The regulation of synaptic dopamine by striatal nicotinic receptors

A new category of drugs that offer a promising therapy for Parkinson's disease are drugs that act at a key subtype of brain receptors for the neurotransmitter acetylcholine, the nicotine-sensitive acetylcholine receptors. This idea has been proclaimed on the basis that drugs that act at these nicotinic receptors might be able to increase the levels of the neurotransmitter dopamine, which is depleted to a critically low level in Parkinson's disease. However, there is conflicting data about the effects of nicotinic drugs which may contraindicate their use in the disease. For example, latest data suggests that these drugs actually reduce dopamine levels because they paradoxically switch off, or desensitize', those receptors. Such an effect would counteract any possible benefit from receptor stimulation in a patient. It is vital that these interactions are clarified for the promise of nicotinic drugs in Parkinson's disease to be realized. In preliminary experiments, we have now identified that these agents might nonetheless be able to increase dopamine, despite receptor desensitization. We will explore how specific nicotinic agents and receptors might enhance dopamine levels using a state-of-the-art method to monitor dopamine in real time. This study will advance our understanding of the neurochemistry of movement regulation, and also will greatly elucidate the prospects for nicotinic receptor drugs in Parkinson's disease.