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BEHAVIORAL PHARMACOLOGY

The -Opioid Receptor Agonist SNC80 [(+)-4-[(R)--[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-(3-methoxybenzyl)-N,N-diethylbenzamide] Synergistically Enhances the Locomotor-Activating Effects of Some Psychomotor Stimulants, but Not Direct Dopamine Agonists, in Rats

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (E.M.J., J.H.W.); Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas (M.G.B.); and Chemical Biology Research Branch, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland (J.E.F., K.C.R.)

The nonpeptidic -opioid agonist SNC80 [(+)-4-[(R)--[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-(3-methoxybenzyl)-N,N-diethylbenzamide] produces many stimulant-like behavioral effects in rodents and monkeys, such as locomotor stimulation, generalization to cocaine in discrimination procedures, and antiparkinsonian effects. Tolerance to the locomotor-stimulating effects of SNC80 develops after a single administration of SNC80 in rats; it is not known whether cross-tolerance develops to the effects of other stimulant compounds. In the initial studies to determine whether SNC80 produced cross-tolerance to other stimulant compounds, it was discovered that amphetamine-stimulated locomotor activity was greatly enhanced in SNC80-pretreated rats. This study evaluated acute cross-tolerance between -opioid agonists and other locomotor-stimulating drugs. Locomotor activity was measured in male Sprague-Dawley rats implanted with radiotransmitters, and activity levels were recorded in the home cage environment. Three-hour SNC80 pretreatment produced tolerance to further -opioid receptor stimulation but also augmented greatly amphetamine-stimulated locomotor activity in a dose-dependent manner. Pretreatments with other -opioid agonists, (+)BW373U86 [(+)-4-[(R)--[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl]-N,N-diethylbenzamide] and oxymorphindole (17-methyl-6,7-dehydro-4,5-epoxy-3,14-dihydroxy-6,7,2',3'-indolomorphinan), also modified amphetamine-induced activity levels. SNC80 pretreatment enhanced the stimulatory effects of the dopamine/norepinephrine transporter ligands cocaine and nomifensine (1,2,3,4-tetrahydro-2-methyl-4-phenyl-8-isoquinolinanmine maleate salt), but not the direct dopamine receptor agonists SKF81297 [R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide] and quinpirole [trans-(-)-(4R)-4,4a, 5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g] quinoline monohydrochloride]. In conclusion, SNC80 enhanced the locomotor-stimulating effects of monoamine transporter ligands suggesting that -opioid receptor activation might alter the functional activity of monoamine transporters or presynaptic monoamine terminals.

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