Ladron-de-Guevara-Miranda, DavidMillon, CarmeloRosell-Valle, CristinaPerez-Fernandez, MercedesMissiroli, MicheleSerrano, AntoniaPavon, Francisco J.Rodriguez-de-Fonseca, FernandoMartinez-Losa, MagdalenaAlvarez-Dolado, ManuelSantin, Luis J.Castilla-Ortega, Estela2023-02-122023-02-122017-03-01Ladrón de Guevara-Miranda D, Millón C, Rosell-Valle C, Pérez-Fernández M, Missiroli M, Serrano A, et al. Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis. Dis Model Mech. 2017 Mar 1;10(3):323-3361754-8403http://hdl.handle.net/10668/19140Cocaine addiction disorder is notably aggravated by concomitant cognitive and emotional pathology that impedes recovery. We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely investigated in cocaine addiction research. Mice were submitted to a chronic cocaine (20 mg/kg/day for 12 days) or vehicle treatment followed by 44 drug-free days. Some mice were then assessed on a battery of emotional (elevated plus-maze, light/dark box, open field, forced swimming) and cognitive (object and place recognition memory, cocaine-induced conditioned place preference, continuous spontaneous alternation) behavioral tests, while other mice remained in their home cage. Relevant hippocampal features [basal c-Fos activity, GABA(+), parvalbumin (PV)(+) and neuropeptide Y (NPY)(+) interneurons and adult neurogenesis (cell proliferation and immature neurons)] were immunohistochemically assessed 73 days after the chronic cocaine or vehicle protocol. The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA(+) cells in the dentate gyrus. Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV+ and NPY+ neurons in the dentate gyrus, and neurogenesis in the hippocampus. Results highlight the importance of hippocampal neuroplasticity for the ingrained cognitive deficits present during chronic cocaine withdrawal.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/Anxietyc-FosParvalbuminNeuropeptide YCell proliferationBehavior-induced neuroplasticityAnxiety-like behaviorConditioned place preferenceExcitatory granule cellsDrug-seeking habitsDentate gyrusNeuropeptide-yParvalbumin immunoreactivityRat hippocampusChronic stressFunctional connectivityAdaptation, PhysiologicalAgingAnimalsBehavior, AnimalCocaineCognition DisordersDentate GyrusEmotionsExploratory BehaviorHippocampusInterneuronsMaleMemory DisordersMice, Inbred C57BLNeurogenesisProto-Oncogene Proteins c-fosSubstance Withdrawal Syndromegamma-Aminobutyric Acidresearch articleopen accessCocaínaHipocampoNeurogénesisTrastornos relacionados con cocaínaÁcido gamma-AminobutíricoMemoria10.1242/dmm.0266821754-8411https://doi.org/10.1242/dmm.026682395717100011