The alarming abuse potential of amphetamine and its profound clinical effects have stimulated considerable research on the neuronal systems and processes underlying the actions of this drug. The neostriatum has been implicated in many of the behavioral effects of amphetamine including the focused, repetitive behaviors (stereotypies) that are enhanced during long-term treatment. Little information is available, however, concerning the neurochemical systems that modulate the neuronal effects of amphetamine in the neostriatum and the relationship of these effects to the amphetamine behavioral response. In this application, experiments are proposed that will shed new light on these issues. Single-unit recording techniques, including electrochemically-quantified iontophoresis and studies of freely-moving animals, will be used to identify changes in the sensitivity of pre- and postsynaptic dopamine receptors that may occur during long-term amphetamine treatment. These techniques also will be used to investigate corresponding changes in serotonergic neurons that recently have been found to modulate the neuronal effects of amphetamine in specific neostriatal regions. A growing body of evidence also suggests that neostriatal neurons are responsive to ascorbic acid and that this effect may have important implications for understanding the actions of amphetamine in this site. In fact, ascorbic acid has been shown to attenuate amphetamine-induced stereotyped behaviors. Thus, a parallel series of experiments are proposed to elucidate the role of ascorbic acid in regulating the neuronal and behavioral actions of amphetamine.
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