	Vol: 15	Nbr: 24	Abs:	Pg: 231-244

Mechanisms and genetic factors underlying co-use of nicotine and alcohol or_x000D_ other drugs of abuse
Periodical: American Journal of Drug and Alcohol Abuse			Index Medicus:
Authors: Cross SJ, Lotfipour S, Leslie FM				ART
Yr: 2017	Vol: 43	Nbr: 2	Abs:	Pg: 171-185

*a2-Null mutant mice have altered levels of neuronal activity in restricted midbrain and limbic brain regions during nicotine withdrawal as demonstrated by cfos expression**
Periodical: Biochemical Pharmacology			Index Medicus:
Authors: Upton M, Lotfipour S				ART
Yr: 2015	Vol: 97	Nbr: 4	Abs:	Pg: 558-565

Maternal cigarette smoking during pregnancy predicts drug use via externalizing behavior in two community-based samples of adolescents
Periodical: Addiction			Index Medicus:
Authors: Lotfipour S, Ferguson E, Leonard G, Miettunen J, Perron M, Pike GB, Richer L, Séguin JR, V				ART
Yr: 2014	Vol: 109	Nbr: 10	Abs:	Pg: 1718-29

Targeted deletion of the mouse a2 nicotinic acetylcholine receptor subunit gene (Chrna2) potentiates nicotine-modulated behaviors
Periodical: Journal of Neuroscience			Index Medicus:
Authors: Lotfipour S, Byun JS, Leach P, Fowler CD, Murphy NP, Kenny PJ, Gould TJ, Boulter J				ART
Yr: 2013	Vol: 1	Nbr: 33	Abs:	Pg: 7728-41

*Deletion of alpha 2 nicotinic acetylcholine receptors ablates learning and memory in maternal nicotine treated adolescent offspring**
Periodical: Journal of Neurochemistry			Index Medicus:
Authors: S Lotfipour				ABS
Yr:	Vol:	Nbr: 142	Abs:	Pg: 215-215

Gestational nicotine sex-dependently alters adolescent dopamine system development
Periodical: Neurotoxicology and Teratology			Index Medicus:
Authors: F Leslie, J Dwyer, S Lotfipour, J Belluzzi				ABS
Yr:	Vol:	Nbr: 61	Abs:	Pg: 150-150