Abstract
Rationale
Adolescence is a period of high vulnerability to drugs of abuse and alterations of the proper developmental trajectory via psychostimulant exposure might change the physiological brain homeostasis.
Objective
By microdissection of brain areas via punching, we investigated whether repeated exposure to cocaine during adolescence (from postnatal day 28 [PND28] to PND42) has altered fibroblast growth factor-2 (FGF-2) messenger RNA (mRNA) levels in selected brain subregions critical for the action of cocaine.
Results
We found a reduction of FGF-2 mRNA levels in ventral tegmental area (VTA), where mesocortical and mesolimbic pathways originate. The analysis of the trophic factor levels in the distal projecting regions revealed a selective reduction of FGF-2 mRNA levels in infralimbic (IL) subregion of the medial prefrontal cortex (the terminal region of the mesocortical pathway) and in the nucleus accumbens core (cNAc) (the terminal region of the mesolimbic pathway). Last, we found reduced FGF-2 mRNA levels also in brain regions which, although in a different manner, contribute to the reward system, i.e., the central nucleus of amygdala (cAmy) and the ventral portion of hippocampus (vHip).
Conclusion
The widespread and coordinated reduction of FGF-2 mRNA levels across the brain’s reward neurocircuitry might represent a defensive strategy set in motion to oppose to the psychostimulant properties of cocaine. Moreover, given the role of FGF-2 in modulating mood disorders, the reduced trophic support here observed might sustain the negative emotional state set in motion by repeated exposure to cocaine.
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References
Baum P, Vogt MA, Gass P, Unsicker K, von Bohlen Und Halbach O (2016) FGF-2 deficiency causes dysregulation of Arhgef6 and downstream targets in the cerebral cortex accompanied by altered neurite outgrowth and dendritic spine morphology. Int J Dev Neurosci 50:55–64
Caffino L, Giannotti G, Malpighi C, Racagni G, Fumagalli F (2015) Short-term withdrawal from developmental exposure to cocaine activates the glucocorticoid receptor and alters spine dynamics. Eur Neuropsychopharmacol 25:1832–1841
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
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
Di Chiara G (2002) Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav Brain Res 137:75–114
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 69:534–540
Evans SJ, Choudary PV, Neal CR, Li JZ, Vawter MP, Tomita H, Lopez JF, Thompson RC, Meng F, Stead JD, Walsh DM, Myers RM, Bunney WE, Watson SJ, Jones EG, Akil H (2004) Dysregulation of the fibroblast growth factor system in major depression. Proc Natl Acad Sci U S A 101:15506–15511
Fadda P, Bedogni F, Fresu A, Collu M, Racagni G, Riva MA (2007) Reduction of corticostriatal glutamatergic fibers in basic fibroblast growth factor deficient mice is associated with hyperactivity and enhanced dopaminergic transmission. Biol Psychiatry 62:235–242
Fanselow MS, Dong HW (2010) Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65:7–19
Flores C, Stewart J (2000a) Basic fibroblast growth factor as a mediator of the effects of glutamate in the development of long-lasting sensitization to stimulant drugs: studies in the rat. Psychopharmacology (Berlin) 151:152–165
Flores C, Stewart J (2000b) Changes in astrocytic basic fibroblast growth factor expression during and after prolonged exposure to escalating doses of amphetamine. Neuroscience 98:287–293
Flores C, Rodaros D, Stewart J (1998) Long-lasting induction of astrocytic basic fibroblast growth factor by repeated injections of amphetamine: blockade by concurrent treatment with a glutamate antagonist. J Neurosci 18:9547–9555
Flores C, Samaha AN, Stewart J (2000) Requirement of endogenous basic fibroblast growth factor for sensitization to amphetamine. J Neurosci 20:RC55
Ford-Perriss M, Abud H, Murphy M (2001) Fibroblast growth factors in the develo** central nervous system. Clin Exp Pharmacol Physiol 28:493–503
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
Gaughran F, Payne J, Sedgwick PM, Cotter D, Berry M (2006) Hippocampal FGF-2 and FGFR1 mRNA expression in major depression, schizophrenia and bipolar disorder. Brain Res Bull 70:221–227
