Stimulant drug abuse is a highly prevalent problem that constitutes a major public health concern. To gain better insight into mechanisms contributing to stimulant drug abuse, the neurochemical mechanisms subserving the behavioral effects of these drugs have been intensively examined. Neurochemically, these drugs increase synaptic concentrations of dopamine (DA) and norepinephrine (NE). Evidence indicates that actions of DA within the striatum and nucleus accumbens are critical components of the rewarding and locomotor activating effects of stimulants. In contrast, NE appears to serve a minimal contributory role in these behavioral actions of stimulants. The potent rewarding effects of these drugs are superimposed upon an alert behavioral state (e.g. prolonged periods of waking/enhanced alertness). The ability of stimulants to maintain waking and enhance alertness has long been exploited and is a contributing factor to the widespread use/abuse of these drugs. However, the degree to which NE or DA participates in the """"""""arousal""""""""-enhancing actions of stimulants and which anatomical site(s) subserve such actions remains enigmatic. A variety of observations suggest that the locus-coeruleus (LC)-noradrenergic system participates in the modulation of behavioral state. Previous studies by the PI demonstrated potent actions of LC on EEG and behavioral indices of waking via actions of beta-receptors located within a region of the basal forebrain encompassing the medial septum and the posterior shell of the nucleus accumbens (MS). Preliminary studies indicate that potent arousal-enhancing effects are observed following amphetamine infusions into this region (e.g. induction and maintenance of waking). These observations suggest that, at least some of, the arousal-enhancing actions of stimulants may be due to enhanced release of NE within MS. The proposed studies assess the degree to which amphetamine acts within this region of the basal forebrain to enhance EEG, EMG, and behavioral indices of arousal and to assess the degree to which NE participates in these actions. Utilizing a combination of anesthetized and unanesthetized preparations, local infusions, in vivo microdialysis to assess NE release, and EEG, EMG, and behavioral measures, these studies will provide novel information concerning the degree to which NE participates in the behavioral effects of stimulants. Information obtained in these studies may provide insight into mechanisms subserving, and treatment of, stimulant drug abuse.
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