Dopamine D3 receptors mediate the discriminative stimulus effects of quinpirole in free-feeding rats

Abstract

The discriminative stimulus effects of dopamine (DA) D3/D2 receptor agonists are thought to be mediated by D2 receptors. To maintain responding, access to food is often restricted, which can alter neurochemical and behavioral effects of drugs acting on DA systems. This study established stimulus control with quinpirole in free-feeding rats and tested the ability of agonists to mimic and antagonists to attenuate the effects of quinpirole. The same antagonists were studied for their ability to attenuate quinpirole-induced yawning and hypothermia. DA receptor agonists apomorphine and lisuride, but not amphetamine and morphine, occasioned responding on the quinpirole lever. The discriminative stimulus effects of quinpirole were attenuated by the D3 receptor-selective antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl (PG01037) and the nonselective D3/D2 receptor antagonist raclopride, but not by the D2 receptor-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]methyl-1H-indole (L-741,626); the potencies of PG01037 and raclopride to antagonize this effect of quinpirole paralleled their potencies to antagonize the ascending limb of the quinpirole yawning dose-response curve (thought to be mediated by D3 receptors). L-741,626 selectively antagonized the descending limb of the quinpirole yawning dose-response curve, and both L-741,626 and raclopride, but not PG01037, antagonized the hypothermic effects of quinpirole (thought to be mediated by D2 receptors). Food restriction (10 g/day/7 days) significantly decreased quinpirole-induced yawning without affecting the quinpirole discrimination. Many discrimination studies on DA receptor agonists use food-restricted rats; together with those studies, the current experiment using free-feeding rats suggests that feeding conditions affecting the behavioral effects of direct-acting DA receptor agonists might also have an impact on the effects of indirect-acting agonists such as cocaine and amphetamine.

Fig. 1.

Discriminative stimulus effects and the percentage of trials completed for lisuride, quinpirole, apomorphine, amphetamine, and morphine in six rats with unlimited access to food and discriminating 0.032 mg/kg quinpirole. Abscissa, dose in milligrams per kilogram of body weight; V, vehicle. Ordinates, mean (±S.E.M.) percentage of responses on the quinpirole lever (top) and mean (±S.E.M.) percentage of trials completed (bottom).

Fig. 2.

Discriminative stimulus effects of quinpirole administered alone (●) and in combination with different doses of L-741,626 (top), PG01037 (middle), and raclopride (bottom). See legend to Fig. 1 for other details.

Fig. 3.

Quinpirole-induced yawning when quinpirole was administered alone (●) and in combination with different doses of L-741,626 (top), PG01037 (middle), and raclopride (bottom) in eight rats with unlimited access to food. Ordinate, mean (±S.E.M.) number of yawns in the 10-min observation period. See legend to Fig. 1 for other details.

Fig. 4.

Quinpirole-induced hypothermia when quinpirole was administered alone (●) and with different doses of L-741,626 (top), PG01037 (middle), and raclopride (bottom). Ordinate, mean (±S.E.M.) change in body temperature (degrees Centigrade). See legend to Fig. 1 for other details.

Fig. 5.

Dose-response curves for the discriminative stimulus effects of quinpirole (top) and quinpirole-induced yawning (bottom) when rats had unlimited access to food (free feeding, ●) and when they were restricted to 10 g/day of food for 7 days (restricted feeding, ▵). Ordinates, mean (±S.E.M.) percentage of responses on the quinpirole lever (top) and mean (±S.E.M.) number of yawns occurring in the 10-min observation period (bottom panel). *, P < 0.05 compared with the same rats when consuming a free-feeding diet at the corresponding dose of quinpirole. See legends to Figs. 1 and 3 for other details.