Abstract
Rationale
During adolescence, the brain is maturing and more sensitive to drugs of abuse that can influence its developmental trajectory. Recently, attention has been focused on basic fibroblast growth factor (FGF-2) given that its administration early in life enhances the acquisition of cocaine self-administration and sensitization at adulthood (Turner et al. (Pharmacol Biochem Behav 92:100–4, 2009), Clinton et al. (Pharmacol Biochem Behav103:6–17, 2012)). Additionally, we found that abstinence from adolescent cocaine exposure long lastingly dysregulates FGF-2 transcription (Giannotti et al. (Psychopharmacology (Berl) 225:553–60, 2013 ).
Objectives
The objectives of the study are to evaluate if (1) a single injection of cocaine (20 mg/kg) at postnatal day 35 alters FGF-2 messenger RNA (mRNA) levels and (2) the first injection influences the trophic response to a second injection (10 mg/kg) provided 24 h or 7 days later.
Results
We found regional differences in the FGF-2 expression pattern as either the first or the second injection of cocaine by themselves upregulated FGF-2 mRNA in the medial prefrontal cortex and nucleus accumbens while downregulating it in the hippocampus. The first injection influences the trophic response of the second. Of note, 24 h after the first injection, accumbal and hippocampal FGF-2 changes produced by cocaine in saline-pretreated rats were prevented in cocaine-pretreated rats. Conversely, in the medial prefrontal cortex and hippocampus 7 days after the first injection, the cocaine-induced FGF-2 changes were modified by the subsequent exposure to the psychostimulant.
Conclusions
These findings show that a single cocaine injection is sufficient to produce enduring changes in the adolescent brain and indicate that early cocaine priming alters the mechanisms regulating the trophic response in a brain region-specific fashion.
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References
Burke AR, Miczek KA (2014) Stress in adolescence and drugs of abuse in rodent models: role of dopamine, CRF, and HPA axis. Psychopharmacol (Berl) 231:1557–1580
Caffino L, Calabrese F, Giannotti G, Barbon A, Verheij MM, Racagni G, Fumagalli F (2013) Stress rapidly dysregulates the glutamatergic synapse in the prefrontal cortex of cocaine-withdrawn adolescent rats. Addict Biol
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 92:1074–1083
Clinton SM, Turner CA, Flagel SB, Simpson DN, Watson SJ, Akil H (2012) Neonatal fibroblast growth factor treatment enhances cocaine sensitization. Pharmacol Biochem Behav 103:6–17
Collins SL, Izenwasser S (2004) Chronic nicotine differentially alters cocaine-induced locomotor activity in adolescent vs. adult male and female rats. Neuropharmacology 46:349–362
Deschaux O, Vendruscolo LF, Schlosburg JE, Diaz-Aguilar L, Yuan CJ, Sobieraj JC, George O, Koob GF, Mandyam CD (2014) Hippocampal neurogenesis protects against cocaine-primed relapse. Addict Biol 19(4):562–574. doi:10.1111/adb.12019
Eren-Kocak E, Turner CA, Watson SJ, Akil H (2011) Short-hairpin RNA silencing of endogenous fibroblast growth factor 2 in rat hippocampus increases anxiety behavior. Biol Psychiatry 69:534–40
Fumagalli F, Bedogni F, Maragnoli ME, Gennarelli M, Perez J, Racagni G, Riva MA (2003) Dopaminergic D2 receptor activation modulates FGF-2 gene expression in rat prefrontal cortex and hippocampus. J Neurosci Res 74:74–80
Fumagalli F, Bedogni F, Slotkin TA, Racagni G, Riva MA (2005) Prenatal stress elicits regionally-selective changes in basal FGF-2 gene expression in adulthood and alters the adult response to acute or chronic stress. Neurobiol Dis 20:731–737
Fumagalli F, Pasquale L, Racagni G, Riva MA (2006) Dynamic regulation of fibroblast growth factor 2 (FGF-2) gene expression in the rat brain following single and repeated cocaine administration. J Neurochem 96:996–1004
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 15:235–246
Fumagalli F, Moro F, Caffino L, Orru A, Cassina C, Giannotti G, Di Clemente A, Racagni G, Riva MA, Cervo L (2013) Region-specific effects on BDNF expression after contingent or non-contingent cocaine i.v. self-administration in rats. Int J Neuropsychopharmacol 16:913–918
