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BEHAVIORAL PHARMACOLOGY

Differential Behavioral Tolerance to the -Opioid Agonist SNC80 ([(+)-4-[(R)--[(2S,5R)-2,5-Dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide) in Sprague-Dawley Rats

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (E.M.J., S.T.K., J.R.T., J.H.W.); and Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (K.C.R.)

Nonpeptidic -opioid agonists produce a number of behaviors, such as antidepressant-like effects, locomotor stimulation, antinociception, and convulsions. To consider this class of compounds as potential therapeutics for humans, the effects of -opioid agonists after repeated administration must be evaluated. Therefore, the present study investigated the effects of repeated -opioid agonist, SNC80 ([(+)-4-[(R)--[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)-methyl]-N,N-diethylbenzamide), administration on its antidepressant-like effects in the forced swim test, locomotor activity, and convulsions in male Sprague-Dawley rats. Tolerance developed rapidly to the convulsive and locomotor-stimulating effects of SNC80 but not to the antidepressant-like effects. In addition, tolerance was evaluated at the level of the receptor-G protein interaction by measuring 5'-O-(3-[³⁵S]thio)triphosphate binding in brains from rats that were pretreated with SNC80. With various exposure durations to SNC80, some brain regions demonstrated tolerance at different times, suggesting that adaptations in the -opioid system may occur during agonist exposure. Overall, the lack of observable tolerance to the antidepressant-like effects of SNC80 indicates that this class of compounds has potential as a novel antidepressant therapy.

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

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