Dopamine fluctuations in the nucleus accumbens during maintenance, extinction, and reinstatement of intravenous D-amphetamine self-administration.

Moment-to-moment fluctuations of nucleus accumbens dopamine (DA) were determined in rats self-administering or passively receiving "yoked" intravenous infusions of D-amphetamine. The initial lever presses of each session caused elevations in DA concentration, usually to an initial peak that was not maintained throughout the rest of the session. As the initial ("loading") injections were metabolized, DA levels dropped toward baseline but were sustained at elevated plateaus by subsequent lever pressing that was spaced throughout the remainder of the 3 hr sessions. During this period, DA levels fluctuated phasically, time-locked to the cycle of periodic lever pressing. Consistent with the known pharmacological actions and dynamics of amphetamine, peak DA elevations were seen approximately 10-15 min after each injection, and the mean DA level was at a low point in the phasic cycle at the time of each new lever press. During extinction periods when saline was substituted for amphetamine, DA levels dropped steadily toward baseline levels despite a dramatic increase in (now-unrewarded) lever pressing. Noncontingent injections during extinction reinstated lever-pressing behavior and increased nucleus accumbens DA concentrations. These data are consistent with the hypothesis that under the conditions of this experiment-during periods of amphetamine intoxication in well-trained animals-the timing of amphetamine self-administration comes primarily under the control of extracellular DA concentrations. The probability of lever pressing during the maintenance phase is highest when DA concentrations fall near a characteristic trigger point, a trigger point that is significantly elevated above baseline, and falls as DA concentrations fall below or increase above that trigger point.