2026 ECNP Congress

PS01-1003

Effect of kappa opioid receptor activation before extinction on reinstatement of cocaine conditioned place preference

Luciano Hanbit Marinelli — E.J. Kuijer, S.J. Bailey, D.J. Heal, S. Smith, S. Wonnacott, C.P. Bailey · University of Bath, Department of Life Sciences, Bath, United Kingdom

2026 ECNP Congress

Introduction

Drug seeking is driven by the formation and persistence of maladaptive drug memories [1]. Extinction-based interventions are a promising approach to reduce the ability of drug-associated environmental cues and contextual associations to induce relapse in humans and reinstatement in rodent models [2]. Kappa opioid receptors (KOPrs) are highly expressed throughout reward-related brain circuits and their activation induces dysphoria in humans and aversion in rodents, playing a key role in stress and drug seeking [3]. In this study, we investigated how KOPr stimulation by the KOPr agonist U50,488, before the first extinction session, affects drug-primed reinstatement of cocaine conditioned place preference (CPP) in mice. Our hypothesis was that the aversive effects of U50,488 would counteract cocaine-induced rewarding contextual memory, thereby blocking reinstatement.

Methods

8-10 weeks old, male and female C57BL/6J mice were place-conditioned with cocaine (15 mg/kg, i.p.) over 4 days. In a first experiment (“closed door”), mice underwent 4 days of confined extinction after conditioning, where mice were confined in either the drug-paired or saline-paired compartment on alternate days. Mice were injected with U50,488 (5 mg/kg, i.p.) or saline (n= 19/group, 11 males and 8 females) 30 minutes before the first extinction session, followed by confinement in the previously drug-paired compartment. In a second experiment (“open door”), mice underwent 5 days of unconfined extinction, with free access to both compartments during each trial. Mice were injected with U50,488 (5 mg/kg, i.p.) or saline (n= 12 females/group) 30 minutes before the first extinction session. This experiment was done on a single cohort of females to minimise procedural confounding factors such as opposite sex odour exposure. For both experiments, mice on the final day were tested for drug-primed reinstatement following a cocaine priming (7.5 mg/kg, i.p.) injection, with free access to both compartments for 15 minutes. Preference scores were the difference in time spent in the drug-paired compartment over the saline-paired compartment ÷ total time. Preference scores between U50,488- and saline-treated groups at extinction and reinstatement were analysed using a two-way ANOVA followed by Sidak’s test.

Results

In the “closed door” experiment, U50,488 had a significant effect on cocaine CPP over extinction and reinstatement (F(1,36)=4.192, p=0.048). Post-hoc analysis revealed a significantly reduced preference at reinstatement in the U50,488-treated group compared to the saline-treated group (preference scores: 0.10±0.04 (U50) vs 0.26±0.05 (saline); p=0.012) and no effect at extinction (preference scores: 0.04±0.03 (U50) vs 0.05±0.04 (saline); p=0.94). No sex differences were identified. In the “open door” experiment, U50,488 had no significant effect on cocaine CPP over extinction and reinstatement (F(1,22)=0.06617, p=0.7994).

Conclusions

U50,488 administration before extinction significantly inhibited drug-primed reinstatement of cocaine seeking but only when selectively paired to the previously drug-paired compartment. As U50,488 had no effect when given prior to unconfined extinction, these results indicate that blockade of reinstatement by U50,488 was via an aversive counterconditioning mechanism rather than enhancing extinction per se. These findings are consistent with previous findings in a rat cocaine self-administration paradigm [4] and show potential in targeting KOPrs for modulating drug-associated memories.

References

  1. Xue Y.X., Luo Y.X., Wu P., et al., 2012. A Memory Retrieval-Extinction Procedure to Prevent Drug Craving and Relapse. Science, 336(6078), 241-245, doi:10.1126/science.1215070
  2. Torregrossa M.M., Taylor J.R., 2013. Learning to forget: manipulating extinction and reconsolidation processes to treat addiction. Psychopharmacology (Berl.), 226(4), 659-672, doi:10.1007/s00213-012-2750-9
  3. Bruchas M.R., Land B.B., Aita M., et al., 2007. Stress-Induced p38 Mitogen-Activated Protein Kinase Activation Mediates κ-Opioid-Dependent Dysphoria. J. Neurosci., 27(43), 11614-11623, doi:10.1523/JNEUROSCI.3769-07.2007
  4. Heinsbroek J.A., Furbish A.B., Peters J., 2018. A single, extinction-based treatment with a kappa opioid receptor agonist elicits a long-term reduction in cocaine relapse. Neuropsychopharmacology, 43, 1492–1497, doi:10.1038/s41386-017-0006-4