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

Abstract

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.

Fig. 1.

Nucleus accumbens dopamine concentrations in rats self-administering intravenous doses (0.25 mg/kg per injection) of d-amphetamine. Dialysate samples were collected at 15 min intervals before the start of the self-administration session at time = 0 (baseline) and at 5 min intervals after the start of the session. Vertical dotted lines represent lever presses and associatedd-amphetamine infusions. DL numbers are rat identification numbers.

Fig. 2.

Mean elevations over baseline in nucleus accumbens dopamine concentrations in rats receiving self-administered or experimenter-administered intravenous injections ofd-amphetamine. For each rat the mean dopamine concentration was calculated for the four samples before and after an injection occurred as well as for the sample during which the injection occurred. Only the results for dialysate samples collected after the first 60 min of the session were used. These data were then averaged within each group. The vertical dashed line represents the time of ad-amphetamine infusion.

Fig. 3.

Nucleus accumbens dopamine concentrations in rats receiving experimenter-administered intravenous doses of d-amphetamine (0.25 mg/kg per injection).Top, These four rats (experienced–yoked) had a history of amphetamine self-administration. Bottom, These four rats (inexperienced–yoked) were naïve to amphetamine and self-administration. Dialysate samples were collected at 10 min intervals before the start of the session at time = 0 (baseline) and at 5 min intervals after the start of the session. Vertical dotted lines represent the receipt of d-amphetamine infusions. A and DL numbers are rat identification numbers.

Fig. 4.

Nucleus accumbens dopamine concentrations in rats lever pressing during a 3 hr extinction period (no drug available) and a 2 hr reinstatement period (drug available). The arrow in each graph represents the time at which a rat received a noncontingent (priming) injection ofd-amphetamine and drug was made available again. Thehorizontal dotted line represents the baseline DA concentration. Dialysate samples were collected at 10 min intervals during the extinction period and at 5 min intervals during the reinstatement period. DL numbers are rat identification numbers.

Fig. 5.

Brain sections taken through the nucleus accumbens showing the locations of microdialysis probes (solid bars) for each of the rats tested here. Drawings are adapted from Pellegrino et al. (1979).