Oxytocin analogue carbetocin reverses impaired emotional-like behaviour during prolonged abstinence from chronic morphine treatment

P Zanos, P Georgiou, R Winsky-Sommerer, I Kitchen, A Bailey. University of Surrey, Faculty of Health and Medical Sciences, GU27XH, Guildford, Surrey, UK

The main hurdle in the treatment of opiate addiction is the maintenance of a long-term abstinent state as relapse is very common. Opiate-withdrawn individuals suffer from emotional impairments including stress, depression and social avoidance, which may serve as a motivational trigger to re-administer the drug (Tate et al., 2008). The neurohypophyseal peptide oxytocin has been shown to reduce abuse potential of drugs (McGregor and Bowen, 2012). Here, we investigated the acute effect of oxytocin analogue carbetocin (CT) on emotional alterations in mice undergoing protracted abstinence from chronic morphine administration.

Male C57BL/6J mice (20-23g, Charles River Laboratories, U.K.) were administered with 7-day “intermittent” saline (4ml/kg) or morphine (Sigma-Aldrich, U,K.; 2 x 20-100mg/kg i.p. per day) and spontaneously withdrawn for 7 days. Depression-and anxiety- like and social interaction behaviours were then assessed by using the forced-swim test (FST), elevated plus-maze (EPM), and 3-chambered sociability test (3-CB) respectively (Nadler et al., 2004; Porsolt et al. 1978; Rodgers and Davli, 1997). We examined whether acute administration of carbetocin (Bachem, Germany; 6.4mg/kg, i.p., 15 minutes prior to testing), was able to reverse the negative emotional symptoms observed following long-term morphine withdrawal. All procedures were approved by the Home Office Animals (Scientific Procedures) Act, 1986.

Morphine-withdrawn animals showed enhanced depressive-like behaviour compared to saline-withdrawn controls as evidenced by a significant increase of immobility time (118.2±5.7 vs. 187.2±13.2 sec,p < 0.001) and decreased latency to reach the first immobility state (75.2±12 vs. 11.0±2.3 sec, p < 0.01). CT significantly decreased this immobility behaviour (125.0±5.8 vs. 187.2±13.2 sec p<0.001) and increased latency to reach the first immobility state (47.8±12.3 vs. 11.0±2.3 sec, p<0.05), while had no significant effect on the immobility behaviour of saline-withdrawn controls (p>0.05) (two-way ANOVA;Bonferroni post-hoc test, n=6-10/group). Morphine-withdrawn mice also exhibited enhanced anxiety-related behaviour compared with controls as observed by a marked decrease in the percentage of open-arm time (12.8±2.3 vs. 40.6±7.7, p< 0.05). CT increased the % open-arm time of the morphine-withdrawn mice (35.8±4.8 vs. 12.8±2.3, p<0.05) and had no significant effect on the % open-arm time of saline control animals (p>0.05) (two-way ANOVA;Bonferroni post-hoc test, n=6-10/group). Finally, 7 days withdrawal from morphine induced social deficits. While, saline-withdrawn mice showed a significant preference for the chamber containing a stranger mouse vs. the empty chamber (297.6±12.6 vs. 231.0±11.3 sec, p<0.05) demonstrating social preference, morphine-withdrawn animals did not show any preference between these 2 chambers (p>0.05) demonstrating a lack of social preference (three-way repeated measures ANOVA;Bonferroni post-hoc test, n=6-10/group). CT significantly increased the time morphine-withdrawn animals spent in the chamber containing the stranger mouse compared to the empty cage (321.3±11.8 vs. 256.3±12.7 sec, p<0.001) while it did not have any significant effects for the saline-withdrawn mice (three-way repeated measures ANOVA;Bonferroni post-hoc test, n=6-10/group).

These results demonstrate that oxytocin analogues can reverse impairment of emotional-like behaviour during protracted abstinence from chronic morphine treatment and may prove to be a novel strategy for the prevention of opiate relapse and the maintenance of abstinence in addicts.

McGregor, I. S. and Bowen, M. T. (2012), Hormones and behavior, 61(3), 331-9.

Nadler, J. J., et al. (2004), Genes, brain, and behavior, 3(5), 303-14.

Porsolt, R. D., et al. (1978), European journal of pharmacology, 47(4), 379-91.

Rodgers, R. J. and Dalvi, A. (1997), Neurosci Behav Rev, 21, 801-10

Tate, S. R., et al. (2008), Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors, 22(1), 47-57.