Sex-specific effects of psychoactive drugs on memory performance in an animal model of Attention-Deficit Hyperactivity Disorder
Dadam, F.; Basmadjian, O. M.; Berardo, G.; Haehnel, F. A.; Solorzano, D. Y.; Sosa, M. E.; Leonangeli, S.; Godino, A.; Varayoud, J.; Paglini, M. G.
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Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental condition characterized by persistent deficits in working memory (WM) and executive control. Dysregulation of the Cyclin-dependent kinase 5 (Cdk5)/p35 signaling pathway has been implicated in ADHD pathophysiology due to its impact on neuronal connectivity and dopamine regulation. Using p35 knockout (p35KO) mice--a validated model exhibiting ADHD-like phenotypes--we investigated sex-specific WM performance, task-related neuronal activation patterns, and responses to acute treatment with methylphenidate (MPH) or fluoxetine (FLX), administered alone or in combination. Under basal conditions, p35KO mice of both sexes exhibited significant WM impairment in the Y-maze test compared with wild type (WT) counterparts, whereas recognition memory remained intact. Analysis of neuronal activation (c-Fos-IR) 90 min after testing revealed region-, sex-, and genotype-dependent alterations. Overall, p35KO animals of both sexes showed reduced c-Fos-IR expression in prefrontal cortical regions, while exhibiting increased c-Fos-IR in hippocampal regions. Acute MPH or FLX treatment improved WM in p35KO males, but this benefit was not observed following combined treatment (MPH+FLX). In contrast, p35KO females showed no WM improvement with any treatment. Notably, WT females exhibited a pronounced decline in WM after exposure to MPH, FLX, or their combination, indicating sex-specific pharmacological sensitivity in healthy animals. These findings support an important role of Cdk5/p35 signaling in the functional engagement of prefrontal and hippocampal networks and demonstrate that pharmacological responses in this ADHD model are strongly influenced by sex and neurobiological background, highlighting the importance of incorporating sex as a biological variable in preclinical and translational ADHD research. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/696253v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@12b4330org.highwire.dtl.DTLVardef@14826c3org.highwire.dtl.DTLVardef@1e8f3d8org.highwire.dtl.DTLVardef@e108a2_HPS_FORMAT_FIGEXP M_FIG C_FIG
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