title: Behavioral effects and central nervous system levels of the broadly available κ-agonist hallucinogen salvinorin A are affected by P-glycoprotein modulation in vivo.
abstract: Active blood-brain barrier mechanisms, such as the major efflux transporter P-glycoprotein (mdr1), modulate the in vivo/central nervous system (CNS) effects of many pharmacological agents, whether they are used for nonmedical reasons or in pharmacotherapy. The powerful, widely available hallucinogen salvinorin A (from the plant Salvia divinorum) is a high-efficacy, selective κ-opioid agonist and displays fast-onset behavioral effects (e.g., within 1 min of administration) and relatively short duration of action. In vitro studies suggest that salvinorin A may be a P-glycoprotein substrate; thus, the functional status of P-glycoprotein may influence the behavioral effects of salvinorin A or its residence in CNS after parenteral administration. We therefore studied whether a competing P-glycoprotein substrate (the clinically available agent loperamide; 0.032-0.32 mg/kg) or a selective P-glycoprotein blocker, tariquidar (0.32-3.2 mg/kg) could enhance unconditioned behavioral effects (ptosis and facial relaxation, known to be caused by κ-agonists in nonhuman primates) of salvinorin A, as well as its entry and residence in the CNS, as measured by cerebrospinal fluid sampling. Pretreatment with either loperamide or tariquidar dose-dependently enhanced salvinorin A-induced ptosis, but not facial relaxation. In a control study, loperamide and tariquidar were inactive when given as a pretreatment to ((+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69,593), a κ-agonist known to be a very poor P-glycoprotein substrate. Furthermore, pretreatment with tariquidar (3.2 mg/kg) also enhanced peak levels of salvinorin A in cerebrospinal fluid after intravenous administration. These are the first studies in vivo showing the sensitivity of salvinorin A effects to modulation by the P-glycoprotein transporter, a major functional component of the blood-brain barrier.
authors.affiliation: Laboratory on the Biology of Addictive Diseases, The Rockefeller University, Box 171, 1230 York Avenue, New York, NY 10065, USA. butelme@rockefeller.edu
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Butelman
authors.forename: Michael
authors.initials: M
authors.lastname: Caspers
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Lovell
authors.forename: Mary Jeanne
authors.initials: MJ
authors.lastname: Kreek
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000818:Animals; D001763:Blepharoptosis / Q000139:chemically induced; D001812:Blood-Brain Barrier / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects*; D004192:Discrimination, Psychological / Q000187:drug effects*; D045785:Diterpenes, Clerodane / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005152:Facial Muscles / Q000187:drug effects; D005260:Female; D006213:Hallucinogens / Q000494:pharmacology*; D008139:Loperamide / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D011804:Quinolines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D027544:Salvia
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D045785:Diterpenes, Clerodane; D006213:Hallucinogens; D011804:Quinolines; D017473:Receptors, Opioid, kappa; D008139:Loperamide; C402343:tariquidar; C090499:salvinorin A