Abstract
Cocaine is a psychostimulant whose abuse causes a social and economic burden for our society. Most of the published literature deals with acute effects of cocaine or short-term abstinence in adult animals but much less information exists on neuroplastic changes following long-term abstinence. We have recently shown that the long-term abstinence following developmental exposure to cocaine results in increased Activity-Regulated Cytoskeletal-associated protein (Arc/Arg3.1) expression in the crude synaptosomal fraction (Giannotti et al. Int J Neuropsychopharmacology 7(4):625–634, 2014). Given that Arc/Arg3.1 localizes not only at active synapse but also in the nucleus (Okuno et al. Cell 149:886–898, 2012; Korb et al. Nat Neurosci 16:874–883 2013; Bloomer et al. Brain Res 1153:20–33 2007), we investigated Arc/Arg3.1 protein levels in the whole homogenate and the nuclear fraction of animals exposed to cocaine during adolescence. We observed the increased expression of Arc/Arg3.1 in both the fractions, suggesting that up-regulation of Arc/Arg3.1 protein may be partly due to the increased nuclear expression of Arc/Arg3.1 in the medial prefrontal cortex (mPFC) of rats sacrificed at postnatal day 90, following 48 days of abstinence. This effect seems to cause reduced Gria1 transcription. We also found reduced expression of fragile X mental retardation gene (FMR1) which normally inhibits Arc/Arg3.1 translation together with reduced expression of Ubiquitin-protein ligase E3A (Ube3a) that normally causes Arc/Arg3.1 protein degradation via ubiquitination. Further, we found increased expression of metabotropic glutamate receptor 5 (GRM5) which is also involved in the regulation of Arc/Arg3.1 expression. Taken together, our findings show that abstinence from developmental exposure to cocaine is associated with alterations in the finely tuned mechanisms that regulate Arc/Arg3.1 expression.
References
Bloomer WA, VanDongen HM, VanDongen AM (2007) Activity-regulated cytoskeleton-associated protein Arc/Arg3.1 binds to spectrin and associates with nuclear promyelocytic leukemia (PML) bodies. Brain Res 1153:20–33
Bramham CR, Alme MN, Bittins M, Kuipers SD, Nair RR, Pai B, Panja D, Schubert M, Soule J, Tiron A, Wibrand K (2010) The Arc of synaptic memory. Exp Brain Res 200(2):125–140
Calabrese F, Richetto J, Racagni G, Feldon J, Meyer U, Riva MA (2013) Effects of withdrawal from repeated amphetamine exposure in peri-puberty on neuroplasticity-related genes in mice. Neuroscience 250:222–231
Chapman RH, Stern JM (1978) Maternal stress and pituitary-adrenal manipulations during pregnancy in rats: effects on morphology and sexual behavior of male offspring. J Comp Physiol Psychol 92(6):1074–1083
Collins SL, Izenwasser S (2004) Chronic nicotine differentially alters cocaine-induced locomotor activity in adolescent vs. adult male and female rats. Neuropharmacology 46(3):349–362
Dynes JL, Steward O (2007) Dynamics of bidirectional transport of Arc mRNA in neuronal dendrites. J Comp Neurol 500(3):433–447
Fosnaugh JS, Bhat RV, Yamagata K, Worley PF, Baraban JM (1995) Activation of arc, a putative “effector” immediate early gene, by cocaine in rat brain. J Neurochem 64(5):2377–2380
Freeman WM, Brebner K, Lynch WJ, Patel KM, Robertson DJ, Roberts DC, Vrana KE (2002) Changes in rat frontal cortex gene expression following chronic cocaine. Brain Res Mol Brain Res 104(1):11–20
Fumagalli F, Bedogni F, Frasca A, Di Pasquale L, Racagni G, Riva MA (2006) Corticostriatal up-regulation of activity-regulated cytoskeletal-associated protein expression after repeated exposure to cocaine. Mol Pharmacol 70(5):1726–1734
Fumagalli F, Franchi C, Caffino L, Racagni G, Riva MA, Cervo L (2009) Single session of cocaine intravenous self-administration shapes goal-oriented behaviours and up-regulates Arc mRNA levels in rat medial prefrontal cortex. Int J Neuropsychopharmacol 12(3):423–429
Fumagalli F, Cattaneo A, Caffino L, Ibba M, Racagni G, Carboni E, Gennarelli M, Riva MA (2010) Sub-chronic exposure to atomoxetine up-regulates BDNF expression and signalling in the brain of adolescent spontaneously hypertensive rats: comparison with methylphenidate. Pharmacol Res 62(6):523–529
