Journal
PSYCHOPHARMACOLOGY
Volume 234, Issue 16, Pages 2499-2514Publisher
SPRINGER
DOI: 10.1007/s00213-017-4637-2
Keywords
SalvinorinA; Behavioural Pharmacology; Self-administration; Cocaine; Drug seeking; Anxiolytic; Conditioned place aversion; Rat; Elevated plusmaze; Forced swim test; Sucrose self-administration
Categories
Funding
- Neurological Foundation of New Zealand
- Health Research Council of New Zealand [DA018151, GM008545]
- AFPE Pre-Doctoral Fellowship in Pharmaceutical Sciences
- Victoria University of Wellington
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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 beta-tetrahydropyran Sal B (beta-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 beta-THP Sal B were evaluated for effects on cocaine-induced hyperactivity, spontaneous locomotor activity and sucrose self-administration. EOM Sal B and beta-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 beta-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 beta-THP Sal B (1 or 2 mg/kg, i.p.). However, beta-THP Sal B decreased time spent in the drug-paired chamber. Conclusion EOMSal B is more potent than Sal A and beta-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.
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