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.Many drugs of abuse as well as many drugs used in the clinic have actions on dopamine (DA) systems; however, there are a number of different DA receptors [i.e., D1-like (D1 and D5) and D2-like (D2, D3, and D4)], and the relative contribution of each receptor subtype to the abuse or therapeutic effects of drugs is not known. For example, DA D3 and D2 receptors are thought to mediate many of the behavioral effects of cocaine because some D3/D2 receptor agonists share behavioral (e.g., discriminative stimulus) effects with cocaine (Caine and

Dopamine D3 and D2 Receptor Mechanisms in the Abuse-Related Behavioral Effects of Cocaine: Studies with Preferential Antagonists in Squirrel Monkeys

“…Consistent with our findings, PG01037 has been found to localize primarily in D3-rich brain regions as determined by pharmacological magnetic resonance imaging (Grundt et al, 2007b) and selectively attenuate the D3-mediated component of quinpirole-induced yawning in rats (Baladi et al, 2010). Unlike PG01037, L-741626 attenuated the cocaine-like DS effects of both sumanirole and PD128907, suggesting less selective effects consistent with previous studies in which L-741626 attenuated the DS effects of another D3 agonist, S32504 [(ϩ)-trans-3,4,4a,5,6, 10b-hexahydro-9-carbamoyl-4-propyl-2H-naphth[1,2-b]-1,4-oxazine] (Millan et al, 2007).…”

Characterization of the Transport, Metabolism, and Pharmacokinetics of the Dopamine D3 Receptor-Selective Fluorenyl- and 2-Pyridylphenyl Amides Developed for Treatment of Psychostimulant Abuse

“…Many behavioral evaluations have been conducted by using the intraperitoneal route of administration and observed compound-specific behavioral effects from a wide range of doses (i.e., 0.30 -56.0 mg/kg) (Spiller et al, 2008;Baladi et al, 2010). Thus, there is the possibility that these analogs could differ in their rate and/or extent of absorption from the peritoneal cavity.…”

Sensitivity to apomorphine-induced yawning and hypothermia in rats eating standard or high-fat chow

“…Dopamine receptor agonist-induced yawning has been used to study changes in dopamine systems that occur under a variety of conditions, and it is well established that the ascending and descending limbs of the agonist (e.g., quinpirole) dose-response curve are mediated by dopamine D3 and D2 receptors, respectively (Baladi et al 2010;Collins et al 2005). A shift downward in the apomorphine doseresponse curve in rats with restricted access to food, as shown in the current study and by others, might be due to decreased sensitivity at D3 receptors, increased sensitivity at D2 receptors, or to both decreased sensitivity at D3 and increased sensitivity at D2 receptors.…”

“…For example, the dose-response curve for dopamine receptor agonist (e.g., quinpirole)-induced yawning is an inverted U-shape with the ascending and descending limbs of the curve being mediated by D3 and D2 receptors, respectively (Baladi et al 2010;Collins et al 2005). In rats eating high-fat chow, both limbs of the dose-response curve are shifted leftward; however, antagonism of quinpirole-induced yawning is not different between rats eating high-fat or standard chow , indicating that the shifts leftward in the former reflect increased sensitivity at D3 (ascending limb) and D2 (descending limb) receptors (Baladi and France 2009;Baladi et al 2010Baladi et al , 2011Collins et al 2005). Food restriction, on the other hand, decreases sensitivity to, or in some cases eliminates, dopamine receptor agonist-induced yawning as evidenced by a flattening of the inverted U-shaped dose-response curve; this flattening is thought to reflect a selective increase in sensitivity at D2 receptors (i.e., descending limb; Collins et al 2008;Sevak et al 2008).…”