title: The 2-methoxy methyl analogue of salvinorin A attenuates cocaine-induced drug seeking and sucrose reinforcements in rats.
abstract: κ Opioid receptor activation by traditional arylacetamide agonists and the novel neoclerodane diterpene κ opioid receptor agonist Salvinorin A (Sal A) results in attenuation of cocaine-seeking behavior in pre-clinical models of addiction. However, adverse effects such as sedation, depression and aversion limit their clinical utility. The Sal A analogue, 2-methoxy-methyl salvinorin B (MOM Sal B) is a longer acting Sal A analogue with high affinity for κ opioid receptors. In this study, we tested MOM Sal B for its ability to modulate cocaine-seeking behavior in rats. MOM Sal B (0.3mg/kg) successfully attenuated cocaine-seeking but also attenuated sucrose reinforcement. No change in activity was observed in either cocaine-induced hyperactivity or spontaneous open field activity tests but increased immobility and decreased swimming times in the forced swim test were observed. This study indicates that κ opioid receptor activation by more potent Sal A analogues modulates cocaine-seeking behavior non-selectively without causing sedation, suggesting an improved side effects profile. However, pro-depressive effects are seen, which may limit the therapeutic potential of this compound. Future studies with Sal A analogues having affinities at other opioid receptors are warranted as they have the potential to identify compounds having effective anti-addiction properties.
authors.affiliation: School of Biological Science, Victoria University of Wellington, PO Box 600, Wellington, New Zealand.
authors.forename: Aashish S
authors.initials: AS
authors.lastname: Morani
authors.forename: Amy
authors.initials: A
authors.lastname: Ewald
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Prevatt-Smith
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
authors.forename: Bronwyn M
authors.initials: BM
authors.lastname: Kivell
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology; D003863:Depression / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology; D045785:Diterpenes, Clerodane / Q000494:pharmacology*; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage*; D013550:Swimming / Q000523:psychology
chemical_list: D045785:Diterpenes, Clerodane; D013395:Sucrose; D003042:Cocaine; C090499:salvinorin A
keywords: Cocaine; Forced swim test; Locomotion; Salvinorin A; Self-administration; Sucrose reinforcement