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Caffeine Improves GABA Transport in the Striatum of Spontaneously Hypertensive Rats (SHR)

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Abstract

The spontaneously hypertensive rat (SHR) is an excellent animal model that mimics the behavioral and neurochemical phenotype of attention-deficit/hyperactivity disorder (ADHD). Here, we characterized the striatal GABA transport of SHR and investigated whether caffeine, a non-selective antagonist of adenosine receptors, could influence GABAergic circuitry. For this purpose, ex vivo striatal slices of SHR and Wistar (control strain) on the 35th postnatal day were dissected and incubated with [3H]-GABA to quantify the basal levels of uptake and release. SHR exhibited a reduced [3H]-GABA uptake and release, suggesting a defective striatal GABAergic transport system. GAT-1 appears to be the primary transporter for [3H]-GABA uptake in SHR striatum, as GAT-1 selective blocker, NO-711, completely abolished it. We also verified that acute exposure of striatal slices to caffeine improved [3H]-GABA uptake and release in SHR, whereas Wistar rats were not affected. GABA-uptake increase and cAMP accumulation promoted by caffeine was reverted by A1R activation with N6-cyclohexyl adenosine (CHA). As expected, the pharmacological blockade of cAMP-PKA signaling by H-89 also prevented caffeine-mediated [3H]-GABA uptake increment. Interestingly, a single caffeine exposure did not affect GAT-1 or A1R protein density in SHR, which was not different from Wistar protein levels, suggesting that the GAT-1-dependent transport in SHR has a defective functional activity rather than lower protein expression. The current data support that caffeine regulates GAT-1 function and improves striatal GABA transport via A1R-cAMP-PKA signaling, specifically in SHR. These results reinforce that caffeine may have therapeutic use in disorders where the GABA transport system is impaired.

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Abbreviations

A1R:

Adenosine A1 receptor

A2AR:

Adenosine A2A receptor

ADHD:

Attention-deficit/hyperactivity disorder

BSA:

Bovine serum albumin

Caf:

Caffeine

cAMP:

Cyclic adenosine 3″,5″-monophosphate

CHA:

(2R,3R,4S,5R)-2-[6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol

CNS:

Central nervous system

DMEM/F12:

Dulbecco’s modified Eagle’s medium/nutrient mixture F-12

ECL kit:

Electrochemiluminescence kit

GABA:

γ-Aminobutyric acid

GAT:

GABA transporter

H-89:

 N-[2-(P-bromocinnamylamino) ethyl]-5-isoquinolinesulfonamide dihydrochloride

HRP:

Horseradish peroxidase

NO-711:

1-[2-[[(Diphenylmethylene)imino]oxy]ethyl]-1,2,5,6-tetrahydro-3 pyridinecarboxylic acid hydrochloride

PAGE:

Polyacrylamide gel electrophoresis

PKA:

Protein kinase A

PVDF:

Polyvinylidene fluoride

Ro 201,724:

4-(3-Butoxy-4-methoxybenzyl)imidazolidin-2-one)

SHR:

Spontaneously Hypertensive Rats

TCA:

Trichloroacetic acid

TBS-T:

Tris-buffered saline with Tween 20

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Acknowledgements

We would like to thank Fabricio and Redinei for animal care.

Funding

This research was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Instituto Nacional de Neurociência Translacional (INNT-INCT), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; 2017/14207–7), and Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior (CAPES).

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Authors and Affiliations

  1. Laboratório de Neurofarmacologia, Instituto Biomédico, Niterói, RJ, Brazil

    Regina Célia Cussa Kubrusly, Thais da Rosa Valli, Mariana Nunes Marinho Ritter Ferreira, Pâmella de Moura, Vladimir Pedro Peralva Borges-Martins, Robertta Silva Martins, Danielle Dias Pinto Ferreira & Maurício dos Santos Pereira

  2. Laboratório de Neurobiologia Celular E Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil

    Robertta Silva Martins

  3. Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, USA

    Matheus Figueiredo Sathler

  4. Laboratório de Neuroquímica, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil

    Ricardo Augusto de Melo Reis

  5. Laboratório de Neuroenergética E Erros Inatos Do Metabolismo, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil

    Gustavo Costa Ferreira

  6. Laboratório de Neurofisiologia, Instituto de Biologia, Universidade Do Estado Do Rio de Janeiro, Rio de Janeiro, Brazil

    Alex Christian Manhães

  7. Laboratório de Neurofisiologia Molecular, Departamento de Biologia Básica E Oral, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil

    Maurício dos Santos Pereira

Authors
  1. Regina Célia Cussa Kubrusly
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  2. Thais da Rosa Valli
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  3. Mariana Nunes Marinho Ritter Ferreira
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  4. Pâmella de Moura
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  5. Vladimir Pedro Peralva Borges-Martins
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  6. Robertta Silva Martins
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  7. Danielle Dias Pinto Ferreira
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  8. Matheus Figueiredo Sathler
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  9. Ricardo Augusto de Melo Reis
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  10. Gustavo Costa Ferreira
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  11. Alex Christian Manhães
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  12. Maurício dos Santos Pereira
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Contributions

RCCK: conceptualization, investigation, funding acquisition, project administration, supervision, validation, review and editing. TRV, RSM, PM, VPPBM: investigation, experimental research and formal analysis. DDPF, MFS: MFS: conceptualization, experimental research, review and editing. RAMR, GCF, ACM: conceptualization, review and editing. MSP: conceptualization, investigation, formal analysis, supervision, validation, original draft preparation, review and editing.

Corresponding author

Correspondence to Maurício dos Santos Pereira.

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Ethics Approval

All experiments were carried out under institutional approval of the Animal Care and Use Committee of Fluminense Federal University (CEUA/865/2016), following Brazilian Law no. 11.794/2008 and the Guide for the Care and Use of Laboratory Animals (National Institutes of Health). All efforts were made to minimize the number and the suffering of animals.

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Kubrusly, R.C.C., da Rosa Valli, T., Ferreira, M.N.M.R. et al. Caffeine Improves GABA Transport in the Striatum of Spontaneously Hypertensive Rats (SHR). Neurotox Res 39, 1946–1958 (2021). https://doi.org/10.1007/s12640-021-00423-0

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