TY - JOUR
T1 - The C-2 derivatives of salvinorin A, ethoxymethyl ether Sal B and β-tetrahydropyran Sal B, have anti-cocaine properties with minimal side effects
AU - Ewald, Amy W.M.
AU - Bosch, Peter J.
AU - Culverhouse, Aimee
AU - Crowley, Rachel Saylor
AU - Neuenswander, Benjamin
AU - Prisinzano, Thomas E.
AU - Kivell, Bronwyn M.
N1 - Publisher Copyright:
© 2017, Springer-Verlag Berlin Heidelberg.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Rationale: Kappa-opioid receptor (KOPr) agonists have pre-clinical anti-cocaine and analgesic effects. However, side effects including sedation, dysphoria, aversion, anxiety and depression limit their therapeutic development. The unique structure of salvinorin A has been used to develop longer acting KOPr agonists. Objectives: We evaluate two novel C-2 analogues of salvinorin A, ethoxymethyl ether Sal B (EOM Sal B) and β-tetrahydropyran Sal B (β-THP Sal B) alongside U50,488 for their ability to modulate cocaine-induced behaviours and side effects, pre-clinically. Methods: Anti-cocaine properties of EOM Sal B were evaluated using the reinstatement model of drug seeking in self-administering rats. EOM Sal B and β-THP Sal B were evaluated for effects on cocaine-induced hyperactivity, spontaneous locomotor activity and sucrose self-administration. EOM Sal B and β-THP Sal B were evaluated for aversive, anxiogenic and depressive-like effects using conditioned place aversion (CPA), elevated plus maze (EPM) and forced swim tests (FSTs), respectively. Results: EOM Sal B (0.1, 0.3 mg/kg, intraperitoneally (i.p.)) dose dependently attenuated drug seeking, and EOM Sal B (0.1 mg/kg, i.p.) and β-THP Sal B (1 mg/kg, i.p.) attenuated cocaine-induced hyperactivity. No effects on locomotor activity, open arm times (EPM) or swimming behaviours (FST) were seen with EOM (0.1 or 0.3 mg/kg, i.p.) or β-THP Sal B (1 or 2 mg/kg, i.p.). However, β-THP Sal B decreased time spent in the drug-paired chamber. Conclusion: EOM Sal B is more potent than Sal A and β-THP Sal B in reducing drug-seeking behaviour with fewer side effects. EOM Sal B showed no effects on sucrose self-administration (0.1 mg/kg), locomotor, depressive-like, aversive-like or anxiolytic effects.
AB - Rationale: Kappa-opioid receptor (KOPr) agonists have pre-clinical anti-cocaine and analgesic effects. However, side effects including sedation, dysphoria, aversion, anxiety and depression limit their therapeutic development. The unique structure of salvinorin A has been used to develop longer acting KOPr agonists. Objectives: We evaluate two novel C-2 analogues of salvinorin A, ethoxymethyl ether Sal B (EOM Sal B) and β-tetrahydropyran Sal B (β-THP Sal B) alongside U50,488 for their ability to modulate cocaine-induced behaviours and side effects, pre-clinically. Methods: Anti-cocaine properties of EOM Sal B were evaluated using the reinstatement model of drug seeking in self-administering rats. EOM Sal B and β-THP Sal B were evaluated for effects on cocaine-induced hyperactivity, spontaneous locomotor activity and sucrose self-administration. EOM Sal B and β-THP Sal B were evaluated for aversive, anxiogenic and depressive-like effects using conditioned place aversion (CPA), elevated plus maze (EPM) and forced swim tests (FSTs), respectively. Results: EOM Sal B (0.1, 0.3 mg/kg, intraperitoneally (i.p.)) dose dependently attenuated drug seeking, and EOM Sal B (0.1 mg/kg, i.p.) and β-THP Sal B (1 mg/kg, i.p.) attenuated cocaine-induced hyperactivity. No effects on locomotor activity, open arm times (EPM) or swimming behaviours (FST) were seen with EOM (0.1 or 0.3 mg/kg, i.p.) or β-THP Sal B (1 or 2 mg/kg, i.p.). However, β-THP Sal B decreased time spent in the drug-paired chamber. Conclusion: EOM Sal B is more potent than Sal A and β-THP Sal B in reducing drug-seeking behaviour with fewer side effects. EOM Sal B showed no effects on sucrose self-administration (0.1 mg/kg), locomotor, depressive-like, aversive-like or anxiolytic effects.
KW - Anxiolytic
KW - Behavioural Pharmacology
KW - Cocaine
KW - Conditioned place aversion
KW - Drug seeking
KW - Elevated plus maze
KW - Forced swim test
KW - Rat
KW - Salvinorin A
KW - Self-administration
KW - Sucrose self-administration
UR - http://www.scopus.com/inward/record.url?scp=85019862764&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019862764&partnerID=8YFLogxK
U2 - 10.1007/s00213-017-4637-2
DO - 10.1007/s00213-017-4637-2
M3 - Article
C2 - 28536865
AN - SCOPUS:85019862764
SN - 0033-3158
VL - 234
SP - 2499
EP - 2514
JO - Psychopharmacology
JF - Psychopharmacology
IS - 16
ER -