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. Psychopharmacol (Berl) 225:553–560
Giannotti G, Caffino L, Calabrese F, Racagni G, Riva MA, 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 17:625–634
Gomez-Pinilla F, Lee JW, Cotman CW (1994) Distribution of basic fibroblast growth factor in the developing rat brain. Neuroscience 61:911–923
Kohtz AS, Paris JJ, Frye CA (2010) Low doses of cocaine decrease, and high doses increase, anxiety-like behavior and brain progestogen levels among intact rats. Horm Behav 57:474–80
Kompagne H, Bardos G, Szenasi G, Gacsalyi I, Harsing LG, Levay G (2008) Chronic mild stress generates clear depressive but ambiguous anxiety-like behaviour in rats. Behav Brain Res 193:311–314
Maldonado AM, Kirstein CL (2005) Handling alters cocaine-induced activity in adolescent but not adult male rats. Physiol Behav 84:321–326
Marin MT, Cruz FC, Planeta CS (2008) Cocaine-induced behavioral sensitization in adolescent rats endures until adulthood: lack of association with GluR1 and NR1 glutamate receptor subunits and tyrosine hydroxylase. Pharmacol Biochem Behav 91:109–114
McGinty JF, Whitfield TW Jr, Berglind WJ (2010) Brain-derived neurotrophic factor and cocaine addiction. Brain Res 1314:183–193
Monfils MH, Driscoll I, Melvin NR, Kolb B (2006) Differential expression of basic fibroblast growth factor-2 in the developing rat brain. Neuroscience 141:213–221
Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates, 5th edn. Academic Press, New York
Reichardt LF (2006) Neurotrophin-regulated signalling pathways. Phil Trans Royal Soc London B 361:1545–1564
Riva MA, Molteni R, Bedogni F, Racagni G, Fumagalli F (2005) Emerging role of the FGF system in psychiatric disorders. Trends Pharmacol Sci 26:228–231
Rocha BA, Fumagalli F, Gainetdinov RR, Jones SR, Ator R, Giros B, Miller GW, Caron MG (1998) Cocaine self-administration in dopamine-transporter knockout mice. Nat Neurosci 1:132–137
Slotkin TA, Seidler FJ, Fumagalli F (2007) Exposure to organophosphates reduces the expression of neurotrophic factors in neonatal rat brain regions: similarities and differences in the effects of chlorpyrifos and diazinon on the fibroblast growth factor superfamily. Environ Health Perspect 115:909–916
Slotkin TA, Seidler FJ, Fumagalli F (2008) Targeting of neurotrophic factors, their receptors, and signaling pathways in the developmental neurotoxicity of organophosphates in vivo and in vitro. Brain Res Bull 76:424–438
Stanis JJ, Andersen SL (2014) Reducing substance use during adolescence: a translational framework for prevention. Psychopharmacol (Berl) 231:1437–1453
Sudai E, Croitoru O, Shaldubina A, Abraham L, Gispan I, Flaumenhaft Y, Roth-Deri I, Kinor N, Aharoni S, Ben-Tzion M, Yadid G (2011) High cocaine dosage decreases neurogenesis in the hippocampus and impairs working memory. Addict Biol 16:251–260
Thomas MJ, Kalivas PW, Shaham Y (2008) Neuroplasticity in the mesolimbic dopamine system and cocaine addiction. Br J Pharmacol 154:327–342
Turner CA, Capriles N, Flagel SB, Perez JA, Clinton SM, Watson SJ, Akil H (2009) Neonatal FGF2 alters cocaine self-administration in the adult rat. Pharmacol Biochem Behav 92:100–104
Turner CA, Clinton SM, Thompson RC, Watson SJ Jr, Akil H (2011) Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals. Proc Natl Acad Sci U S A 108:8021–8025
Acknowledgment
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 report no biomedical financial interests or potential conflicts of interest.
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Giuseppe Giannotti and Lucia Caffino contributed equally to this manuscript and can be both considered first authors
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Giannotti, G., Caffino, L., Malpighi, C. et al. A single exposure to cocaine during development elicits regionally-selective changes in basal basic Fibroblast Growth Factor (FGF-2) gene expression and alters the trophic response to a second injection. Psychopharmacology 232, 713–719 (2015). https://doi.org/10.1007/s00213-014-3708-x
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DOI: https://doi.org/10.1007/s00213-014-3708-x