Fumagalli F, Calabrese F, Luoni A, Bolis F, Racagni G, Riva MA (2012) Modulation of BDNF expression by repeated treatment with the novel antipsychotic lurasidone under basal condition and in response to acute stress. Int J Neuropsychopharmacol 15(2):235–246
Giannotti G, Caffino L, Calabrese F, Racagni G, Fumagalli F (2013) Dynamic modulation of basic Fibroblast Growth Factor (FGF-2) expression in the rat brain following repeated exposure to cocaine during adolescence. Psychopharmacology 225(3):553–560
Giannotti G, Caffino L, Calabrese F, Racagni G, Riva MA and Fumagalli F (2014) Prolonged abstinence from developmental cocaine exposure dysregulates BDNF and its signaling network in the medial prefrontal cortex of adult rats. Int J Neuropsychopharmacol 7(4):625-634
Greer PL, Hanayama R, Bloodgood BL, Mardinly AR, Lipton DM, Flavell SW, Kim TK, Griffith EC, Waldon Z, Maehr R, Ploegh HL, Chowdhury S, Worley PF, Steen J, Greenberg ME (2010) The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 140(5):704–716
Grimm JW, Lu L, Hayashi T, Hope BT, Su TP, Shaham Y (2003) Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving. J Neurosci 23(3):742–747
Hearing MC, Miller SW, See RE, McGinty JF (2008) Relapse to cocaine seeking increases activity-regulated gene expression differentially in the prefrontal cortex of abstinent rats. Psychopharmacology 198(1):77–91
Hearing MC, Schwendt M, McGinty JF (2011) Suppression of activity-regulated cytoskeleton-associated gene expression in the dorsal striatum attenuates extinction of cocaine-seeking. Int J Neuropsychopharmacol 14(6):784–795
Jonkman S, Kenny PJ (2013) Molecular, cellular, and structural mechanisms of cocaine addiction: a key role for microRNAs. Neuropsychopharmacology 38(1):198–211
Korb E, Wilkinson CL, Delgado RN, Lovero KL, Finkbeiner S (2013) Arc in the nucleus regulates PML-dependent GluA1 transcription and homeostatic plasticity. Nat Neurosci 16(7):874–883
Lyford GL, Yamagata K, Kaufmann WE, Barnes CA, Sanders LK, Copeland NG, Gilbert DJ, Jenkins NA, Lanahan AA, Worley PF (1995) Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 14(2):433–445
Okuno H, Akashi K, Ishii Y, Yagishita-Kyo N, Suzuki K, Nonaka M, Kawashima T, Fujii H, Takemoto-Kimura S, Abe M, Natsume R, Chowdhury S, Sakimura K, Worley PF, Bito H (2012) Inverse synaptic tagging of inactive synapses via dynamic interaction of Arc/Arg3.1 with CaMKIIbeta. Cell 149(4):886–898
Park S, Park JM, Kim S, Kim JA, Shepherd JD, Smith-Hicks CL, Chowdhury S, Kaufmann W, Kuhl D, Ryazanov AG, Huganir RL, Linden DJ, Worley PF (2008) Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron 59(1):70–83
Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates, 5th edn. Academic Press, New York
Shepherd JD, Bear MF (2011) New views of Arc, a master regulator of synaptic plasticity. Nat Neurosci 14(3):279–284
Yin Y, Edelman GM, Vanderklish PW (2002) The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes. Proc Natl Acad Sci U S A 99(4):2368–2373
Ying SW, Futter M, Rosenblum K, Webber MJ, Hunt SP, Bliss TV, Bramham CR (2002) Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci 22(5):1532–1540
Ziolkowska B, Kielbinski M, Gieryk A, Soria G, Maldonado R, Przewlocki R (2011) Regulation of the immediate-early genes arc and zif268 in a mouse operant model of cocaine seeking reinstatement. J Neural Transm 118(6):877–887
Acknowledgments
This work was supported by the Dipartimento Politiche Antidroga, Presidenza del Consiglio dei Ministri, Grant CAINO 2, to Fabio Fumagalli.
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The authors declare that they have no conflict of interest.
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Caffino, L., Giannotti, G., Malpighi, C. et al. Long-Term Abstinence from Developmental Cocaine Exposure Alters Arc/Arg3.1 Modulation in the Rat Medial Prefrontal Cortex. Neurotox Res 26, 299–306 (2014). https://doi.org/10.1007/s12640-014-9472-1
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DOI: https://doi.org/10.1007/s12640-014-9472-1