title: A new digitized method of the compulsive gnawing test revealed dopaminergic activity of salvinorin A in vivo.
abstract: The compulsive gnawing (CG) test has been used for numerous years as an assay to determine the dopaminergic activity of various compounds. We developed a new method of quantification via a digitization step which allowed a more precise measurement of the gnawing activity. It was the aim of the present study to explore possible dopaminergic effects of salvinorin A (SA), the major active compound of Salvia divinorum, using the new digitized CG test. A group of experiments using male C57BL/6 mice were performed to validate the new method of quantification showing only significant increases of gnawing when the dopamine reuptake inhibitors buproprion (20 mg/kg, p.0.) and nomifensine (10 mg/kg, i.p.) were given concomitantly with apomorphine (10 mg/kg, i.p.). Different concentrations of the SA (1.0, 2.5, 5, and 10 mg/kg, i.p.) were tested with positive dopaminergic activity when administered with apomorphine which differed from the semisynthetic counterpart U-69593. Furthermore, the activity observed with SA was unsuccessfully antagonized by the κ-opioid receptor antagonist norbinaltorphimine (NorBNI; 10 and 20 mg/kg, i.p.), while the dopamine antagonist haloperidol did successfully block (0.06 mg/kg, i.p.) the gnawing activity seen with SA. Our data further strengthen the argument that salvinorin A is not a selective κ-opioid receptor agonist and is the first in vivo study that veers from salvinorin A acting solely like its synthetic counterparts. Furthermore, the digitized CG test system used in this study provides a new computational method to accurately detect behavior associated with dopaminergic neurotransmission.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610-0494, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Phipps
authors.forename: Veronika
authors.initials: V
authors.lastname: Butterweck
mesh_terms: D000703:Analog-Digital Conversion; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003192:Compulsive Behavior / Q000139:chemically induced; D004195:Disease Models, Animal; D045785:Diterpenes, Clerodane / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D008409:Mastication / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D009292:Narcotic Antagonists / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D027544:Salvia / Q000737:chemistry
chemical_list: D045785:Diterpenes, Clerodane; D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D009292:Narcotic Antagonists; D010936:Plant Extracts; D017473:Receptors, Opioid, kappa; C090499:salvinorin A