Monoaminergic psychomotor stimulants: discriminative stimulus effects and dopamine efflux

Abstract

The present studies were conducted to investigate the relationship between discriminative stimulus effects of indirectly acting monoaminergic psychostimulants and their ability to increase extracellular levels of dopamine (DA) in the nucleus accumbens (NAcb) shell. First, the behavioral effects of methamphetamine (MA), cocaine (COC), 1-[2-[bis(4-fluorophenyl-)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909), d-amphetamine, and methylphenidate were established in rats trained to discriminate intraperitoneal injections of 0.3 mg/kg MA from saline. In other studies, in vivo microdialysis was used to determine the effects of MA, COC, and GBR 12909 on extracellular DA levels in the NAcb shell. Results show that all drugs produced dose-related and full substitution for the discriminative stimulus effects of 0.3 mg/kg MA. In microdialysis studies, cumulatively administered MA (0.3-3 mg/kg), COC (3-56 mg/kg), and GBR 12909 (3-30 mg/kg) produced dose-dependent increases in DA efflux in the NAcb shell to maxima of approximately 1200 to 1300% of control values. The increase in DA levels produced by MA and COC was rapid and short-lived, whereas the effect of GBR 12909 was slower and longer lasting. Dose-related increases in MA lever selection produced by MA, COC, and GBR 12909 corresponded with graded increases in DA levels in the NAcb shell. Doses of MA, COC, and GBR 12909 that produced full substitution increased DA levels to approximately 200 to 400% of control values. Finally, cumulatively administered MA produced comparable changes in DA levels in both naive and 0.3 mg/kg MA-trained rats. These latter results suggest that sensitization of DA release does not play a prominent role in the discriminative stimulus effects of psychomotor stimulants.

Fig. 1.

The NAcb, the major terminal areas of the mesolimbic dopaminergic system. The superimposed rectangles show the limits of the positions of the dialyzing portions of the microdialysis probes. Sh, NAcb shell; Co, nucleus accumbens core; CPu, caudate putamen. [Based on Paxinos and Watson (1987).]

Fig. 2.

Effects of MA and related compounds in rats trained to discriminate injections of MA (0.3 mg/kg) from saline under a discrete-trial avoidance/escape procedure (top) and under an FR 20 schedule of food reinforcement (bottom). A, ordinates: percentage of trials completed on the MA-associated key. B, percentage of responses on the MA-associated key. Abscissae, cumulative drug dose in milligrams per kilogram (log scale). Each point represents the mean (±S.E.M.) effect in at least six rats. V, vehicle.

Fig. 3.

Time course of the effects of systemic cumulative administration of vehicle (V), MA (left, 0.3–5.6 mg/kg), COC (center, 3–30 mg/kg; 5.6–56 mg/kg), and GBR 12909 (right, 3–30 mg/kg) on extracellular levels of DA in dialysates samples taken from the NAcb. Arrows indicate the time at which incremental cumulative injections were administered. Ordinates, percentage of basal DA levels; abscissae, time in minutes after injection. Each point represents the mean (±S.E.M.) effect expressed as a percentage of basal values, uncorrected for probe recovery. All data points for all drugs are generated from n of at least four to six subjects. Filled symbols represent values significantly different from basal DA values (p < 0.05).

Fig. 4.

Behavioral effects of MA, COC, and GBR 12909 in rats trained to discriminate MA under the two drug discrimination procedures and changes in extracellular levels of DA in the NAcb of drug-naive rats. Left ordinates, percentage of responding on the MA-associated key; right ordinates, percentage of basal DA levels. Each point in the dialysis data represents the average of the three samples taken at each time point (10, 20, and 30 min) after each cumulative injection; abscissae, cumulative drug dose in milligrams per kilogram.

Fig. 5.

Effects of cumulatively administered MA on extracellular levels of DA in the NAcb in drug-naive rats (data from Fig. 4; n = 6) and rats trained to discriminate 0.3 mg/kg MA under the food reinforcement schedule (n = 6). Ordinates, percentage of basal DA levels; abscissae top, time in minutes after injection; abscissae bottom, cumulative drug dose in milligrams per kilogram (log scale). V, vehicle.