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

Author(s):Show less -

Kubrusly, Regina Celia Cussa ^[1] ; da Rosa Valli, Thais ^[1] ; Ferreira, Mariana Nunes Marinho Ritter ^[1] ; de Moura, Pamella ^[1] ; Borges-Martins, Vladimir Pedro Peralva ^[1] ; Martins, Robertta Silva ^{[1, 2]} ; Ferreira, Danielle Dias Pinto ^[1] ; Sathler, Matheus Figueiredo ^[3] ; de Melo Reis, Ricardo Augusto ^[4] ; Ferreira, Gustavo Costa ^[5] ; Manhaes, Alex Christian ^[6] ; dos Santos Pereira, Mauricio ^{[1, 7]}

Affiliation

^[1] Inst Biomed, Lab Neurofarmacol, Niteroi, RJ - Brazil

^[2] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Neurobiol Celular & Mol, Rio De Janeiro - Brazil

^[3] Colorado State Univ, Dept Biomed Sci, Ft Collins, CO 80523 - USA

^[4] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Neuroquim, Rio De Janeiro - Brazil

^[5] Univ Fed Rio de Janeiro, Inst Bioquim Med Leopoldo Meis, Lab Neuroenerget & Erros Inatos Metabol, Rio De Janeiro - Brazil

^[6] Univ Estado Rio de Janeiro, Inst Biol, Lab Neurofisiol, Rio De Janeiro - Brazil

^[7] Univ Sao Paulo, Fac Odontol Ribeirao Preto, Dept Biol Basica & Oral, Lab Neurofisiol Mol, Ribeirao Preto - Brazil

• Document type: Journal article
• Source: NEUROTOXICITY RESEARCH; OCT 2021.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 17/14207-7 - The action of cannabinoid drugs in L-dopa-induced dyskinesia: analysis of neuroinflammation and glutamate release in glial cells
• Grantee: Maurício dos Santos Pereira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral