Nicotinic systems in central nervous systems disease: degenerative disorders and beyond.

Advances in the understanding of the structure, function, and distribution of central nervous system (CNS) nicotinic receptors has provided the impetus for new studies examining the role(s) that these receptors and associated processes may play in CNS functions. Further motivation has come from the realization that such receptors are changed in degenerative neurologic diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Ongoing investigations of the molecular substructure of CNS nicotinic receptors and their pharmacology have begun to open up new possibilities for novel CNS therapeutics with nicotinic agents. Exploiting these possibilities will require understanding of the role(s) that these receptor systems play in human cognitive, behavioral, motor, and sensory functioning. Clues from careful studies of human cognition and behavior are beginning to emerge and will provide direction for studies of potentially therapeutic novel nicotinic agents. Modulation of these receptors with the ultimate goal of producing therapeutic benefits is the goal of these investigations and drug development. This paper will review studies from our laboratory and others that point to the importance of CNS nicotinic mechanisms in normal human cognitive and behavioral functioning as well as their role in disease states. In addition, this paper will examine potential clinical applications of nicotine and/or nicotinic agonists in a variety of CNS disorders with particular emphasis on structural brain disease including: movement disorders such as Parkinson's disease and Tourette's syndrome, cognitive/behavioral disorders such as Alzheimer's disease, attention deficit/hyperactivity disorder, and schizophrenia, and other more speculative applications. Important results from early therapeutic studies of nicotine and/or nicotinic agonists in these disease states are presented. For example, recent studies with nicotine and novel nicotinic agonists such as ABT-418 by our group in AD patients suggest that nicotinic stimulation can improve the acquisition and retention of verbal information and decrease errors. Preliminary results from a series of studies examining the acute and subchronic quantitative effects of nicotine on cognitive and motor functioning in Parkinson's disease suggest that acute nicotine administration and stimulation improves some aspects of cognitive and motor performance and may improve the processing speed of more complex tasks. The most likely near-term applications of novel nicotinic agonists in CNS disorders are likely to be in those disorders that are degenerative in nature, e.g. Parkinson's disease and Alzheimer's disease, or other movement disorders such as Tourette's syndrome. The most likely direct therapeutic role for nicotinic agonists is as augmentation therapy in combination with other agents rather than as monotherapy, except early in disease states or as a prophylactic or preventative treatment.