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, non-drug 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 NPA and antagonist L-741,626 produced leftward and rightward shifts in cocaine dose-effect curves, respectively, while the partial agonist terguride had no effect. All three drugs dose-dependently decreased food-maintained responding. Chronically, NPA and L-741,626 effects on cocaine self-administration showed marked tolerance, while 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 increased cocaine choice, whereas an intermediate dose of the D3 antagonist PG01037 produced a therapeutically desirable decrease in cocaine choice early in treatment; however, tolerance developed to this effect, 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. Additionally, 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.
- The American Society for Pharmacology and Experimental Therapeutics