Long-lasting memory deficits in mice withdrawn from cocaine are concomitant to neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis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 We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely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 The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA+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 Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV+ and NPY+ neurons in the dentate gyrus, and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.

Impaired decision making following escalation of cocaine self‐administration predicts vulnerability to relapse in rats

“…Although it should be noted that despite broadly consistent performance, all rats performed incrementally worse over time, a finding that parallels the long‐lasting cognitive deficits that cocaine appears to induce in human (see Rogers and Robbins for review). Long‐lasting deficits have also been reported in other animal studies, although these findings are not unequivocal as a recent study showed that stimulant‐induced deficits were remediated over a time course similar to the one used here . These apparent discrepancies are likely related to differences in inter‐testing training, which can have a pronounced effect on the cognitive process taxed (see Cocker and Winstanley for discussion).…”

Age-related changes in sexual function and steroid-hormone receptors in the medial preoptic area of male rats

“…Control sections run in parallel had omission of the primary antibody. Although we did not conduct pre-adsorption of the antibodies in this study, all of the primary antibodies are well-characterized (Massart et al 2015; Picot et al 2014; Ladron de Guevara-Miranda et al 2017), and expression patterns were entirely consistent with the literature (i.e., labeling was nuclear, with expected distribution). The following day, sections were incubated in anti-rabbit biotinylated secondary antibody (1:500 in blocking solution; Vector Labs, Burlingame, CA, USA) before avidin-biotin conjugate (1:000 in 0.1M PB; Vectastain ABC Elite kit; Vector Laboratories, Burlingame, CA).…”

“…Sections were then incubated with biotinylated tyramine (1:1000 in 0.1M PB; Perkin Elmer, Waltham, MA) for 10 min, and visualized with Alexa 488-tagged streptavidin (1:400 in 0.1M PB; Life Technologies, Grand Island, NY). After washing thoroughly with 0.1M PB, sections were then incubated with mouse anti-Fos primary antibody (1:600; Santa Cruz Biotechnology sc-271243, RRID: 1563391, Ladron de Guevara-Miranda et al 2017) in blocking solution, overnight at room temperature. The following day, sections were incubated for 60 minutes with Alexa 555 goat-anti mouse secondary (1:400 in 0.1M PB; Life Technologies, Grand Island, NY).…”

Social rank-associated stress vulnerability predisposes individuals to cocaine attraction

“…Hippocampal dopamine secretion and uptake mainly originates from adrenergic neurons of the locus coeruleus (LC) 25 , 26 and diffusely targets neurons in the CA1 region 19 . Hippocampus has been implicated as the main “node” in the cocaine addiction brain circuit, potentially through production of new, novel inter-neuronal circuits 27 – 29 . LC is also known to play an important role in driving drug addiction in response to stress based on its influence on the hippocampus and encoding of novel stimulus memories 30 .…”