A satellite meeting to the 33rd Annual Meeting of the Society for Neuroscience, held last month in New Orleans, addressed nicotine and nicotinic receptors, and their potential for Parkinson's disease therapy. Organized by Maryka Quik, Parkinson's Institute, Sunnyvale, California, and Al Collins, University of Colorado, Boulder, the event drew around 300 people. The goal of this symposium was to bring together researchers with expertise in the pathogenesis of Parkinson's disease and scientists investigating basic and clinical aspects relating to neuronal nicotinic receptors. Advisors to the organizers included Paul Clarke, McGill University, Montreal, Sue Wonnacott, University of Bath, United Kingdom, and Dino Di Monte, also of the Parkinson's Institute.

Fourteen short talks covered three main areas: the biology of nicotinic receptors and their role in dopaminergic function; the potential of nicotinic drugs in the symptomatic treatment of Parkinson's disease; and smoking, nicotine and protection against nigrostriatal damage.

Clearly, a lot of progress had been made in the basic biology in the last decade. In the first three talks—by Collins, Wonnacott, John Dani, Baylor College of Medicine, Houston—we learned that nicotinic receptors are very complex. At least 10 α and four β subunits exist, which can combine to form functional heteromeric and homomeric receptors. Additional complexity arises from the fact that many of these receptor complexes desensitize rapidly, and until recently, pharmacological tools to study the various subtypes did not exist. However, the use of knockout mice and the combined use of molecular biology, neurochemistry, and electrophysiology has provided evidence that at least the α4, β2, α6 subunits are important in the regulation of dopamine release.

The use of nicotinic receptor drugs for symptomatic treatment is also complicated. As mentioned above, multiple subtypes of receptor exist, and targeting dopaminergic function in substantia nigra and striatum may be difficult without also modulating reward pathways in the ventral tegmental area and nucleus accumbens. That said, however, it is clear that activation of nicotinic receptors can produce behavioral and biochemical changes in the rodent brain. Moreover, a large and accumulating body of evidence suggests that nicotine can improve cognition and alter plasticity processes; this may be of particular interest with regard to Alzheimer's disease and other, nonmotor symptoms of PD.

G. Ross, University of Hawaii, provided a nice overview that clearly illustrated that smokers have a decreased incidence of PD. This effect has been reported in several independent studies and is probably one of the major drivers for researchers to try and work out how this effect is being produced. A series of talks (R. Tyndale, Lorise Gahring, University of Utah, Salt Lake City; Michael O'Neill, Eli Lilly and Co., Windlesham, UK) presented preclinical data showing that nicotine has protective properties in various in-vitro culture systems and in some rodent models of PD. The potential neuroprotective mechanisms discussed included altering neurochemistry, receptor expression and signaling pathways; antioxidant properties; induction of growth factors; and induction of metabolic enzymes. However, it was clear that the mechanism(s) are not yet elucidated and that data are mixed (i.e., some papers reporting protection; others, no effect; or indeed, increase of injury). In addition to clarifying the data with nicotine itself, further work is needed to test more selective ligands (nicotine has effects of multiple receptor subtypes), and to understand which receptor subtypes are responsible.

The final talks illustrated some of the newer models of PD that may be used to study further the protective actions of smoking/nicotine. These include the use of paraquat in mice (DiMonte); rotenone in rats (Timothy Greenamyre, Emory University, Atlanta); and MPTP in primates (Quik). The first two models are slow and progressive; they differ from other models in that ubiquitin- and α-synuclein-positive inclusion bodies are present. These inclusion bodies at least in part mimic Lewy bodies, a hallmark of PD in the human brain.

Overall, this was an enjoyable meeting with lots of interaction among cellular, neurochemical, and behavioral scientists. The availability of more selective ligands, knockout mice, and newer models of PD will hopefully allow this area to progress rapidly in the next three to five years. Unfortunately, the conference coincided with the Parkinson's Foundation Symposium, which was in progress a few blocks away at Hotel Monaco. It would be nice to see a follow-up conference, perhaps with an even greater presence of PD specialists, in the future.—Michael O'Neill.


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