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Neurotoxic effects of nicotine: anatomy, mechanisms, effects

Institution: University of California, Los Angeles
Investigator(s): Gaylord Ellison, Ph.D.
Award Cycle: 1999 (Cycle 8) Grant #: 8RT-0005 Award: $183,424
Subject Area: Nicotine Dependence
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
We propose to study the patterns of neural degeneration in brain induced by nicotine (i.e., cell death, or death of parts of brain cells). This includes: what are the primary brain structures involved, what are the doses necessary to induce the degeneration, and what are the drug regimens of nicotine which are most potent in inducing degeneration. We seek to determine not how much neurotoxicity we can achieve with massive doses, but rather what are the parts of brain which first demonstrate vulnerability at the lowest doses possible. This makes it likely that these would be the "weak link" structures which would show alterations in humans. Degeneration has already been shown in our previous animal studies utilizing continuous nicotine administration.

Once the critical brain regions are determined, and the lowest doses which produce this degeneration, we will attempt to determine the mechanisms involved in this neurotoxicity. Not only why does this particular part of brain degenerate, but also what happens chemically to produce the damage? Studying how various types of brain receptors respond to the lowest effective (neurotoxic) dose, and whether prolonged and highly repeated exposure to nicotine is especially damaging, will provide clues as to why these parts of brain degenerate first. We will also determine whether rats exposed to nicotine prenatally show degeneration in the critical anatomical structures found in adults, or if other structures are involved in the fetal damage.

Other studies will investigate how the neurotoxicity is altered by prior exposure to the drug. We will also study other novel psychopharmacological agents related to nicotine, both to determine if they are as neurotoxic as nicotine and if they produce the cognitive enhancement produced by nicotine. A most promising outcome would be if it could be determined that some more selective nicotinic agonists do not induce the toxicity, yet still have the apparent beneficial effects of nicotine in stimulating cognitive function and delaying the onset of various age-related diseases.
Publications

Selective neurotoxic effects of nicotine on axons in fasciculus retroflexus further support evidence that this is a weak link in brain across multiple drugs of abuse
Periodical: Neuropharmacology Index Medicus:
Authors: Carlson J, Armstrong B, Switzer RC III, Ellison G ART
Yr: 2000 Vol: 39 Nbr: Abs: Pg: 2792-2798

Nicotine produces selective degeneration in the medial habenula and fasciculus retroflexus
Periodical: Brain Research Index Medicus:
Authors: Carlson J, Noguchi K, Ellison G ART
Yr: 0 Vol: Nbr: Abs: Pg: