The Laboratory of Neurochemistry, now jointly led by Drs. Paul Whiteaker and Ronald J. Lukas, focuses on nicotinic acetylcholine receptors, which are critical to chemical signaling and electrical wiring in the brain and body. These receptors are involved in mood and emotion, attention and cognition, autonomic homeostasis, and movements. Because they play such broad roles, it is not surprising that nicotinic receptor actions and deficits have been associated with a variety of neuropsychiatric diseases.
Nicotinic acetylcholine receptors normally respond to the natural chemical signaling agent, acetylcholine, which is released from activated nerve (or other) cells. Nicotinic receptors also are targets of tobacco-based nicotine and are relevant to tobacco-related diseases and drug abuse. As examples of the clinical relevance of these nicotinic receptors, their numbers are decreased in Parkinson’s and Alzheimer’s diseases, perhaps indicating roles in disease etiology and progression or in protection from neurodegeneration.
Nicotinic receptors also are involved in neuromuscular disorders, having been identified as targets for autoimmune responses or gene mutations causing myasthenia gravis, and located in the dystrophin-related complex targeted in muscular dystrophy. Mutations in nicotinic receptors also are associated with inherited forms of epilepsy.
These receptors likely play critical roles in nicotine dependence, which ultimately is the cause of all tobacco-related diseases. On the other hand, our laboratory has advanced hypotheses that tobacco use represents a form of nicotine self-medication, which develops in some individuals to correct chemical and electrical signaling deficits associated with emotional difficulties, cognitive difficulties, or both.
Indeed, individuals with mental health problems, including depression, anxiety, and attention deficit disorder, are at higher risk of developing nicotine dependence. About 40% of the mentally ill, including as many as 90% of schizophrenics, are smokers. More recently, individual genetic variations in some receptors have been associated with heightened susceptibility to nicotine dependence and to lung cancer.
Drug codependence also is evident, in that upwards of 90% of alcoholics smoke. Nicotinic receptors are targets of much pharmaceutical research, in part because nicotine itself has the ability to improve attention and/or cognition in Parkinson’s, Alzheimer’s, or attention deficit disorder subjects, improve mood in depressed individuals, and reduce the frequency of ticks in Tourette’s patients. However, there are times in life, especially in perinatal periods and during adolescence and young adulthood, when abnormal signaling through nicotinic receptors mediated by nicotine can have influences on perhaps many of the body’s organ systems.
There are several lines of study in the laboratory. First and foremost, because there is not just one type of nicotinic acetylcholine receptor, fundamental work involves identification and classification of the diverse family of nicotinic receptors, each of which is defined by the building blocks or subunits that constitute them. These studies identify subunits and receptor subtypes in different tissues and organ systems, exploit tumor cell lines as factories naturally making nicotinic receptors like those found in normal tissue, or involve creation of genetically engineered cell lines fashioned to examine features of nicotinic receptors suspected or known to exist.
Molecular and cellular biology, immunology, protein chemistry, pharmacology, and electrophysiology approaches converge in our laboratory’s operations. This provides an enriched understanding of receptor composition, function, and roles. For example, identification of differences in the ability of diverse nicotinic receptor subtypes to interact with specific drugs is used not only to discriminate between receptor subtypes, but also to discover new drugs that are selective or specific in their preference for a given receptor subtype. This creates the opportunity to find a nicotine-like drug that could elevate mood by acting at one receptor subtype, or a selected group of subtypes. This could reduce nicotine dependence liability by avoiding interactions with receptors in the pleasure-reward center of the brain.
We continue to work to define which of the seventeen subunits identified to date combine to make unique receptor subtypes, and features of every subtype identified then need to be characterized. Studies of the effects of chronic nicotine exposure on receptor numbers and function are being done to define how the brain changes in response. Fundamental features of nicotinic receptors in pleasure-reward, emotional, and attention centers are being studied.
Studies extend beyond muscle and nerve cells. For example, there is evidence that nicotinic receptors exist in the blood vessels that permeate many organs, including the brain. In the brain, they contribute to the formation of the blood-brain barrier and influence cytotoxic and vasogenic phases of edema during stroke.
Other studies concern the roles nicotinic receptors play in interactions between the nervous system and immune system and in lung tumor growth. Bone formation and reproductive organ function also seem to be influenced by nicotine exposure, implying that nicotinic receptors are found on cells found in those tissues as well.
Nicotinic receptors also can be used as models to test new techniques and expand the breadth of biotechnological knowledge. For example, genetically engineered cells and site-directed mutagenesis studies are being used not only to define the structure-function relationships for the many interesting domains of nicotinic receptors, but also as models of genetically based neurological diseases and in studies to define the functional consequences of such mutations.
Ronald J. Lukas