Developmental Exposure to Cocaine Dynamically Dysregulates Cortical Arc/Arg3.1 Modulation in Response to a Challenge.
During adolescence, the medial prefrontal cortex (mPFC) is still developing. We have previously shown that developmental cocaine exposure alters mPFC's ability to cope with challenging events. In this manuscript, we exposed rats developmentally treated with cocaine to a novelty task and analyzed the molecular changes of mPFC. Rats were exposed to cocaine from post-natal day (PND) 28 to PND 42 and sacrificed at PND 43, immediately after the novel object recognition (NOR) test. Cocaine-treated rats spent more time exploring the novel object than saline-treated counterparts, suggesting an increased response to novelty. The messenger RNA (mRNA) and protein levels of the immediate early gene Arc/Arg3.1 were reduced in both infralimbic (IL) and prelimbic (PL) cortices highlighting a baseline reduction of mPFC neuronal activity as a consequence of developmental exposure to cocaine. Intriguingly, significant molecular changes were observed in the IL, but not PL, cortex in response to the combination of cocaine exposure and test such as a marked upregulation of both Arc/Arg3.1 mRNA and protein levels only in cocaine-treated rats. As for proteins, such increase was observed only in the post-synaptic density and not in the whole homogenate, suggesting psychostimulant-induced changes in trafficking of Arc/Arg3.1 or an increased local translation. Notably, the same profile of Arc/Arg3.1 was observed for post-synaptic density (PSD)-95 leading to the possibility that Arc/Arg3.1 and PSD-95 bridge together to promote aberrant synaptic connectivity in IL cortex following repeated exposure to cocaine during brain development.
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.
Lucia
L
Caffino
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.
Giuseppe
G
Giannotti
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.
Francesca
F
Mottarlini
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.
Giorgio
G
Racagni
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy. Fabio.Fumagalli@unimi.it.
Fabio
0000-0002-8814-7706
F
Fumagalli
D000818:Animals; D003042:Cocaine / Q000009:adverse effects*; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D000076122:Disks Large Homolog 4 Protein; D005106:Exploratory Behavior / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis; D065726:Limbic Lobe / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D057907:Post-Synaptic Density / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D021641:Recognition, Psychology / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
D003598:Cytoskeletal Proteins; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C092069:activity regulated cytoskeletal-associated protein; D003042:Cocaine
Activity-regulated cytoskeletal-associated protein; Cocaine; Immediately early genes; Infralimbic cortex