Low doses of amphetamine-like stimulants exert arousal- and attention-enhancing actions. The ability of stimulants to enhance alert waking has long-been exploited and is a contributing factor to the widespread illicit use of these drugs. Additionally, these drugs are used widely in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. The neurochemical mechanisms subserving the behavioral effects of moderate-to-high doses of these drugs have been examined intensively. 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. The rewarding effects of these drugs are superimposed upon an alert behavioral state (e.g. prolonged periods of waking/enhanced alertness). Previous studies by the PI demonstrate potent actions of the locus coeruleus-noradrenergic system on EEG and behavioral indices of waking via actions of beta-and alpha1 -receptors located within the medial basal forebrain. Additionally, the PI has demonstrated that amphetamine acts within the same basal forebrain regions to exert arousal-enhancing (wake-promoting) actions. Recent studies also suggest arousal-enhancing actions of DA. The PI has initiated a research program that assesses the contribution of NE and DA to the arousal-enhancing actions of stimulants and identifies the neurocircuitry underlying these actions. Recent studies demonstrate potent arousal-enhancing actions of the peptides, hypocretins. Dysregulation of hypocretin neurotransmission appears to be an etiological factor in the arousal disorder, narcolepsy. Stimulants elicit an activation of hypocretin neurons, suggesting the participation of hypocretins in at least a subset of the behavioral actions of these drugs, including their therapeutic action in the treatment of narcolepsy. Utilizing a combination of behavioral, pharmacological, and anatomical methods, the proposed studies will provide novel information concerning the degree to which NE, DA and hypocretins participate in the behavioral effects of. Information obtained in these studies may provide insight into mechanisms underlying, and future treatment of, stimulant drug abuse, ADHD and narcolepsy.
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