title: Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis.
abstract: 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 We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely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 The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of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 Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV+and NPY+neurons in the dentate gyrus, and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.
authors.affiliation: Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Instituto de Investigación Biomédica de Málaga (IBIMA), Facultad de Psicología, Universidad de Málaga, 29071 Málaga, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Ladrón de Guevara-Miranda
authors.affiliation: Departamento de Fisiología, Instituto de Investigación Biomédica de Málaga (IBIMA), Facultad de Medicina, Universidad de Málaga, 29071 Málaga, Spain.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Millón
authors.affiliation: Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Instituto de Investigación Biomédica de Málaga (IBIMA), Facultad de Psicología, Universidad de Málaga, 29071 Málaga, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rosell-Valle
authors.affiliation: Laboratory of Cell-based Therapy for Neuropathologies, Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), 41092 Sevilla, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Pérez-Fernández
authors.affiliation: Laboratory of Cell-based Therapy for Neuropathologies, Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), 41092 Sevilla, Spain.
authors.forename: Michele
authors.initials: M
authors.lastname: Missiroli
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, 29010 Málaga, Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Serrano
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, 29010 Málaga, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Pavón
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, 29010 Málaga, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez de Fonseca
authors.affiliation: Laboratory of Cell-based Therapy for Neuropathologies, Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), 41092 Sevilla, Spain.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Martínez-Losa
authors.affiliation: Laboratory of Cell-based Therapy for Neuropathologies, Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), 41092 Sevilla, Spain manuel.alvarez@cabimer.es luis@uma.es estela.castilla@ibima.eu.
authors.forename: Manuel
authors.initials: M
authors.lastname: Álvarez-Dolado
authors.affiliation: Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Instituto de Investigación Biomédica de Málaga (IBIMA), Facultad de Psicología, Universidad de Málaga, 29071 Málaga, Spain manuel.alvarez@cabimer.es luis@uma.es estela.castilla@ibima.eu.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Santín
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, 29010 Málaga, Spain manuel.alvarez@cabimer.es luis@uma.es estela.castilla@ibima.eu.
authors.forename: Estela
authors.identifier: 0000-0002-4496-1167
authors.initials: E
authors.lastname: Castilla-Ortega
mesh_terms: D000222:Adaptation, Physiological; D000375:Aging / Q000473:pathology; D000818:Animals; D001522:Behavior, Animal; D003042:Cocaine / Q000009:adverse effects*; D003072:Cognition Disorders / Q000150:complications / Q000503:physiopathology; D018891:Dentate Gyrus / Q000473:pathology / Q000503:physiopathology; D004644:Emotions; D005106:Exploratory Behavior; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology; D007395:Interneurons / Q000473:pathology*; D008297:Male; D008569:Memory Disorders / Q000150:complications* / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D055495:Neurogenesis; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000150:complications* / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D005680:gamma-Aminobutyric Acid; D003042:Cocaine
keywords: Anxiety; Behavior-induced neuroplasticity; Cell proliferation; Neuropeptide Y; Parvalbumin; c-Fos