Academic Background:

B.S.                University of California, Riverside                1995
M.S.                University of California, Riverside                1996
Ph.D.              Vanderbilt University                                 2001

Postdoctoral Scholar                                             2002-2006
Department of Biology
California Institute of Technology

Assistant Professor                                           2006-present
Department of Psychiatry
University of Massachusetts Medical School

Neuronal nicotinic acetylcholine receptors in addiction and neurological disease.

  
Nicotine addiction elicited by smoking tobacco is responsible for over 3 million deaths annually making it the largest cause of preventable mortality in the world.  Nicotine is a naturally occurring alkaloid found in tobacco and is the primary addictive component of cigarette smoke. Vaporized nicotine is rapidly absorbed through the lungs where it enters the blood stream.  Within seconds of inhaling, nicotine base readily crosses the blood-brain barrier where it gains access to neuronal nicotinic acetylcholine receptors (nAChRs) expressed throughout the central nervous system (CNS). In its protonated form, nicotine mimics the endogenous neurotransmitter, acetylcholine, and can activate nAChRs, utilizing the cholinergic system which, under normal conditions, plays an important role in reward, anxiety, cognition, attention, and many other physiological processes.  This ability of nicotine to “hijack” nAChRs is thought to underlie the molecular basis of nicotine addiction.

What are nicotinic acetylcholine receptors?

Neuronal nAChRs are ligand gated cation-selective ion channels that, when activated, can depolarize and activate neurons, as well as modulate neurotransmitter release.  Currently, 12 neuronal nicotinic acetylcholine receptor subunits have been identified (a2-10 and b 2-4). The majority of subunits form functional heteromeric pentamers while a subset may form homomeric receptors.  Thus, a myriad of nAChR subtypes exist.

Neuronal nAChRs in nicotine addiction.

It is becoming increasingly clear that nicotine dependence begins with activation of nAChRs.  However, which nAChR subtypes are involved in the addictive properties of nicotine?  Recent work has highlighted the idea that different subtypes may mediate different dependence-related behaviors.  For example, activation of one particular nAChR subtype may be responsible for the rewarding properties of nicotine whereas chronic activation of a separate subtype may be responsible for withdrawal symptoms upon nicotine cessation.  A primary goal of our lab is to identify specific nAChR subtypes critical for behaviors associated with addiction including reward, tolerance, sensitization, and withdrawal.

Acute nicotine exposure elicits many physiological effects including reward, hypothermia, and, at high enough concentrations, seizures. However, smokers expose themselves to nicotine chronically.  It is this chronic exposure that produces long term physiological and behavioral changes associated with dependence.   A second goal of our lab is to identify circuits and gene products that undergo adaptations because of chronic nAChR activation (or desensitization) and trigger a nicotine dependent state.

Neuronal nAChRs in the regulation of dopamine neurotransmission.

Parkinson’s disease (PD) is a devastating movement disorder that affects approximately one percent of the population over the age of 60.  The disease is characterized by slowness of movement (bradykinesia), rigidity, and resting tremor. PD is caused by the disruption of dopamine release in basal ganglia due to the progressive death of dopaminergic neurons in substantia nigra. The reason for this neuronal loss is unknown. To date, the predominant PD treatment is L-dopa, an isomer to the precursor of dopamine (DA) that is used to boost remaining DA release in surviving DAergic neurons.  Because of L-dopa’s fading efficacy over time, more recent research has focused on identifying neuroprotective agents that promote midbrain DAergic neuron survival. Remarkably, strong epidemiological data indicates PD is less prevalent in smokers. In addition, animal studies have found that nicotine, the addictive component of tobacco smoke, protects DAergic neurons from chemical insult.  Thus, nicotine has emerged as a potential neuroprotective agent in PD.  An additional goal of the lab is to understand how nicotinic receptors regulate dopamine neurotransmission in brain regions implicated in Parkinson’s disease.