Foundation Grantee Uses Molecular and Genetic Techniques To Better Understand Tobacco Dependence

Shahrdad Lotfipour, Ph.D.
Shahrdad Lotfipour, PhD

Shahrdad Lotfipour, Ph.D., began studying the pharmacology of drugs of abuse as part of a United States Fulbright Fellowship. This led him to graduate studies at the University of California where he studied the consequences of developmental exposure to nicotine and the role of other compounds in tobacco smoke that interact with nicotine to mediate addiction.

His graduate work was followed by a post-doctoral fellowship in the United Kingdom examining the effects of maternal cigarette smoking on the brain and behavior of adolescent offspring. These experiences instilled in Dr. Lotfipour a deep desire to understand the molecular and cellular pathways influencing tobacco addiction.

Tobacco addiction affects billions of people worldwide. In the United States alone the associated health consequences cost an estimated $100 billion annually and more than 400,000 people lose their lives each year because of tobacco-related disease. It is clear that new and innovative strategies are needed to assist in smoking prevention and cessation programs. Discoveries obtained through molecular and genetic studies will no doubt assist in the pursuit of this goal. Furthermore, given the links between tobacco addiction and a number of brain and behavior disorders, including depression, anxiety and attention deficit hyperactivity disorder (ADHD), such studies may also be useful for understanding the mechanisms mediating other mental illnesses.

A NARSAD Young Investigator Grant is supporting Dr. Lotfipour's current research at the UCLA Hatos Center for Neuropharmacology, which is focused on identifying specific nicotinic receptors (nAChRs) in the brain that are responsible for tobacco addiction and withdrawal. In particular, much of Dr. Lotfipour's research will focus on nAChR subtypes assembled from the α2 nAChR subunit gene (Chrna2), which is one of 11 different nAChR subunit genes expressed in the human brain.

Transcription of the Chrna2 gene is most active in the interpeduncular nucleus (IPN), a brain region known for its association with drug reward and withdrawal. Previous work has shown that mice with the Chrna2 gene removed exhibit two significant traits: the loss of a process which may modify how nicotine influences the formation of memories and an absence of adverse physical withdrawal behaviors following cessation of chronic nicotine treatment.

The induction of nicotine dependence and expression of withdrawal are complex physiological processes with unique behavioral consequences. There is no doubt that chronic nicotine treatment induces long-term neurophysiological changes that involve multiple nAChR subtypes and a variety of neuroanatomical loci and circuits. However, experiments using mice with the Chrna2 gene removed should provide answers to two interesting questions: First, is the nAChR α2-subunit absolutely required for expression of aversive symptoms associated with nicotine withdrawal? And second, are α2-expressing neurons within the IPN sufficient for induction of nicotine dependence and expression of withdrawal?

Dr. Lotfipour hopes results from his studies will provide a rationale for designing new therapies directed at α2-containing nAChRs to help minimize the discomfort associated with withdrawal, and thereby decrease the incidence of relapse and the plethora of health problems associated with long-term tobacco abuse. Results may also identify how specific nAChR subunit genes influence individual susceptibility to tobacco abuse.