Identifying the alpha6 nicotinic receptor subtypes that govern the control of striatal dopamine transmission by nicotine

Tobacco smoking is one of the largest preventable causes of illness and death worldwide. The Royal College of Physicians have estimated that smoking-related ill health generates at least 1,000 hospital admissions per day in England alone, and is the cause of a fifth of all UK deaths. Although these detrimental effects on our health can readily be prevented by stopping smoking, in practice as any smoker knows, giving up the habit is difficult. Smoking is addictive. We urgently need to improve the means available to smokers to aid their chances of extinguishing a smoking habit once and for all. In order to do this it is essential that we improve our understanding of the fundamental mechanisms of how nicotine acts in the brain. We already know that like cocaine and amphetamine, nicotine is addictive because it increases levels of the neurochemical dopamine in brain centres related to reward where nicotine mimics the effects of natural rewards. But we do not understand how nicotine can do this. In particular, we have still not fully identified the molecules, or neurochemical receptors, on nerve cell membranes that nicotine binds to and that are responsible for enhancing dopamine in these reward centres.
The work we propose will identify which of nicotine?s many receptors are the receptors central to nicotine?s addictive properties. We will deduce which receptors are most important by using a state-of-the-art method to detect the effects of nicotine on dopamine in these brain centres in mice who carry different types of these receptors. If we can identify the right receptor, we will have found a target site for action for a future pharmaceutical treatment to combat nicotine addiction.

Nicotine addiction through tobacco smoking is amongst the largest single preventable causes of morbidity and premature mortality in the world. Yet, we still lack complete knowledge of the fundamental neuronal mechanisms underlying nicotine action, and certainly lack definitive treatments for nicotine addiction. Striatal dopamine transmission is a key player in the development of nicotine addiction. Despite detailed characterization of the diverse stoichiometries of the heteromeric nicotinic receptors expressed within striatum, little is known about the functional relevance of each receptor type in nicotine?s actions. Alpha6-subunit-containing (alpha6*) receptors are attracting much attention as promising targets for pharmacotherapies in dopaminergic disorders because unlike other subunits, their expression is relatively restricted to dopamine neurons. Moreover, we now have unpublished data to suggest that alpha6*-receptors play a previously unappreciated dominant role in the control of dopamine neurotransmission by nicotine in the nucleus accumbens (Exley et al., submitted).
Alpha6*-receptors are proposed to exist in three forms variously containing alpha4 and beta3 co-subunits (Salminen et al., 2007). In this project, we will identify the alpha6*-receptors responsible for the control of striatal dopamine neurotransmission by nicotine and endogenous acetylcholine. The effects of nicotine on dopamine neurotransmission depend critically on endogenous striatal acetylcholine (Rice and Cragg 2004, Cragg 2006). We will use real-time electrochemical technologies, namely fast-scan cyclic voltammetry to detect synaptic dopamine transients with subsecond time resolution at carbon-fibre microelectrodes in acutely living slices of mouse striatum where acetylcholine neuron activity is intact. We will identify the function of the diverse portfolio of alpha6*-receptors in the control of dopamine neurotransmission using transgenic mice with subunit-specific deletions (alpha6, alpha4, beta3) in combination with pharmacological tools. Since nicotinic receptor control of dopamine transmission is specific to the frequency of action potentials reaching the dopamine synapse (Rice and Cragg 2004; Zhang and Sulzer 2004), the design of these experiments will necessarily involve exploring dopamine transients released across the range of physiologically relevant activity in dopamine neurons including low frequency tonic ( 10 Hz) and high-frequency reward-related activity (20-100 Hz).
These experiments should reveal the identity (alpha and beta subunit composition) of the alpha6-receptors responsible for the powerful control of endogenous dopamine neurotransmission by nicotine. These data will not only enhance our understanding of nicotine?s synaptic mechanisms of action but moreover, should also provide a key therapeutic target for the design of pharmaceutical strategies to treat nicotine addiction as well as other disorders of dopamine dysfunction including Parkinson?s disease.