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Caffeine Regulates GABA Transport Homeostasis in the Adolescent Mouse Frontal Cortex via Adenosine A1 Receptor and

Robertta Silva Martins1,2, Vladimir Pedro Peralva Borges-Martins3, Carlos Henrique de Carvalho Teixeira1

  • 1Laboratório de Neurofarmacologia, Instituto Biomédico, Universidade Federal Fluminense, Niterói, Brazil.

Journal of Neurochemistry
|July 13, 2026
PubMed

Insights

Caffeine intake in adolescent mice increases GABA uptake and release in the frontal cortex by affecting adenosine receptors and PKC activity. This study reveals caffeine

Area of Science:

  • Neuroscience
  • Pharmacology
  • Adolescent Brain Development

Background:

  • Adolescence is a critical period of brain development, marked by heightened vulnerability to external factors like psychoactive drug use.
  • Caffeine (CAFF), a widely consumed psychoactive substance, targets adenosine receptors (A1R and A2AR) and can influence neurotransmitter systems, including GABA homeostasis.
  • Understanding caffeine's impact on the adolescent brain is crucial for assessing its cognitive and neurochemical effects.

Purpose of the Study:

  • To investigate the effects of caffeine intake on GABA uptake and release in the frontal cortex of adolescent mice.
  • To elucidate the underlying molecular mechanisms, including the roles of adenosine receptors and protein kinase C (PKC) activity.
  • To assess caffeine's influence on GABAergic homeostasis during adolescence.

Main Methods:

  • Adolescent Swiss mice were administered daily subcutaneous injections of caffeine (10, 20, 40 mg/kg) for five days.
  • Post-treatment, frontal cortex tissue was analyzed for [3H]-GABA uptake and release, cAMP levels, and expression of GAT-1, A1R, A2AR, PKA, and PKC.
  • Calcium (Ca2+) imaging was performed on primary neuronal cultures treated with caffeine (200 μM), with or without specific inhibitors (NO-711, Gö 6983).

Main Results:

  • Caffeine significantly increased [3H]-GABA uptake across all tested doses, an effect inhibited by the GAT-1 inhibitor NO-711.
  • Caffeine administration (20 and 40 mg/kg) also enhanced [3H]-GABA release.
  • Caffeine elevated A1R levels and increased PKC activity (pPKC/PKC ratio), which was reversed by the PKC inhibitor Gö 6983, indicating a role for PKC in mediating caffeine's effects on GABA transport and neuronal calcium transients.

Conclusions:

  • Caffeine consumption alters GABAergic homeostasis in the adolescent frontal cortex.
  • The observed increase in GABA transport is mediated by enhanced PKC activity.
  • These findings highlight caffeine's neurochemical impact during a sensitive developmental period.
Keywords:
GABAGAT‐1PKCadenosine A1 receptoradolescencecaffeine

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