NARSAD Young Investigator Grantee Studies Genetic and Neurobiological Mechanisms Underlying Nicotine Addiction

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Shahrdad Lotfipour, Ph.D., of the University of California, Los Angeles, Expert on substance abuse and addiction
Shahrdad Lotfipour, Ph.D.

Shahrdad Lotfipour, Ph.D., of the University of California, Los Angeles, used his 2010 NARSAD Young Investigator Grant to study the mechanisms behind nicotine addiction. Conducting experiments in mice enabled Dr. Lotfipour and colleagues to measure the role of brain receptors activated by nicotine. The research may have long-term implications for study of many conditions involving the brain, including: tobacco dependence, obesity, schizophrenia, bipolar disorder, epilepsy and adolescent drug use. The study’s wide relevance follows from the fact that it explores the impact of a cellular receptor found in many places in the brain and nervous system of mammals, including humans.

The receptor at the focus of the study is called the nicotinic acetylcholine receptor (nAChR). Acetylcholine is one of many neurotransmitters: it carries messages between nerve cells. The nAChR gets its name because it can also be activated by nicotine. In the brain, nAChRs come in various varieties, involving combinations of a dozen molecular building blocks, called subunits. As they reported in The Journal of Neuroscience on May 1st, Dr. Lotfipour and colleagues created a line of mice in which brain nAChRs were missing one key subunit, called alpha2 (α2). The behavior of normal mice, whose cells included α2, were compared with mice in which α2 was missing.

The mice behaved similarly, yet there were illuminating differences in behaviors normally affected by nicotine. Mice without α2 in their nAChRs were less coordinated than their normal cage-mates and were more sensitive to nicotine’s pain-relieving effects. They were also more likely to initially seek nicotine and preferred higher doses, and were more prone to withdrawal later―a clue to nicotine and other addiction behaviors in people. Surprisingly though, the withdrawal symptoms seemed to be dependent on whether the mice were in a habituated (home cage) or novel environment. Only in a novel environment were these mice found to have higher overall withdrawal scores.

Also, female mice without the α2 subunit performed differently than males on tests involving conditioned fear, which is a way of testing memories processed in the brain’s hippocampus, amygdala and prefrontal cortex. Other tests suggested that emotional memories enhanced by nicotine depend on the presence of the α2 subunit.

Additional studies are needed to further clarify the mechanisms behind these findings. Dr. Lotfipour says the initial NARSAD Grant funding was crucial to start this line of study and has led to significant further grant support. “I am absolutely grateful for the support of the Brain & Behavior Research Foundation and feel it has been instrumental in developing my scientific career,” he says.

Read the study abstract.

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