title: Prolonged abstinence from developmental cocaine exposure dysregulates BDNF and its signaling network in the medial prefrontal cortex of adult rats.
abstract: Although evidence exists that chronic cocaine exposure during adulthood is associated with changes in BDNF expression, whether and how cocaine exposure during adolescence modulates BDNF is still unknown. To address this issue, we exposed rats to repeated cocaine injections from post-natal day (PD) 28 to PD 42, a period that roughly approximates adolescence in humans, and we carried out a detailed analysis of the BDNF system in the medial prefrontal cortex (mPFC) of rats sacrificed 3 d (PD 45) and 48 d (PD 90) after the last cocaine treatment. We found that developmental exposure to cocaine altered transcriptional and translational mechanisms governing neurotrophin expression. Total BDNF mRNA levels, in fact, were enhanced in the mPFC of PD 90 rats exposed to cocaine in adolescence, an effect sustained by changes in BDNF exon IV through the transcription factors CaRF and NF-kB. While a profound reduction of specific BDNF-related miRNAs (let7d, miR124 and miR132) may contribute to explaining the increased proBDNF levels, the up-regulation of the extracellular proteases tPA is indicative of increased processing leading to higher levels of released mBDNF. These changes were associated with increased activation of the trkB-Akt pathway resulting in enhanced pmTOR and pS6 kinase, which ultimately produced an up-regulation of Arc and a consequent reduction of GluA1 expression in the mPFC of PD 90 cocaine-treated rats. These findings demonstrate that developmental exposure to cocaine dynamically dysregulates BDNF and its signaling network in the mPFC of adult rats, providing novel mechanisms that may contribute to cocaine-induced changes in synaptic plasticity.
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannotti
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Caffino
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Calabrese
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Racagni
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Riva
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Fumagalli
mesh_terms: D000367:Age Factors; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018765:Dopamine Uptake Inhibitors; D035683:MicroRNAs; D012333:RNA, Messenger; D003042:Cocaine