Abstract
The main challenge in treating opioid addicts is to maintain abstinence due to the affective consequences associated with withdrawal which may trigger relapse. Emerging evidence suggests a role of the neurohypophysial peptide oxytocin (OT) in the modulation of mood disorders as well as drug addiction. However, its involvement in the emotional consequences of drug abstinence remains unclear. We investigated the effect of 7-day opioid abstinence on the oxytocinergic system and assessed the effect of the OT analogue carbetocin (CBT) on the emotional consequences of opioid abstinence, as well as relapse. Male C57BL/6J mice were treated with a chronic escalating-dose morphine regimen (20–100 mg/kg/day, i.p.). Seven days withdrawal from this administration paradigm induced a decrease of hypothalamic OT levels and a concomitant increase of oxytocin receptor (OTR) binding in the lateral septum and amygdala. Although no physical withdrawal symptoms or alterations in the plasma corticosterone levels were observed after 7 days of abstinence, mice exhibited increased anxiety-like and depressive-like behaviors and impaired sociability. CBT (6.4 mg/kg, i.p.) attenuated the observed negative emotional consequences of opioid withdrawal. Furthermore, in the conditioned place preference paradigm with 10 mg/kg morphine conditioning, CBT (6.4 mg/kg, i.p.) was able to prevent the stress-induced reinstatement to morphine-seeking following extinction. Overall, our results suggest that alterations of the oxytocinergic system contribute to the mechanisms underlying anxiety, depression, and social deficits observed during opioid abstinence. This study also highlights the oxytocinergic system as a target for developing pharmacotherapy for the treatment of emotional impairment associated with abstinence and thereby prevention of relapse.
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Acknowledgements
We thank Prof Ingrid Nylander for valuable advice on OT peptide measurements, Dr Sheryl Moy and Ms Pamela Farshim for advice given on the behavioral tests, as well as Dr van der Veen and Helen Keyworth for advice on statistical analyses. This study was supported by Spyroula and Soteris Zanos, Lilia and Charalambos Georgiou and by a Royal Society grant (RG120556; P.I. Alexis Bailey). We declare that over the past 3 years PZ has received financial support from Mr and Mrs Zanos and PG has received financial support from Mr and Mrs Georgiou. The sponsors had no involvement in the design of the study and in the collection, analyses, and interpretation of the data, nor in the writing of the report and the decision to submit this article for publication. PZ, PG, SRW, SMH, IK, RWS, AB wrote the paper; PZ, PG performed the experiments; PZ, PG, RWS analysed the data; AB, PZ, PG designed the experiments; AB conceived the idea for the experiments and was PI for the study.
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Zanos, P., Georgiou, P., Wright, S. et al. The Oxytocin Analogue Carbetocin Prevents Emotional Impairment and Stress-Induced Reinstatement of Opioid-Seeking in Morphine-Abstinent Mice. Neuropsychopharmacol 39, 855–865 (2014). https://doi.org/10.1038/npp.2013.285
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DOI: https://doi.org/10.1038/npp.2013.285
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