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BEHAVIORAL PHARMACOLOGY

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

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (G.T.C., D.M.C., J.H.W.); and Medicinal Chemistry Section, National Institutes on Drug Abuse-Intramural Research Program, National Institutes of Health, Baltimore, Maryland (A.H.N., P.G.)

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 N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole) 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 pramipexole-induced 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 pramipexole-induced 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.

Address correspondence to: Dr. James H. Woods, Department of Pharmacology, 1301 Medical Science Research Building III, 1150 W. Medical Center Drive, University of Michigan Medical School, Ann Arbor, MI 48109-0632. E-mail: jhwoods{at}umich.edu