Differential Behavioral and Biochemical Responses to Caffeine in Male and Female Rats from a Validated Model of Attention Deficit and Hyperactivity Disorder
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Epidemiological studies suggest sex differences in attention deficit and hyperactivity disorder (ADHD) symptomatology. The potential benefits of caffeine have been reported in the management of ADHD, but its effects were not properly addressed with respect to sex differences. The present study examined the effects of caffeine (0.3 g/L) administered since childhood in the behavior and brain-derived neurotrophic factor (BDNF) and its related proteins in both sexes of a rat model of ADHD (spontaneously hypertensive rats—SHR). Hyperlocomotion, recognition, and spatial memory disturbances were observed in adolescent SHR rats from both sexes. However, females showed lack of habituation and worsened spatial memory. Although caffeine was effective against recognition memory impairment in both sexes, spatial memory was recovered only in female SHR rats. Besides, female SHR rats showed exacerbated hyperlocomotion after caffeine treatment. SHR rats from both sexes presented increases in the BDNF, truncated and phospho-TrkB receptors and also phospho-CREB levels in the hippocampus. Caffeine normalized BDNF in males and truncated TrkB receptor at both sexes. These findings provide insight into the potential of caffeine against fully cognitive impairment displayed by females in the ADHD model. Besides, our data revealed that caffeine intake since childhood attenuated behavioral alterations in the ADHD model associated with changes in BDNF and TrkB receptors in the hippocampus.
KeywordsADHD Caffeine BDNF Sex differences Adolescence
The authors acknowledge Brazilian funding agencies (CAPES, CNPq, FAPERGS).
F.N., D.P., A.S.A, and D.M.M. performed the experiments and revised the manuscript. F.N and L.O.P designed the study, analyzed and interpreted data, and wrote the manuscript.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- 2.American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, DCGoogle Scholar
- 11.Kent L, Green E, Hawi Z, Kirley A, Dudbridge F, Lowe N, Raybould R, Langley K et al (2005) Association of the paternally transmitted copy of common valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD. Mol Psychiatry 10:939–943CrossRefPubMedGoogle Scholar
- 12.Kim BN, Cummins TDR, Kim JW, Bellgrove MA, Hong SB, Song SH, Shin MS, Cho SC et al (2011) Val/Val genotype of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with a better response to OROS-MPH in Korean ADHD children. Int J Neuropsychopharmacol 14:1399–1410CrossRefPubMedGoogle Scholar
- 13.Lanktree M, Squassina A, Krinsky M, Strauss J, Jain U, Macciardi F, Kennedy JL, Muglia P (2008) Association study of brain-derived neurotrophic factor (BDNF) and LIN-7 homolog (LIN-7) genes with adult attention-deficit/hyperactivity disorder. Am J Med Genet Part B, Neuropsychiatr Genet Off Publ Int Soc Psychiatr Genet 147B:945–951CrossRefGoogle Scholar
- 14.Tsai SJ (2016) Role of neurotrophic factors in attention deficit hyperactivity disorder. Cytokine Growth Factor Rev S1359-6101(16):30138–30131Google Scholar
- 16.Amiri A, Torabi Parizi G, Kousha M, Saadat F, Modabbernia MJ, Najafi K, Atrkar Roushan Z (2013) Changes in plasma brain-derived neurotrophic factor (BDNF) levels induced by methylphenidate in children with attention deficit–hyperactivity disorder (ADHD). Prog Neuro-Psychopharmacol Biol Psych 47:20–24CrossRefGoogle Scholar
- 18.Ramos-Quiroga JA, Corominas-Roso M, Palomar G, Gomez-Barros N, Ribases M, Sanchez-Mora C, Bosch R, Nogueira M et al (2014) Changes in the serum levels of brain-derived neurotrophic factor in adults with attention deficit hyperactivity disorder after treatment with atomoxetine. Psychopharmacology 231:1389–1395CrossRefPubMedGoogle Scholar
- 27.Russell VA (2011) Overview of animal models of attention deficit hyperactivity disorder (ADHD). Curr Protoc Neurosci 9:9.35Google Scholar
- 29.Pandolfo P, Machado NJ, Köfalvi A, Takahashi RN, Cunha RA (2013) Caffeine regulates frontocorticostriatal dopamine transporter density and improves attention and cognitive deficits in an animal model of attention deficit hyperactivity disorder. Eur Neuropsychopharmacol 23:317–328CrossRefPubMedGoogle Scholar
- 30.Pires VA, Pamplona FAF, Pandolfo P, Fernandes D, Prediger RD, Takahashi RN (2009) Adenosine receptor antagonists improve short-term object-recognition ability of spontaneously hypertensive rats: a rodent model of attention-deficit hyperactivity disorder. Behav Pharmacol 20:134–145CrossRefPubMedGoogle Scholar
- 31.Pires VA, Pamplona FA, Pandolfo P, Prediger RDS, Takahashi RN (2010) Chronic caffeine treatment during prepubertal period confers long-term cognitive benefits in adult spontaneously hypertensive rats (SHR), an animal model of attention deficit hyperactivity disorder (ADHD). Behav Brain Res 215:39–44CrossRefPubMedGoogle Scholar
- 34.Botanas CJ, Lee H, de la Peña JB, dela Peña IJ, Woo T, Kim HJ, Han DH, Kim BN et al (2016) Rearing in an enriched environment attenuated hyperactivity and inattention in the spontaneously hypertensive rats, an animal model of attention-deficit hyperactivity disorder. Physiol Behav 155:30–37CrossRefPubMedGoogle Scholar
- 42.Kim J, Park H, Yu SL, Jee S, Cheon KA, Song DH, Kim SJ, Im WY et al (2016) Effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) on spontaneously hypertensive rats, an animal model of attention-deficit/hyperactivity disorder. Int J Dev Neurosci 53:83–89CrossRefPubMedGoogle Scholar
- 49.Bergman O, Westberg L, Lichtenstein P, Eriksson E, Larsson H (2011) Study on the possible association of brain-derived neurotrophic factor polymorphism with the developmental course of symptoms of attention deficit and hyperactivity. Int J Neuropsychopharmacol 14:1367–1376CrossRefPubMedGoogle Scholar
- 57.Gomes JR, Costa JT, Melo CV, Felizzi F, Monteiro P, Pinto MJ, Inacio AR, Wieloch T et al (2012) Excitotoxicity downregulates TrkB.FL signaling and upregulates the neuroprotective truncated TrkB receptors in cultured hippocampal and striatal neurons. J Neurosci 32:4610–4622CrossRefPubMedGoogle Scholar
- 61.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 62:523–529CrossRefPubMedGoogle Scholar
- 71.Ardais AP, Rocha AS, Borges MF, Fioreze GT, Sallaberry C, Mioranzza S, Nunes F, Pagnussat N et al (2016) Caffeine exposure during rat brain development causes memory impairment in a sex selective manner that is offset by caffeine consumption throughout life. Behav Brain Res 303:76–84CrossRefPubMedGoogle Scholar
- 74.Sallaberry C, Ardais AP, Rocha A, Borges MF, Fioreze GT, Mioranzza S, Nunes F, Pagnussat N et al (2018) Sex differences in the effects of pre- and postnatal caffeine exposure on behavior and synaptic proteins in pubescent rats. Prog Neuro-Psychopharmacol Biol Psychiatry 81:416–425CrossRefGoogle Scholar