Mechanisms of Amphetamine Action on Dopaminergic Signaling

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Considerable research effort has justifiably been directed towards identifying the mechanisms of amphetamine action. However, whether amphetamine acts on phasic dopaminergic signaling, as has been shown recently for cocaine, another psychostimulant, is not known. Some involvement is anticipated, given the role proposed for this mode of dopaminergic neurotransmission in learning and motivated behavior and amphetamine's use in treating attention deficit hyperactivity disorder and its highly addictive nature. On the other hand, while both drugs inhibit dopamine uptake, amphetamine, but not cocaine, depletes vesicular stores of dopamine. Consequently, amphetamine may not share with cocaine the ability to increase the amplitude of dopamine concentration transients in the nucleus accumbens, presumably elicited by phasic or burst firing and exocytotic release. Examining the link between amphetamine and phasic dopaminergic signaling is significant, because the behaviorally relevant mechanisms by which this psychostimulant acts are not fully elucidated. In particular, documented dissociations between amphetamine's effects on behavior and dialysate dopamine suggest other targets besides tonic dopaminergic signaling. In contrast to phasic dopaminergic signaling, which generates dopamine concentration transients in terminal fields, tonic dopaminergic signaling maintains a low, steady-state or ambient level of brain extracellular dopamine. To address these important issues related to amphetamine action, the present project will investigate the effects of amphetamine on phasic dopaminergic signaling. The first aim will compare the stimulant effects of amphetamine in rats and Syrian hamsters. While separate studies suggest that Syrian hamsters are less sensitive to amphetamine than other rodents including rats, this difference has not been established under the same conditions. By comparing neurochemical measurements in these two species in the subsequent experiments, the behavioral relevance of amphetamine effects on phasic dopaminergic signaling will be uniquely assessed. The second aim will determine the effects of amphetamine on dopamine uptake and exocytotic dopamine release in the nucleus accumbens, which have not been established in vivo. These presynaptic mechanisms regulate dopamine transient amplitude. The third aim will characterize the effects of amphetamine on the frequency and amplitude of dopamine concentration transients in the nuclues accumbens directly using the same approach, fast-scan cyclic voltammetry in freely moving animals, that was previously used to establish cocaine effects on phasic dopaminergic signaling. This research will investigate how amphetamine, which is used both as a therapeutic agent and a drug of abuse, affects the brain. New microsensor technology will be employed in laboratory animals to characterize amphetamine's effect on brain chemistry related to learning and motivaton.