Relationship between low‐dose amphetamine‐induced arousal and extracellular norepinephrine and dopamine levels within prefrontal cortex

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Abstract
Despite the well‐known and potent arousal‐enhancing effects of amphetamine (AMPH)‐like stimulants, the neurobiological substrates of AMPH‐induced arousal have rarely been examined explicitly. Available evidence suggests the possible participation of noradrenergic and/or dopaminergic systems in the arousal‐enhancing actions of AMPH‐like stimulants. The current studies examined the extent to which low‐dose AMPH‐induced increases in waking are related to AMPH‐induced increases in extracellular norepinephrine (NE) and dopamine (DA) levels within the prefrontal cortex (PFC), as measured by in vivo microdialysis. Vehicle injections elicited brief epochs of waking. Vehicle‐induced waking was closely associated with a brief and moderate (50% above baseline) increase in NE levels. DA levels were less sensitive to the arousing actions of vehicle injections, with maximal increases of approximately 25% above baseline observed. 0.15 mg/kg and 0.25 mg/kg AMPH increased time spent awake, which resulted primarily from increases in quiet waking. Although the magnitude of the waking response did not differ substantially between the two doses across time, a trend for a more rapid recovery to baseline waking levels was observed at the higher dose, possibly suggesting the development of a relatively rapid‐onset tolerance to the wake‐promoting actions of AMPH at this dose. At the 0.15 mg/kg dose, AMPH elicited maximum increases of approximately 175% and 125% above baseline levels for NE and DA, respectively. The time course of AMPH‐induced increases in waking closely paralleled the time course of AMPH‐induced increases in both NE and DA efflux. These observations are consistent with the hypothesis that both increased DA and NE efflux contribute to the low‐dose behavioral effects of AMPH‐like stimulants, including the arousal‐enhancing actions of these drugs. Additionally, these observations also suggest a possibly greater sensitivity of NE efflux, relative to DA, to moderately arousing conditions including low‐dose AMPH‐like stimulant administration. Synapse 46:140–149, 2002.