Antidepressant effects of the nonpeptidic delta -opioid receptor agonist SNC80.

The present study investigated the antidepressant-like effects of the nonpeptidic delta-opioid receptor agonist [(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide (SNC80) in Sprague-Dawley rats and examined the relation between the antidepressant properties and the stimulant, convulsive, and seizurogenic effects of SNC80. In order to measure the antidepressant-like effects, behaviors were measured in the forced swim test following acute or repeated SNC80 administration. The forced swim test is a behavioral assay used to identify compounds that have similar effects to known antidepressants. This procedure has good predictive validity for identifying compounds that are successful antidepressants in humans. Other measures were collected from rats including convulsions measured by observation and locomotor and electroencephalographic activity measured by telemetry systems. Additionally, some ex vivo competition and [ 35S]GTPgammaS binding experiments were conducted to further augment observed behavioral changes. Using these experimental paradigms, the antidepressant-like effects of the delta-opioid agonists SNC80 were compared to determine the interdependence of the drug-induced effects. These studies demonstrated that the molecular structure modifications of SNC80 altered the convulsive effects of nonpeptidic delta-opioid agonists, suggesting that novel compounds or changes in existing compound structures might identify drugs that have antidepressant activity without producing convulsions. In addition to developing new compounds, the convulsions and antidepressant properties were separable based on differential sensitivity to tolerance development and infusion speed. For example, repeated SNC80 administration produced tolerance to the convulsive and locomotorstimulating effects; however, tolerance did not develop to the antidepressant-like effects of SNC80. Also, decreasing infusion rates of SNC80 nearly eliminated convulsions without altering the antidepressant-like effects of SNC80. Although the antidepressant effects were independent of delta-opioid agonist-induced behavioral convulsions, nonconvulsive seizures might contribute to the SNC80-induced antidepressant activity. However, lower doses of SNC80 that produced antidepressant effects did not produce nonconvulsive seizures. Tolerance also developed to the SNC80-induced epileptiform activity with repeated administration without affecting antidepressant properties of SNC80. In conclusion, these data demonstrated that the antidepressant activity was independent from the locomotor-stimulating, convulsive, and seizurogenic effects of the nonpeptidic delta-opioid agonist SNC80. These findings suggest that nonpeptidic delta-opioid agonists may have therapeutic potential for treating depression in humans.PhDHealth and Environmental SciencesPharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124705/2/3150231.pd