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 (Berlin) 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
Giannotti G, Caffino L, Malpighi C, Melfi S, Racagni G, Fumagalli F (2015) 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 (Berlin) 232:713–719
Gogtay N, Ordonez A, Herman DH, Hayashi KM, Greenstein D, Vaituzis C, Lenane M, Clasen L, Sharp W, Giedd JN, Jung D, Nugent TF 3rd, Toga AW, Leibenluft E, Thompson PM, Rapoport JL (2007) Dynamic map** of cortical development before and after the onset of pediatric bipolar illness. J Child Psychol Psychiatry 48:852–862
Hafenbreidel M, Twining RC, Rafa Todd C, Mueller D (2015) Blocking infralimbic basic fibroblast growth factor (bFGF or FGF2) facilitates extinction of drug seeking after cocaine self-administration. Neuropsychopharmacology 40:2907–2915
He S, Zhang T, Hong B, Peng D, Su H, Lin Z, Fang Y, Jiang K, Liu X, Li H (2014) Decreased serum fibroblast growth factor-2 levels in pre- and post-treatment patients with major depressive disorder. Neurosci Lett 579:168–172
Ishikawa A, Nakamura S (2006) Ventral hippocampal neurons project axons simultaneously to the medial prefrontal cortex and amygdala in the rat. J Neurophysiol 96:2134–2138
Koob GF (2015) The dark side of emotion: the addiction perspective. Eur J Pharmacol 753:73–87
Luo YX, Xue YX, Shen HW, Lu L (2013) Role of amygdala in drug memory. Neurobiol Learn Mem 105:159–173
Makris N, Oscar-Berman M, Jaffin SK, Hodge SM, Kennedy DN, Caviness VS, Marinkovic K, Breiter HC, Gasic GP, Harris GJ (2008) Decreased volume of the brain reward system in alcoholism. Biol Psychiatry 64:192–202
McFarland K, Lapish CC, Kalivas PW (2003) Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 23:3531–3537
McGinty JF, Whitfield TW Jr, Berglind WJ (2010) Brain-derived neurotrophic factor and cocaine addiction. Brain Res 1314:183–193
Moorman DE, James MH, McGlinchey EM, Aston-Jones G (2015) Differential roles of medial prefrontal subregions in the regulation of drug seeking. Brain Res 1628:130–146
Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Academic Press/Elsevier, Amsterdam
Pierce RC, Bari AA (2001) The role of neurotrophic factors in psychostimulant-induced behavioral and neuronal plasticity. Rev Neurosci 12:95–110
Pierce RC, Kumaresan V (2006) The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse? Neurosci Biobehav Rev 30:215–238
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
Robbins TW, Ersche KD, Everitt BJ (2008) Drug addiction and the memory systems of the brain. Ann N Y Acad Sci 1141:1–21
Roceri M, Molteni R, Fumagalli F, Racagni G, Gennarelli M, Corsini G, Maggio R, Riva M (2001) Stimulatory role of dopamine on fibroblast growth factor-2 expression in rat striatum. J Neurochem 76:990–997
Rogers JL, See RE (2007) Selective inactivation of the ventral hippocampus attenuates cue-induced and cocaine-primed reinstatement of drug-seeking in rats. Neurobiol Learn Mem 87:688–692
Saunders BT, Richard JM (2011) Shedding light on the role of ventral tegmental area dopamine in reward. J Neurosci 31:18195–18197
See RE, Fuchs RA, Ledford CC, McLaughlin J (2003) Drug addiction, relapse, and the amygdala. Ann N Y Acad Sci 985:294–307
Thierry AM, Blanc G, Sobel A, Stinus L, Glowinski J (1973) Dopaminergic terminals in the rat cortex. Science 182:499–501
Thomas MJ, Kalivas PW, Shaham Y (2008) Neuroplasticity in the mesolimbic dopamine system and cocaine addiction. Br J Pharmacol 154:327–342
Verheij MM, de Mulder EL, De Leonibus E, van Loo KM, Cools AR (2008) Rats that differentially respond to cocaine differ in their dopaminergic storage capacity of the nucleus accumbens. J Neurochem 105:2122–2133
Acknowledgments
We would like to thank the Zardi Gori Foundation for funding this project through a grant to FF.
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Giannotti, G., Caffino, L., Mottarlini, F. et al. Region-specific effects of developmental exposure to cocaine on fibroblast growth factor-2 expression in the rat brain. Psychopharmacology 233, 2699–2704 (2016). https://doi.org/10.1007/s00213-016-4315-9
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DOI: https://doi.org/10.1007/s00213-016-4315-9