This proposal focuses on the effects of stimulant drugs on cortical cholinergic transmission. It is driven by the theory that changes in cortical cholinergic transmission mediate the hyper-attentional biases postulated to contribute to processes of craving and relapse in addiction. This monopolization of attentional resources bias the addict toward the processing of drug-related cues and reduces the likelihood of evaluating alternative behaviors and coping strategies. A more thorough understanding of the neurobiological mechanisms underlying these cognitive changes will aid in the development of more efficacious ways to treat this major public health problem. The proposed experiments utilize an innovative enzyme-selective microelectrode array to reveal the effects of psychostimulants (nicotine and amphetamine) on cortical neurochemistry. The studies are designed to validate the rapid, in situ detection of extracellular ACh using these microelectrodes as a sensitive measure of cholinergic transmission. ACh-derived signals will be determined at a temporal (i.e. second-by-second) and spatial (i.e. 10-20 mu m) resolution that far exceeds conventional techniques. We will first test this electrochemical method in anaesthetized rats (in order to optimize several electrochemical, neurobiological, and procedural variables). After optimizing the parameters of electrochemical recording, we will then validate the method in awake rats following the administration of psychostimulants and environmental stimuli - stimuli that have been shown to increase cortical ACh release following more conventional methods. But, this is only a starting point for a series of important experiments on the neurochemistry of attentional mechanisms in conditions of drug abuse. For the first time, we will be able to study cholinergic transmission within a time-frame that is consistent with the cognitive processes that have been linked to cortical cholinergic transmission and believed to underlie compulsive drug use. In much the same fashion that enhanced voltammetric techniques, and the focus on phasic DA release, have revealed new perspectives on the contributions of accumbens DA to drug-seeking behaviors the ACh- and choline-sensitive microelectrode arrays will allow us to measure cholinergic transmission in subsecond time periods and within discrete regions in order to address important issues in addiction. ? ? ?
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| Burmeister, Jason J; Pomerleau, Francois; Huettl, Peter et al. (2008) Ceramic-based multisite microelectrode arrays for simultaneous measures of choline and acetylcholine in CNS. Biosens Bioelectron 23:1382-9 |
| Sarter, Martin; Bruno, John P; Parikh, Vinay (2007) Abnormal neurotransmitter release underlying behavioral and cognitive disorders: toward concepts of dynamic and function-specific dysregulation. Neuropsychopharmacology 32:1452-61 |
| Bruno, John P; Gash, Clelland; Martin, Brad et al. (2006) Second-by-second measurement of acetylcholine release in prefrontal cortex. Eur J Neurosci 24:2749-57 |
