2026 ECNP Congress

EP01-1010

Ketamine attenuates cocaine-associated memory reactivation through astrocyte-dependent mechanisms in the nucleus accumbens

Ben Rodolpho — A. da Silva, F. Cruz · Federal University of São Paulo, Pharmacology, São Paulo, Brazil

2026 ECNP Congress

Cocaine addiction is a chronic neuropsychiatric disorder characterized by persistent synaptic plasticity within reward and motivation neural circuits[1]. A major treatment challenge is the high relapse rate, often triggered by reactivation of drug-associated memories following re-exposure to cocaine-linked environmental contexts[1]. These memories are encoded by specific cell populations termed neuronal ensembles, whose activation within the nucleus accumbens (NAc) is critical for reinstatement of cocaine-seeking behavior[2]. Astrocytes contribute to ensemble formation and persistence by promoting synaptic strengthening, maintaining homeostatic regulation, and modulating synaptogenesis[3]. Ketamine, a glutamatergic modulator with rapid and sustained neuroplastic effects, has emerged as a promising therapeutic strategy for disorders involving maladaptive circuit remodeling[4]. Beyond its effects on neuronal plasticity, ketamine modulates astrocyte function, restoring glutamatergic homeostasis and promoting adaptive plasticity in corticolimbic circuits[5]. We hypothesize that ketamine can block or attenuate the reactivation of cocaine-associated memories, assessed by the conditioned place preference (CPP) paradigm, and that this effect is mediated, at least partially, by astrocytic activity within the NAc. Our first experiment investigated whether footshock stress could reinstate cocaine-induced CPP. Thirty-four male C57BL/6J mice underwent a CPP protocol in an apparatus with two conditioning compartments connected by a neutral central area. After habituation, animals underwent pre-conditioning (two 30-min sessions of free access), followed by a 15-min preconditioning test. Mice then received eight conditioning sessions over four days, with alternating intraperitoneal injections of saline or cocaine (10 mg/kg) paired with opposite compartments; controls received saline only. A post-conditioning test was performed 24 h later. Extinction comprised eight saline-paired sessions over four days, followed by an extinction test. Reinstatement was induced by acute footshock (15 shocks/5 min, 0.7 mA, 1s), immediately followed by a 15-min test. Behavior was recorded with ANY-maze. The CPP score was calculated as the percentage of time spent in the drug-paired compartment relative to the total time spent in both conditioning compartments. GLM analysis revealed a Group × Phase interaction [X²(3) = 25.545; p < 0.001], but no three-way interaction (Group × Phase × Stress) [X²(3) = 5.307; p = 0.151]. Holm post-hoc showed, for the cocaine group, differences between pre- and post-conditioning (Z = −6.209; p < 0.001) and between post-conditioning and extinction (Z = 4.844; p < 0.001). Saline and cocaine groups differed at post-conditioning (Z = −4.272; p < 0.001). These results indicate the protocol effectively induced and extinguished cocaine CPP. However, absence of any stress-related interaction indicates that the reinstatement protocol was ineffective. The next steps of this project are to investigate, in a broader manner, the effects of ketamine on the reactivation of cocaine-induced CPP, since the footshock protocol was ineffective in reliably inducing reinstatement in our experiment. Specifically: (1) determine whether ketamine attenuates the reactivation of cocaine-associated CPP; (2) investigate the effects of ketamine on astrocytic and neuronal activity in the (NAc) during cocaine memory reactivation; (3) characterize the activation profile of neuronal ensembles and astrocytes recruited during the reactivation of cocaine-associated memories; and (4) identify cocaine- and ketamine-induced transcriptional changes in neurons and astrocytes associated with cocaine memory reactivation.

References

  1. Lüscher, C., & Malenka, R. C. (2011). Drug-Evoked Synaptic Plasticity in Addiction: From Molecular Changes to Circuit Remodeling. Neuron, 69(4), 650–663.
  2. Cruz, F. C., Babin, K. R., Leao, R. M., Goldart, E. M., Bossert, J. M., Shaham, Y., & Hope, B. T. (2014). Role of Nucleus Accumbens Shell Neuronal Ensembles in Context-Induced Reinstatement of Cocaine-Seeking. The Journal of Neuroscience, 34(22), 7437–7446.
  3. Wang, J., Holt, L. M., Huang, H. H., Sesack, S. R., Nestler, E. J., & Dong, Y. (2022). Astrocytes in cocaine addiction and beyond. Molecular Psychiatry, 27(1), 652–668.
  4. Menke, N., Hoffman, E., Gaylor, K., & Shobassy, A. (2025). Ketamine: An emerging agent in the management of neuropsychiatric disorders. Asian Journal of Psychiatry, 106, 104351.
  5. Duque, M., Chen, A. B., Hsu, E., Narayan, S., Rymbek, A., Begum, S., Saher, G., Cohen, A. E., Olson, D. E., Li, Y., Prober, D. A., Bergles, D. E., Fishman, M. C., Engert, F., & Ahrens, M. B. (2025). Ketamine induces plasticity in a norepinephrine-astroglial circuit to promote behavioral perseverance. Neuron, 113(3), 426-443.e5.