Abstract
ABSTRACTCocaine 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 We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely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 The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA+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 Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV+ and NPY+ neurons in the dentate gyrus, and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.
Highlights
The use of illicit drugs is one of the most serious health problems in the western world, and cocaine is the most widely used psychostimulant drug (EMCDDA, 2015; UNODC, 2015)
This study describes long-lasting memory deficits in mice withdrawn from cocaine, that show persistent neuroadaptations in the hippocampal dentate gyrus (DG) concerning increased basal neuronal activity as well as an altered regulation of the GABAergic neurons and Adult hippocampal neurogenesis (AHN) after behavioral training
Mice were submitted to a chronic cocaine treatment for 12 days and to 44 days of a drug-free period before the behavioral assessment started
Summary
The use of illicit drugs is one of the most serious health problems in the western world, and cocaine is the most widely used psychostimulant drug (EMCDDA, 2015; UNODC, 2015). Cocaine-dependent individuals show broad cognitive deficits [including attention, working memory, reference memory, behavioral inhibition or cognitive flexibility (Spronk et al, 2013; Vonmoos et al, 2013, 2014)] that are therapeutically relevant as they predict relapse and low levels of treatment retention (Aharonovich et al, 2006; Fox et al, 2009; Teichner et al, 2002) These affective and cognitive symptoms in cocaine addicts are, at least in part, caused by the repeated cocaine use (Vonmoos et al, 2014), and pre-clinical studies have shown that cocaine exposure and withdrawal induce both emotional (Perrine et al, 2008; Sarnyai et al, 1995) and cognitive alterations (Briand et al, 2008; Krueger et al, 2009; Mendez et al, 2008) in rodents
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