PT - JOURNAL ARTICLE AU - Ladrón de Guevara-Miranda, David AU - Millón, Carmelo AU - Rosell-Valle, Cristina AU - Pérez-Fernández, Mercedes AU - Missiroli, Michele AU - Serrano, Antonia AU - Pavón, Francisco J. AU - Rodríguez de Fonseca, Fernando AU - Martínez-Losa, Magdalena AU - Álvarez-Dolado, Manuel AU - Santín, Luis J. AU - Castilla-Ortega, Estela TI - Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis AID - 10.1242/dmm.026682 DP - 2017 Mar 01 TA - Disease Models & Mechanisms PG - 323--336 VI - 10 IP - 3 4099 - http://dmm.biologists.org/content/10/3/323.short 4100 - http://dmm.biologists.org/content/10/3/323.full SO - Dis Models Mech2017 Mar 01; 10 AB - Cocaine 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 We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely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 The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA+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 Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV+ and NPY+ neurons in the dentate gyrus, and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.