NICOTINIC MODULATION OF DOPAMINE RELEASE STUDIED WITH A CHANNEL-BASED BIOSENSOR

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DESCRIPTION (provided by applicant): Modulation of dopamine release is one way that drugs of abuse likely hijack reward circuitry and lead to addiction. For instance, nicotine directly modulates dopamine release through nicotinic receptors on presynaptic terminals of dopaminergic neurons. However, current methodologies to monitor dopamine release and its modulation are missing an important level of spatiotemporal sensitivity that is taken for granted at fast transmitter synapses like glutamate and GABA synapses. Ligand-gated channels on target cells at fast synapses allows faithful detection of single quanta with temporal resolution below 1 ms. This level of resolution is not possible with current electrochemical and optical techniques that are applied to dopamine synapses, which activate G protein coupled receptors rather than ionotropic receptors. Here we propose to heterologously introduce an invertebrate ligand-gated dopamine channel into postsynaptic targets of rodent dopamine neurons. This will allow us to study dopamine release and nicotinic modulation of dopamine release with spatiotemporal resolution typically reserved for fast synapses. We anticipate that this new methodology will fill an important gap in our understanding of the actions of abused substances and may lead to new therapeutic strategies. PUBLIC HEALTH RELEVANCE: Drug abuse and addiction take an enormous societal toll. In any attack on the problem, we should include strategies to enhance understanding of the earliest changes wrought by drugs of abuse on brain signaling systems. Unfortunately, we are currently unable to peer into the fastest, earliest changes in signaling induced by abused drugs because of limitations in methodologies. We propose to introduce a new tool that will allow us to examine changes induced by nicotine, an exemplar drug of abuse, with unprecedented resolution. We will thereby gain new insights into how nicotine and other abused drugs hijack normal brain circuitry and signaling.