1998 Recipient

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John A. Dani, Ph.D.

Nicotinic cholinergic mechanisms underlying disease and tobacco addiction

Dr. Dani's laboratory studies the fundamental mechanisms for processing information in the brain. The same receptors, neurotransmitters, and synapses that normally govern all of our moods and behaviors can be misdirected by disease or commandeered by drugs to bring about addiction. An understanding of basic synaptic mechanisms, therefore, offers points of entry for methods aimed at relieving or preventing diseases and drug addiction.

Successful synaptic transmission is a low probability event, but Dr. Dani's research showed that nicotinic cholinergic activity ensures that important events can emerge out of the electrical noise of the brain. For example, early in the development of Alzheimer's dementia cholinergic projections degeneration and the number of nicotinic receptors decreases. Dr. Dani's work indicated that the diminished capacity of Alzheimer's patients can arise, in part, from the loss of synaptic fidelity caused by loss of nicotinic cholinergic functions.

Related work also explained aspects of the addictive power of nicotine obtained from tobacco. Midbrain dopamine neurons normally help to shape behavior by reinforcing biologically rewarding actions. Dr. Dani proved that these midbrain dopamine neurons initially respond vigorously to nicotine before falling quiet and less responsive. In simple terms, the initial rapid firing of the neurons reinforces the addiction to nicotine by providing the perception of pleasure, but their later unresponsiveness causes short-term tolerance to the drug. The research led to a new model for nicotine addiction that accounts for behavioral effects in terms of the underlying molecular and cellular events, and suggested a common route for other drugs of addiction.

Dr. Dani's nomination was based on the following publications:

Gray R, Rajan AS, Radcliffe KA, Yakehiro M, Dani JA. Hippocampal synaptic transmission enhanced by low concentrations of nicotine. Nature. 1996 Oct 24;383(6602):713-6.

Pidoplichko VI, DeBiasi M, Williams JT, Dani JA. Nicotine activates and desensitizes midbrain dopamine neurons. Nature. 1997 Nov 27;390(6658):401-4.