Effects of Acute and Chronic Treatments with Dopamine D2 and D3 Receptor Ligands on Cocaine versus Food Choice in Rats

Abstract

Dopamine D₃ receptor ligands are potential medications for psychostimulant addiction. Medication assessment may benefit from preclinical studies that evaluate chronic medication effects on choice between an abused drug and an alternative, nondrug reinforcer. This study compared acute and chronic effects of dopamine D₂- and D₃-preferring ligands on choice between intravenous cocaine and palatable food in rats. Under baseline conditions, cocaine maintained dose-dependent increases in cocaine choice and reciprocal decreases in food choice. Acutely, the D₂ agonist R-(-)-norpropylapomorphine (NPA) and antagonist L-741,626 [3-[[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole] produced leftward and rightward shifts in cocaine dose-effect curves, respectively, whereas the partial agonist terguride had no effect. All three drugs dose-dependently decreased food-maintained responding. Chronically, the effects of R-(-)-norpropylapomorphine and L-741,626 on cocaine self-administration showed marked tolerance, whereas suppression of food-reinforced behavior persisted. Acute effects of the D₃ ligands were less systematic and most consistent with nonselective decreases in cocaine- and food-maintained responding. Chronically, the D₃ agonist PF-592,379 [5-[(2R,5S)-5-methyl-4-propylmorpholin-2-yl]pyridin-2-amine] increased cocaine choice, whereas an intermediate dose of the D₃ antagonist PG01037 [N-[(E)-4-[4-(2,3-dichlorophenyl)piperazin-1-yl]but-2-enyl]-4-pyridin-2-ylbenzamide] produced a therapeutically desirable decrease in cocaine choice early in treatment; however, tolerance to this effect developed, and lower and higher doses were ineffective. D₃ ligands failed to significantly modify total cocaine intake but caused persistent decreases in food intake. Thus, D₂-and D₃-preferring ligands showed distinct profiles, consistent with different pharmacological actions. In addition, these results highlight the role of acute versus chronic treatment as a determinant of test drug effects. With the possible exception of the D₃ antagonist PG01037, no ligand was promising in terms of cocaine addiction treatment.

Fig. 1.

Acute dosing effects of dopamine D₂-preferring ligands on concurrent cocaine self-administration and food-reinforced responding as a function of cocaine dose. The abscissae show the unit dose of cocaine (in milligrams per kilogram per injection), and the ordinates show cocaine injections earned (top), food reinforcers earned (center), and percent cocaine choice (bottom), per component. Group sizes are presented in Table 2. Choice data for higher pretreatment doses may have a lower group size because of missing values and are not shown when responding was reduced to the point that percent choice could be calculated for fewer than two rats. *P < 0.05; **P < 0.01; ***P < 0.001 (versus vehicle, Bonferroni post-test after significant ANOVA).

Fig. 2.

Acute dosing effects of dopamine D₃-preferring ligands on concurrent cocaine self-administration (top), food-reinforced responding (center), and percent cocaine choice (bottom), as a function of cocaine dose. Group sizes are presented in Table 2. Other details are as in Fig. 1.

Fig. 3.

Acute effects of dopamine D₂-preferring or D₃-preferring ligands on total cocaine intake and total food reinforcers per session. The abscissae show the dose of pretreatment drug (in milligrams per kilogram), and the ordinates show total cocaine intake (in milligrams per kilogram per session) (top) or total food reinforcers earned per session (bottom). Group sizes are presented in Table 2. *P < 0.05; **P < 0.01 (Dunnett multiple-comparisons test versus vehicle after significant ANOVA).

Fig. 4.

Acute versus chronic effects of continuously administered dopamine D₂-preferring ligands on concurrent cocaine self-administration and food-reinforced responding. Data from baseline, day 1 (2 hours of administration), and day 7 (1 week of continuous administration) are shown. The abscissae show the unit dose of cocaine (in milligrams per kilogram per injection), and the ordinates show cocaine injections earned (top), food reinforcers earned (center), and percent cocaine choice (bottom), per component. Group sizes are presented in Table 3. Choice data for higher pretreatment doses may be a lower group size because of missing values and are not shown when responding was reduced to the point that percent choice could be calculated for fewer than two rats. *P < 0.05; **P < 0.01; ***P < 0.001 (versus baseline, Bonferroni post-test after significant ANOVA). Red asterisks refer to day 1, and blue asterisks refer to the chronic 1-week test.

Fig. 5.

Acute versus chronic effects of continuously administered dopamine D₃-preferring ligands on concurrent cocaine self-administration, food-reinforced responding, and percent cocaine choice. Group sizes are presented in Table 3. Other details are as in Fig. 4.

Fig. 6.

Acute versus chronic effects of continuously administered dopamine D₂-preferring or D₃-preferring ligands on total cocaine intake and total food reinforcers per session. Data from baseline, day 1 (2 hours of administration), and day 7 (1 week of continuous administration) are shown. The abscissae show the dose of pretreatment drug (in milligrams per kilogram), and the ordinates show total cocaine intake (in milligrams per kilogram per session) (top) or total food reinforcers earned per session (bottom). Group sizes are presented in Table 3. *P < 0.05; **P < 0.01 (Dunnett multiple-comparisons test versus baseline after significant ANOVA).