The oxytocin analogue carbetocin prevents stress- and priming-induced reinstatement to opioid-seeking in mice.

Polymnia Georgiou, Panos Zanos, Susanna Hourani, Ian Kitchen, Alexis Bailey. University of Surrey, Guildford, UK

Relapse to drug-seeking is a major challenge in the treatment of opioid addiction as no effective pharmacotherapy is currently available. Opioid addicts experience severe negative emotional symptoms including stress, anxiety and depression during abstinence, which may comprise a motivational trigger to re-administer the drug and relapse1. The neurohypophysial peptide oxytocin has been shown to have pro-social and mood enhancing properties as well as a key role in drug addiction in both humans and animals2. However, the effects of oxytocin on relapse to opioid-seeking remain largely unknown. Here, we investigated whether the oxytocin analogue carbetocin is able to reverse stress- and priming- induced reinstatement to opioid-seeking in mice.

Male C57BL/6J mice (20-25g) were exposed to morphine (10 mg/kg, s.c./day for 4 days) in a conditioned place preference (CPP) paradigm3. After conditioning, mice were left to extinguish CPP behaviour for 4-5 days by exposure to the CPP apparatus in the absence of the drug. Following extinction, morphine CPP was successfully reinstated by exposure to either a 6-min forced-swim stress session (stress-induced reinstatement) or a priming injection of morphine (2 mg/kg, i.p.) (priming-induced reinstatement) in saline pre-treated animals. Carbetocin pre-treatment (dissolved in saline, 6.4 mg/kg, i.p., 5 min prior to the forced-swim stress or the morphine priming injection) prevented the reinstatement of morphine CPP (Table 1). Moreover, carbetocin (6.4 mg/kg, i.p./day for 4 days) did not induce place preference or aversion using the CPP paradigm in a separate cohort of male C57BL/6J mice (time spent in the Carbetocin-paired compartment: Pre-conditioning, 342.733 ± 20.526 vs Post-conditioning, 382.167 ± 38.139).

Table 1: Effect of CBT on stress- and priming-induced reinstatement of morphine-seeking

Two-way ANOVA followed by Holm-Sidak post-hoc test (mean ± SEM time spent in the morphine-paired compartment) *p<0.05, **p<0.01 vs Pre-conditioning, # p<0.05 vs Post- Conditioning, † p<0.05, ††† p<0.001 vs Post-Extinction

These results suggest that the activation of the oxytocinergic system by an oxytocin analogue might be a novel therapeutic strategy which would help former opioid addicts to remain in a drug-free state and prevent relapse following abstinence.

1. Le Moal and Koob, Eur. Neuropsychopharm, 17:377, 2007; 2. McGregor and Bowen, Horm. Behav., 61:31, 2012; 3. Zanos et al., Neuropsychopharm, doi: 10.1038/npp.2013.285, 2013