Food Restriction Alters N′-Propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (Pramipexole)-Induced Yawning, Hypothermia, and Locomotor Activity in Rats: Evidence for Sensitization of Dopamine D2 Receptor-Mediated Effects

Abstract

Food restriction enhances sensitivity to the reinforcing effects of a variety of drugs of abuse including opiates, nicotine, and psychostimulants. Food restriction has also been shown to alter a variety of behavioral and pharmacological responses to dopaminergic agonists, including an increased sensitivity to the locomotor stimulatory effects of direct-and indirect-dopamine agonists, elevated extracellular dopamine levels in responses to psychostimulants, as well as suppression of agonist-induced yawning. Behavioral and molecular studies suggest that augmented dopaminergic responses observed in food-restricted animals result from a sensitization of the dopamine D2 receptor; however, little is known about how food restriction affects dopamine D3 receptor function. The current studies were aimed at better defining the effects of food restriction on D2 and D3 receptor function by assessing the capacity of 5,6, to induce yawning, penile erection (PE), hypothermia, and locomotor activity in free-fed and food-restricted rats. Food restriction resulted in a suppression of pramipexole-induced yawning, a sensitized hypothermic response, and an enhanced locomotor response to pramipexole, effects that are suggestive of an enhanced D2 receptor activity; no effect on pramipexoleinduced PE was observed. Antagonist studies further supported a food restriction-induced enhancement of the D2 receptor activity because the D2 antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole (L741,626) recovered pramipexoleinduced yawning to free-fed levels, whereas yawning and PE were suppressed following pretreatment with the D3 antagonist N-{4- [4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride (PG01037). The results of the current studies suggest that food restriction sensitized rats to the D2-mediated effects of pramipexole while having no effect on the D3-mediated effects of pramipexole.

Dopamine D3 Receptors Mediate the Discriminative Stimulus Effects of Quinpirole in Free-Feeding Rats

“…However, food restriction (10 g/day for 7 days) that markedly decreased sensitivity to quinpiroleinduced yawning had no effect on the discriminative stimulus effects of quinpirole in the same group of rats, supporting the hypothesis that D2 receptors are not involved in the discriminative stimulus effects of quinpirole in freefeeding rats. Food restriction in the current study reduced body weight to approximately 90% of free-feeding weight, somewhat less than body weight loss reported in other studies using food restriction and studying dopamine drugs (e.g., 80 -85%; Weathersby and Appel, 1986;Carr et al, 2003;Collins et al, 2008;Koffarnus et al, 2009). Together with the current antagonism studies, these data support the view that D3 receptors mediate the discriminative stimulus effects of quinpirole in free-feeding rats and that sensitivity of D3 receptors to agonists is not markedly affected by food restriction.…”

“…However, results of behavioral as well as molecular studies indicate that the effect of food restriction is to increase sensitivity of D2 receptors (Carr et al, 2003;Collins et al, 2008;Thanos et al, 2008). If the discriminative stimulus effects of DA receptor agonists in freefeeding rats are mediated by D2 receptors, then it might be expected that food restriction would increase sensitivity to those effects, as reflected by a leftward shift in the doseresponse curve.…”

“…Food restriction also decreases the sensitivity of rats to yawning induced by DA receptor agonists including quinpirole and pramipexole (Collins et al, 2008;Sevak et al, 2008;Baladi and France, 2009). DA receptor agonist-induced yawning generates an inverted U-shaped dose-response curve, with the ascending limb thought to be mediated by D3 receptors and the descending limb by D2 receptors, and the decreased sensitivity to agonist-induced yawning in food-restricted rats is thought to be due to increased sensitivity of D2 receptors (Collins et al, 2008). Although the discriminative stimulus effects of pramipexole are thought to be mediated by D2, but not D3, receptors (Koffarnus et al, 2009), it is unclear whether food restriction that modifies some effects of DA receptor agonists (e.g., yawning) also modifies the discriminative stimulus effects of DA receptor agonists.…”

“…For example, food restriction decreases extracellular DA (Pothos et al, 1995), increases D2 receptor binding (Thanos et al, 2008), and increases coupling between DA receptors and G proteins (Carr et al, 2003). Food restriction also decreases the sensitivity of rats to yawning induced by DA receptor agonists including quinpirole and pramipexole (Collins et al, 2008;Sevak et al, 2008;Baladi and France, 2009). DA receptor agonist-induced yawning generates an inverted U-shaped dose-response curve, with the ascending limb thought to be mediated by D3 receptors and the descending limb by D2 receptors, and the decreased sensitivity to agonist-induced yawning in food-restricted rats is thought to be due to increased sensitivity of D2 receptors (Collins et al, 2008).…”

Pramipexole-Induced Increased Probabilistic Discounting: Comparison Between a Rodent Model of Parkinson's Disease and Controls

“…Finally, in food reinforcement studies, animals typically are food deprived to motivate them to perform the operant tasks. Food restriction alters the behavioral effects of PPX (Collins et al, 2008), which could confound outcomes of discounting tests with the agonist. To summarize, ICSS afforded a means to unambiguously assess discounting during chronic drug administration, following subsequent, long-term cessation of treatment, and drug reinstatement, all in the same test subjects.…”