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Caffeine Consumption plus Physical Exercise Improves Behavioral Impairments and Stimulates Neuroplasticity in Spontaneously Hypertensive Rats (SHR): an Animal Model of Attention Deficit Hyperactivity Disorder

Abstract

Attention deficit hyperactivity disorder (ADHD) is a prevalent and disabling disorder, mainly characterized by hyperactivity, inattention, and impulsivity, but also by olfactory and memory impairments that frequently persist throughout lifetime. The pathophysiology of ADHD is complex, involving several brain regions and neural pathways including alterations in adenosine neuromodulation. The administration of caffeine (a non-selective adenosine receptor antagonist) and physical exercise have been independently pointed as effective approaches for the management of ADHD symptoms. Here, we evaluated the effects of caffeine consumption (0.3 mg/mL in drinking water) plus physical exercise in running wheels during 6 weeks—starting during either adolescence (30 days old) or adulthood (4–5 months old)—on behavioral performance (including olfactory discrimination, open field, object recognition, and water maze tests) on the brain levels of monoamines (by high-performance liquid chromatography), on proteins related to synaptic plasticity and on brain-derived neurotrophic factor signaling (by Western blot analysis) in spontaneously hypertensive rats (SHRs), a validated animal model of ADHD. SHRs displayed persistent impairments of olfactory and short-term recognition memory from adolescence to adulthood, which were accompanied by lower levels of synaptosomal-associated protein 25 (SNAP-25) in the prefrontal cortex and hippocampus. The association of caffeine plus physical exercise during adolescence or adulthood restored the olfactory discrimination ability and, in an independent manner, improved short-term recognition memory of SHRs. These benefits were not associated to alterations in locomotor activity or in the hypertensive phenotype. The association of caffeine consumption plus physical exercise during adolescence increased the levels of SNAP-25, syntaxin, and serotonin in the hippocampus and prefrontal cortex, and striatal dopamine levels in SHRs. These results provide new evidence of the potential of caffeine and physical exercise, starting at adolescence or adult life, to improve behavioral impairments and stimulate neuroplasticity in ADHD.

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Funding

This work was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-FCT), Programa de Apoio aos Núcleos de Excelência (PRONEX - Project NENASC), Fundação de Apoio à Pesquisa do Estado de Santa Catarina (FAPESC), Ciência sem Fronteiras, La Caixa Foundation (LCF/PR/HP17/52190001), Centro 2020 (CENTRO-01-0145-FEDER-000008:BrainHealth 2020 and CENTRO-01-0246-FEDER-000010), and FCT (POCI-01-0145-FEDER-03127). A.P.F., M.G.S., B.S.S., D.L.S., A.K.B., and T.C. received scholarships from CAPES or CNPq. A.L. and R.D.P. are supported by research fellowship from CNPq.

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Correspondence to Rui Daniel Prediger.

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RAC is a scientific consultant for the Institute for Scientific Information on Coffee. All other authors declare no biomedical financial interests or potential conflicts of interest.

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ESM 1
figure 8

Effects of caffeine consumption plus physical exercise on the intake of liquids and food, on body mass, on the distance traveled in the running wheels and on systolic blood pressure of SHR. (A, B) Consumption of liquids and food (C, D) by experimental unit (equivalent to the consumption of two animals) during six weeks of treatment, for adolescent- and adult-treated animals, respectively. Body mass of animals treated during adolescence (E) and adulthood (F). Data are means ± S.E.M (n = 8–10 animals/group). *p < 0.05 compared to the first day of treatment. #p < 0.05 compared to control group (vehicle/sedentary using a Two-way ANOVA followed by Newman-Keuls post-hoc tests). Total distance traveled in the running wheels during six weeks of treatment, for adolescent- (G) and adult-treated (H) animals. Data are means ± S.E.M (n = 8–10 animals/group). *p < 0.05 compared to the first day of treatment using a One-way ANOVA followed by Newman-Keuls post-hoc tests. Systolic blood pressure of animals along six weeks of treatment for adolescent SHRs (I), and after treatment for adult SHRs (J). Data are means ± S.E.M (n = 8–10 animals/group). *p < 0.05 compared to the first day of treatment using a Two-way ANOVA followed by Newman-Keuls post-hoc tests. (PNG 740 kb)

ESM 2
figure 9

Effects of caffeine consumption plus physical exercise on the levels of BDNF-related proteins in different brain areas of adolescent-treated SHRs. Immunocontent of mature-BDNF (A, B, C), truncated-BDNF (D, E, F), phospho-TrkB (G, H, I) and CREB (J, K, L) in the prefrontal cortex, hippocampus and striatum of adolescent-treated SHRs. Data are means ± SEM (n = 4–6 animals/group). Two-way ANOVA revealed no statistical differences. (PNG 562 kb)

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França, A.P., Schamne, M.G., de Souza, B.S. et al. Caffeine Consumption plus Physical Exercise Improves Behavioral Impairments and Stimulates Neuroplasticity in Spontaneously Hypertensive Rats (SHR): an Animal Model of Attention Deficit Hyperactivity Disorder. Mol Neurobiol 57, 3902–3919 (2020). https://doi.org/10.1007/s12035-020-02002-4

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  • DOI: https://doi.org/10.1007/s12035-020-02002-4

Keywords

  • ADHD
  • SHR
  • Caffeine
  • Physical exercise
  • Adolescent
  • Adult